Important Safety Information

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

Noninfectious Pneumonitis:...

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Indication

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

Dosing & Administration

Dosing

  • AFINITOR® (everolimus) Tablets and AFINITOR DISPERZ® (everolimus tablets for oral suspension) are available for treatment of subependymal giant cell astrocytoma (SEGA) with tuberous sclerosis complex (TSC) that requires therapeutic intervention but cannot be curatively resected1
  • Each formulation should be used in conjunction with therapeutic drug monitoring1
  • Do not combine AFINITOR Tablets and AFINITOR DISPERZ to achieve the desired total dose1
Available strengths of AFINITOR

Administration

There are 3 steps involved in AFINITOR dosing and administration:

STEP 1: STARTING DOSE1

  • Dosing is individualized based on body surface area (BSA, in m2) and can be calculated using either formula2,3
    BSA formula
  • The recommended starting dose is 4.5 mg/m2 once daily until disease progression or unacceptable toxicity

STEP 2: ADMINISTER AFINITOR1

AFINITOR Tablets

  • Administer AFINITOR Tablets at the same time every day
  • Administer consistently either with or without food
  • AFINITOR Tablets 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 AFINITOR DISPERZ at the same time every day
  • Administer consistently either with or without food
  • Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation
  • Prepare suspension in water only

AFINITOR DISPERZ™ (everolimus tablets for oral suspension) administration by oral syringeUsing an oral syringe:

  1. Place the prescribed dose of AFINITOR DISPERZ into a 10-mL syringe. Do not exceed a total dose of 10 mg per syringe. If higher doses are required, prepare an additional syringe. Do not break or crush tablets.
  2. Draw approximately 5 mL of water and 4 mL of air into the syringe.
  3. Place the filled syringe into a container (tip up) for 3 minutes, until the AFINITOR DISPERZ tablets are in suspension.
  4. Gently invert the syringe 5 times immediately prior to administration.
  5. After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe.

AFINITOR DISPERZ™ (everolimus tablets for oral suspension) administration by small drinking glassUsing a small drinking glass: 

  1. Place the prescribed dose of AFINITOR DISPERZ into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total dose of 10 mg of AFINITOR DISPERZ per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets.
  2. Allow 3 minutes for suspension to occur.
  3. Stir the contents gently with a spoon, immediately prior to drinking.
  4. After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to resuspend remaining particles. Administer the entire contents of the glass.

Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.1

Click below to view the Instructions for Use video for AFINITOR DISPERZ.

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STEP 3: MONITOR FOR DRUG CONCENTRATION AND DOSE MODIFICATIONS1

Therapeutic drug monitoring

  • Monitor everolimus whole blood trough concentrations at the following time points:
  • 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 therapeutic drug monitoring throughout treatment.

  • Once a stable dose is attained, monitor trough concentrations regularly for the duration of AFINITOR treatment:
    • Every 3 to 6 months in patients with changing BSA
    • Every 6 to 12 months in patients with stable BSA

Dose Modifications

Severe Hepatic impairment1

  • The recommended starting dose is 2.5 mg/m2 orally once daily
  • Adjust dose based on everolimus trough concentrations as recommended

Moderate CYP3A4/PgP inhibitors1

  • Reduce the daily dose by 50%
  • Change to every-other-day dosing if the reduced dose is lower than the lowest available strength
  • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days
  • Assess trough concentrations when initiating and discontinuing the inhibitor

CYP3A4/PgP inducers1

  • 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
  • Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days

PgP, p-glycoprotein.

Dosing Calculator

Determine the appropriate starting dose for your patients with TSC-associated SEGA.

Dosing Calculator

Determine the appropriate starting dose for your patients with TSC-associated SEGA.

Agreement

This application is intended for use by licensed health care practitioners in the United States.

Use the below calculator to enter in your patient's information and select Calculate to find the appropriate dose of AFINITOR for your patient.

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RECOMMENDED STARTING DOSE

The recommended starting dosage of AFINITOR or AFINITOR DISPERZ is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity. Dosing is individualized based on body surface area (BSA, in m2).

 

The recommended starting dosage for patients with severe hepatic impairment (Child-Pugh class C) is 2.5 mg/m2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended. In patients taking PgP and CYP3A4 inhibitors, reduce the daily dose by 50%. Change to every-other-day dosing if the reduced dose is lower than the lowest available strength. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. Assess trough concentrations when initiating and discontinuing the inhibitor. Avoid the concomitant use of PgP and strong CYP3A4 inhibitors. Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a PgP and moderate CYP3A4 inhibitor.

 

In patients taking PgP and CYP3A4 inducers, 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. Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days. Avoid concomitant use of St. John’s wort (Hypericum perforatum).

 

Monitor everolimus whole blood trough levels routinely in all patients. When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment.

 

Assess trough concentrations approximately 2 weeks after any of the following: initiation of treatment, a change in dose, a change in coadministration of CYP3A4/PgP inducers and/or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ.

 

Titrate the dose in increments to attain trough concentrations of 5 to 15 ng/mL: Consider efficacy, safety, concomitant medication, and the current trough concentration when planning for dose titration.

 

Adjust the dose using the following equation: new dose* = current dose x (target concentration/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.

 

Once a stable dose is attained, monitor trough concentrations regularly for the duration of treatment: every 3 to 6 months in patients with changing BSA, and every 6 to 12 months in patients with stable BSA.

CALCULATED DOSE

The recommended starting dose of AFINITOR or AFINITOR DISPERZ for this patient is:

Round dose to the nearest strength of either AFINITOR Tablets or AFINITOR DISPERZ. 

This Dosing Calculator is being provided "AS IS" and is intended for use only by qualified health care providers. All calculations should be confirmed before use. Novartis makes no claims as to the accuracy of the information contained herein. The information provided is not a substitute for clinical judgment. Novartis is not liable for any decisions made or actions taken in reliance on this information.

 

References:

  1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
  2. Orimadegun AE, Omisanjo AO. Evaluation of five formulae for estimating body surface area of Nigerian children. Ann Med Health Sci Res. 2010;4(6):889-898.
  3. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317:1098.

IMPORTANT SAFETY INFORMATION

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

Noninfectious Pneumonitis: Noninfectious pneumonitis is a class effect of rapamycin derivatives. Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR/AFINITOR DISPERZ in clinical trials, some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. Consider a diagnosis of noninfectious pneumonitis in patients presenting with nonspecific respiratory signs and symptoms. Consider opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Continue AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes suggestive of noninfectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR/AFINITOR DISPERZ has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including those with opportunistic pathogens. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections, such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, sepsis, sepsis shock, or resulting in multisystem organ failure) or fatal. The incidence of grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients <6 years of age. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

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

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR/AFINITOR DISPERZ for angioedema.

Stomatitis: Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/AFINITOR DISPERZ at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. Stomatitis most often occurs within the first 8 weeks of treatment. When starting AFINITOR/AFINITOR DISPERZ, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

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

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

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

Risk of Infection or Reduced Immune Response With Vaccinations: The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ therapy has not been studied. Due to the potential increased risk of infection and/or reduced immune response to the vaccine, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR/AFINITOR DISPERZ. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of live vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Embryo-Fetal Toxicity: Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose.

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

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

Please see full Prescribing Information.

Indication

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