Important Safety Information

AFINITOR is contraindicated in patients with hypersensitivity to everolimus, other rapamycin derivatives, or any excipients. There have been reports of noninfectious pneumonitis (including some with…

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Indication

AFINITOR® (everolimus) Tablets is indicated for the treatment of adults with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced, or metastatic disease.

AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.

Safety Profile

Warnings and Precautions

AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis:

  • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR; some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed
  • Monitor for clinical symptoms or radiological changes
  • Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis
  • Manage noninfectious pneumonitis by dose interruption until symptoms resolve, follow with a dose reduction, and consider the use of corticosteroids
  • Discontinue AFINITOR if toxicity recurs at grade 3 or for grade 4 cases.
  • For patients who require use of corticosteroids, prophylaxis for PJP may be considered
  • The development of pneumonitis has been reported even at a reduced dose

Infections:

  • AFINITOR 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, leading to sepsis, respiratory failure, or hepatic failure) or fatal
  • Physicians and patients should be aware of the increased risk of infection with AFINITOR
  • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR
  • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered
  • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment
  • PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors:

  • Patients taking concomitant ACE inhibitor therapy 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

Stomatitis:

  • Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR 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, 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 been observed in patients treated with AFINITOR

Impaired Wound Healing:

  • Everolimus 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 in the perisurgical period

Laboratory Tests and Monitoring:

  • Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function
  • Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR
  • Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Monitoring of complete blood count is recommended prior to treatment and periodically thereafter

Drug-Drug Interactions:

  • Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)
  • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem)
  • Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less

Hepatic Impairment:

  • Exposure to everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk
  • For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended

Vaccinations:

  • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR

Embryo-Fetal Toxicity:

  • Fetal harm can occur if AFINITOR is administered to a pregnant woman. 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 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 and for 4 weeks after the last dose

Adverse Reactions

 

aIncludes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation.
bIncludes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea.
cIncludes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease.

 

 

Adverse Reaction Management

Severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction of AFINITOR therapy) or discontinuation

  • If a reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered

 

DOSE ADJUSTMENT AND MANAGEMENT RECOMMENDATIONS FOR NONINFECTIOUS PNEUMONITIS

Grade 1 Asymptomatic, clinical or diagnostic observations only; intervention not indicated
  • No dose adjustment required
  • Initiate appropriate monitoring
Grade 2 Symptomatic, medical intervention indicated; limiting instrumental activities of daily living (ADL)
  • Consider interrupting therapy, rule out infection, and consider treatment with corticosteroids until symptoms improve to grade ≤1
  • Reinitiate treatment at a lower dose
  • Discontinue treatment if failure to recover within 4 weeks
Grade 3 Severe symptoms; limiting self-care ADL; O2 indicated
  • Interrupt treatment until symptoms resolve to grade ≤1
  • Rule out infection and consider treatment with corticosteroids
  • Consider reinitiating treatment at a lower dose. If toxicity recurs at grade 3, consider discontinuation
Grade 4 Life-threatening respiratory compromise; urgent intervention indicated (eg, tracheotomy or intubation)
  • Discontinue treatment, rule out infection, and consider treatment with corticosteroids

DOSE ADJUSTMENT AND MANAGEMENT RECOMMENDATIONS FOR STOMATITIS

Grade 1 Asymptomatic or mild symptoms
  • No dose adjustment required
  • Manage with nonalcoholic or salt water (0.9%) mouthwash several times a day
Grade 2 Moderate pain; not interfering with oral intake; modified diet indicated
  • Temporary dose interruption until recovery to grade ≤1
  • Reinitiate treatment at the same dose
  • If stomatitis recurs at grade 2, interrupt dose until recovery to grade ≤1. Reinitiate treatment at a lower dose
  • Manage with topical analgesic mouth treatments (ie, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids (ie, triamcinolone oral paste)a,b
Grade 3 Severe pain; interfering with oral intake
  • Temporary dose interruption until recovery to grade ≤1
  • Reinitiate treatment at a lower dose
  • Manage with topical analgesic mouth treatments (ie, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids (ie, triamcinolone oral paste)a,b
Grade 4 Life-threatening consequences; urgent intervention indicated
  • Discontinue treatment and treat with appropriate medical therapy

aAvoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis, as they may worsen mouth ulcers.
bAntifungal agents should not be used unless fungal infection has been diagnosed.

