Important Safety Information

AFINITOR is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives. There have been reports of noninfectious pneumonitis (including...

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Indication

AFINITOR® (everolimus) Tablets is indicated for the treatment of adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced, or metastatic disease.

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

Dosing & Administration

Dosing

One pill, once a day

The recommended dose for AFINITOR® (everolimus) Tablets is one 10-mg tablet once daily

AFINITOR® (everolimus) Tablets dose

Once-daily dose is taken at the same time every day.
Should be taken consistently with, or consistently without, food.
Tablets should be swallowed whole with a glass of water. Do not crush.

  • 10-mg starting dose is recommended regardless of age, gender, body weight, or renal function
  • Dose modification is required in patients with hepatic impairment and may be required for drug interactions (CYP3A4/PgP inhibitors or inducers), and adverse reactions
  • Avoid use with strong CYP3A4/PgP inhibitors or inducers, grapefruit, grapefruit juice, or St. John's wort

Dose Management

The once-daily dose of AFINITOR may be adjusted as needed

7.5-mg, 5-mg, and 2.5-mg tablets are available if dose adjustment is required for adverse events, drug interactions, and hepatic impairment:

  • Management of adverse reactions may require temporary dose interruption, reduction, or discontinuation based on severity
  • If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered

AFINITOR® (everolimus) Tablets 7.5 mg
  • In mild hepatic impairment (Child-Pugh class A) the recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated
AFINITOR® (everolimus) Tablets 5 mg
  • In moderate hepatic impairment (Child-Pugh class B), the recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated
  • Avoid the use of concomitant PgP and strong CYP3A4 inducers where alternatives exist. Consider doubling the daily dose of AFINITOR in 5-mg increments or less if coadministration of a PgP and strong CYP3A4 inducer cannot be avoided. Multiple increments may be required
    • Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days

 

AFINITOR® (everolimus) Tablets 2.5 mg
  • In severe hepatic impairment (Child-Pugh class C), if the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded
  • Avoid concomitant use of PgP and strong CYP3A4 inhibitors
    • Use caution when coadministered with PgP and moderate CYP3A4 inhibitors. Decrease to 2.5 mg daily if coadministration of a PgP and moderate CYP3A4 inhibitor is required
    • A dosage increase from 2.5 mg daily to 5 mg daily may be considered based on patient tolerance
    • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days

 

Abbreviations: CYP3A4, cytochrome P450 3A4; PgP, P-glycoprotein.

Dosage Modifications for Adverse Reactions

Management of adverse reactions may require temporary dose interruption, reduction, or discontinuation based on severity.1

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

 

RECOMMENDED DOSAGE MODIFICATIONS FOR AFINITOR FOR NONINFECTIOUS PNEUMONITIS1,2

 

Grade 1
  • No dose adjustment required
  • Initiate appropriate monitoring
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

 

RECOMMENDED DOSAGE MODIFICATIONS FOR AFINITOR FOR STOMATITIS1,2

 

Grade 1
  • No dose adjustment required
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

 

Ulceration typical of grade 1 stomatitis

Ulceration typical of grade 1 stomatitis in patients taking AFINITOR
Reprinted with permission from ELSEVIER, A2613

Ulceration typical of grade 2 stomatitis

 Ulceration typical of grade 2 stomatitis in patients taking AFINITOR
Reprinted with permission from ELSEVIER, A2614

Ulceration typical of grade 3 stomatitis

Ulceration typical of grade 3 stomatitis in patients taking AFINITOR
Reprinted with permission from ELSEVIER, 1053

Ulceration typical of grade 4 stomatitis

Ulceration typical of grade 4 stomatitis in patients taking AFINITOR
Reprinted with permission from ELSEVIER, 1053

Click here to discover how you can help reduce stomatitis in your patients starting AFINITOR.

RECOMMENDED DOSAGE MODIFICATIONS FOR AFINITOR FOR METABOLIC EVENTS (EG, HYPERGLYCEMIA, DYSLIPIDEMIA)1,2

 

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
  • 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

 

RECOMMENDED DOSAGE MODIFICATIONS FOR AFINITOR FOR OTHER NONHEMATOLOGIC TOXICITIES (EXCLUDING METABOLIC EVENTS)1,2

 

Grade 1
  • If toxicity is tolerable, no dose adjustment required
  • Initiate appropriate medical therapy and monitor
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

 

RECOMMENDED DOSAGE MODIFICATIONS FOR AFINITOR FOR THROMBOCYTOPENIA1,2

 

Grade 1
  • No dose adjustment required
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

 

RECOMMENDED DOSAGE MODIFICATIONS FOR AFINITOR FOR NEUTROPENIA1,2

 

Grade 1 OR Grade 2
  • No dose adjustment required
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

 

RECOMMENDED DOSAGE MODIFICATIONS FOR AFINITOR FOR FEBRILE NEUTROPENIA1,2

 

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

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 2. Data on file. Novartis Pharmaceuticals Corp; 2017. 3. de Oliveira MA, Martins e Martins F, Wang Q, et al. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol. 2011;47(10):998-1003. 4. Ferté C, Paci A, Zizi M, et al. Natural history, management and pharmacokinetics of everolimus-induced-oral ulcers: insights into compliance issues. Eur J Cancer. 2011;47(15):2249-2255.

Important Safety Information

AFINITOR® (everolimus) Tablets is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR; some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of grade 3 and 4 noninfectious pneumonitis was up to 4% and up to 0.2%, respectively. Fatal outcomes have been observed. Monitor for clinical symptoms or radiological changes. Consider opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. For grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue AFINITOR based on severity. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents is required. 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, sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of grade 3 and 4 infections was up to 10% and up to 3%, respectively. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR based on severity of infection. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents is required.

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

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor with AFINITOR may be at increased risk for angioedema (eg, 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 for angioedema.

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 occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR. The incidence of grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting AFINITOR and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

Impaired Wound Healing: AFINITOR 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.

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

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

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

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 (63%), infections (58%), diarrhea (41%), peripheral edema (39%), fatigue (37%), and rash (30%). The most common grade 3/4 adverse reactions (incidence ≥5%) were infections (11%), stomatitis (9%), diarrhea (9%), and fatigue (5%). 

Laboratory Abnormalities: The most common laboratory abnormalities (incidence ≥50%, all grades) were anemia (81%), hypercholesterolemia (71%), lymphopenia (66%), increased aspartate transaminase (57%), and hyperglycemia (55%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were lymphopenia (16%), hyperglycemia (6%), hypokalemia (6%), increased alanine transaminase (5%), and anemia (5%).

Please see full Prescribing Information.

 

Indication

AFINITOR is indicated for the treatment of adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced, or metastatic disease.

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