Dosing
The recommended starting dosage of AFINITOR DISPERZ® (everolimus tablets for oral suspension) is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity.
Dose modifications in TSC-associated partial-onset seizures1
FOR PATIENTS WITH SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH CLASS C):
- The recommended starting dose is 2.5 mg/m2 once daily
- Adjust dose based on everolimus trough concentrations as recommended
FOR PATIENTS REQUIRING COADMINISTRATION OF MODERATE CYP3A4/PGP 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
- Patients should avoid ingesting grapefruit and grapefruit juice
FOR PATIENTS REQUIRING COADMINISTRATION OF CYP3A4/PGP 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
- Patients should avoid concomitant use of St John's Wort (Hypericum perforatum)
AFINITOR DISPERZ (AVAILABLE STRENGTHS)
Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.
Administration
- Administer AFINITOR DISPERZ at the same time every day
- Administer AFINITOR DISPERZ either consistently with food or consistently without food
- If a dose of 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 DISPERZ should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed
- Wear gloves to avoid possible contact with everolimus when preparing suspension 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
AFINITOR DISPERZ can be taken as a suspension in a small drinking glass or with an oral syringe.
Using an oral syringe to prepare oral suspension:
- 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.
- 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 AFINITOR DISPERZ tablets are in suspension.
- Gently invert the syringe 5 times immediately prior to administration.
- 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.
Using a small drinking glass to prepare oral suspension:
- 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.
- 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 resuspend remaining particles. Administer the entire contents of the glass.
Monitor for drug concentration and tolerability1
Therapeutic drug level
- 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/P-glycoprotein (PgP) inducers and/or inhibitors
- A change in hepatic function
Titrate
- Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL
- Consider efficacy, safety, concomitant medication, and the current trough concentration when planning for dose titration. Individualize dose titration based on the following proportion
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 AFINITOR DISPERZ treatment:
- Every 3 to 6 months in patients with changing body surface area
- Every 6 to 12 months in patients with stable body surface area
TOLERABILITY AND ADVERSE REACTIONS1
Temporarily interrupt or permanently discontinue AFINITOR DISPERZ for severe or intolerable adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50%.
If dose reduction is required for patients receiving the lowest available strength, administer every other day.
See Table 2 in full Prescribing Information for a summary of recommendations for dose reduction, interruption, or discontinuation of AFINITOR DISPERZ in the management of adverse reactions.
Continue treatment until disease progression or unacceptable toxicity occurs.1
Dose Modifications
DOSING MODIFICATIONS FOR ADVERSE REACTIONS1
- Temporarily interrupt or permanently discontinue AFINITOR DISPERZ for severe or intolerable adverse reactions
- If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50%
HEPATIC IMPAIRMENT1
- The recommended starting dosage of AFINITOR DISPERZ for patients with severe hepatic impairment (Child-Pugh class C) is 2.5 mg/m2 once daily
- Adjust dose based on everolimus trough concentrations as recommended
PGP AND CYP3A4 INHIBITORS1
- Dose modification: 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 DISPERZ with a PgP and moderate CYP3A4 inhibitor
PGP AND CYP3A4 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
Reference: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.
IMPORTANT SAFETY INFORMATION
AFINITOR DISPERZ® (everolimus tablets for oral suspension) is 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 in clinical trials, some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event.
Indication
AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures.
IMPORTANT SAFETY INFORMATION
AFINITOR DISPERZ® (everolimus tablets for oral suspension) 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 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 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 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, 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. 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 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 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 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 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 DISPERZ for angioedema.
Stomatitis
Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR or 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 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 or 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 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 vascular endothelial growth factor (VEGF) signaling pathway. Therefore, AFINITOR DISPERZ has the potential to adversely affect wound healing. Withhold 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 occurs. The safety of resuming treatment upon resolution of wound healing complications has not been established.
Metabolic Disorders
Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR or 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 DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR DISPERZ and once yearly thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR DISPERZ. For grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR DISPERZ based on severity.
Myelosuppression
Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR or 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 DISPERZ, every 6 months for the first year of treatment, and annually thereafter. Withhold or permanently discontinue AFINITOR DISPERZ based on severity.
Risk of Infection or Reduced Immune Response With Vaccinations
The safety of immunization with live vaccines during 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 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.
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 before, during, or after AFINITOR DISPERZ treatment. Monitor patients closely when administering AFINITOR DISPERZ during, or sequentially with, radiation treatment.
Embryo-Fetal Toxicity
Based on animal studies and the mechanism of action, 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 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 DISPERZ and for 4 weeks after the last dose.
Adverse Reactions
The most common adverse reaction reported for AFINITOR DISPERZ (incidence ≥30%, all grades) was stomatitis (55% low trough, 64% high trough). The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis, pneumonia, and irregular menstruation. Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).
Laboratory Abnormalities
The most common laboratory abnormality (incidence ≥50%, all grades) was hypercholesterolemia (86% low trough, 85% high trough). The most common grade 3/4 laboratory abnormality (incidence ≥2%) was neutropenia.