 

Ulceration typical of grade 1/2 stomatitis

Ulceration

 

 

DOSE ADJUSTMENT AND MANAGEMENT RECOMMENDATIONS FOR OTHER NONHEMATOLOGIC TOXICITIES (EXCLUDING METABOLIC EVENTS)

Grade 1
  • If toxicity is tolerable, no dose adjustment required
  • Initiate appropriate medical therapy and monitor
Grade 2
  • If toxicity is tolerable, no dose adjustment required
  • Initiate appropriate medical therapy and monitor
  • If toxicity becomes intolerable, temporary dose interruption until recovery to grade ≤1. Reinitiate treatment at the same dose
  • If toxicity recurs at grade 2, interrupt treatment until recovery to grade ≤1. Reinitiate treatment at a lower dose
Grade 3
  • Temporary dose interruption until recovery to grade ≤1
  • Initiate appropriate medical therapy and monitor
  • Consider reinitiating treatment at a lower dose. If toxicity recurs at grade 3, consider discontinuation
Grade 4
  • Discontinue treatment and treat with appropriate medical therapy

DOSE ADJUSTMENT AND MANAGEMENT RECOMMENDATIONS FOR METABOLIC EVENTS (EG, HYPERGLYCEMIA, DYSLIPIDEMIA)

Grade 1
  • No dose adjustment required
  • Initiate appropriate medical therapy and monitor
Grade 2
  • No dose adjustment required
  • Manage with appropriate medical therapy and monitor
Grade 3
  • Temporary dose interruption
  • Reinitiate treatment at a lower dose
  • Manage with appropriate medical therapy and monitor
Grade 4
  • Discontinue treatment and treat with appropriate medical therapy

Severity grade descriptions: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.

Reference: Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017.

Important Safety Information

AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR; some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. Monitor for clinical symptoms or radiological changes. Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Manage noninfectious pneumonitis by dose interruption until symptoms resolve, follow with a dose reduction, and consider the use of corticosteroids. Discontinue AFINITOR if toxicity recurs at grade 3 or for grade 4 cases. For patients who require use of corticosteroids, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR 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, leading to sepsis, respiratory failure, or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment.

PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required.

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor therapy 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.  

Stomatitis: Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR 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, 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 been observed in patients treated with AFINITOR.

Impaired Wound Healing: Everolimus 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 in the perisurgical period.

Laboratory Tests and Monitoring: Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function.

Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Monitoring of complete blood count is recommended prior to treatment and periodically thereafter.

Drug-Drug Interactions: Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less.

Hepatic Impairment: Exposure to everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. 

Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. 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 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 and for 4 weeks after the last dose.

Adverse Reactions: The most common adverse reactions (incidence ≥30%) were stomatitis (70%), rash (59%), diarrhea (50%), fatigue (45%), edema (39%), abdominal pain (36%), nausea (32%), fever (31%), headache (30%), and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence ≥5%) were stomatitis (7%) and diarrhea (5.5%). Deaths primarily due to adverse events during the double-blind treatment phase occurred in 7 patients taking AFINITOR. 

Laboratory Abnormalities: The most common laboratory abnormalities (incidence ≥50%, all grades) were: decreased hemoglobin (86%) and bicarbonate (56%); increased fasting glucose (75%), alkaline phosphatase (74%), cholesterol (66%), and aspartate transaminase (56%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were: decreased hemoglobin (15%), lymphocytes (16%), and phosphate (10%), and increased glucose (17%) and alkaline phosphatase (8%).

Please see full Prescribing Information.

Indication

AFINITOR is indicated for the treatment of adults with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced, or metastatic disease.

AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.

Reference: Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017.