Afinitor Dosing: Calculate, Administer, Monitor

Afinitor is administered as a once-daily oral dose

1Calculate based on body surface area (BSA)1

The recommended starting dose of Afinitor for patients with SEGA associated with TS is based on BSA.

BSA starting daily dose1

BSA starting daily dose
BSA starting daily dose
 

Use the Afinitor Starting Dose Calculator for recommended starting daily dosage.

2Administer starting dose1

Afinitor should be administered orally once daily at the same time every day, either consistently with food or consistently without food.

  • Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed
  • For patients unable to swallow tablets, Afinitor tablet(s) should be dispersed completely in a glass of water (containing approximately 30 mL) by gently stirring, immediately prior to drinking. The glass should be rinsed with the same volume of water and the rinse completely swallowed to ensure the entire dose is administered

Drug-drug interactions

Avoid co-administration with strong CYPA4 inhibitors (eg, ketoconazole, itraconazole)

  • If patients require co-administration of a moderate CYP3A4 and/or PgP inhibitor, reduce the Afinitor dose by approximately 50% to maintain trough concentrations of 5 to 10 ng/mL

Avoid co-administration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine)

  • If patients require co-administration with a strong CYP3A4 inducer, double the Afinitor dose; subsequent dosing should be individualized based on therapeutic drug monitoring

Hepatic impairment

  • Afinitor should not be used in patients with severe hepatic impairment
  • In patients with moderate hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring

Please see additional information for Afinitor dose modification.

3Monitor for drug concentration, efficacy, and tolerability1,2

Therapeutic drug level

  • Trough concentrations should be assessed approximately 2 weeks after: commencing treatment, any change in dose, or initiation or change in co-administration of CYP3A4 or PgP inducers or inhibitors
Initiating and maintaining therapy with Afinitor
initiating-afinitor-image
 

SEGA volume

  • Evaluate ~3 months after commencing therapy and periodically thereafter
    • Adjust dose based on changes in SEGA volume, corresponding to trough concentration and tolerability
  • Responses have been observed at trough concentrations as low as 3 ng/ml; therefore, once acceptable efficacy has been achieved, additional dose increase may not be necessary

Tolerability and adverse reactions

  • Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy
  • If dose reduction is required for patients receiving 2.5 mg daily, alternate day dosing should be considered

Dose Modifications in SEGA

Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of Afinitor therapy. If dose reduction is required for patients receiving 2.5 mg daily, consider alternate day dosing.1

CYP3A4 and/or P-glycoprotein (PgP) Inhibitors

Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole).

Use caution when co-administered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4 and/or PgP inhibitor, reduce the Afinitor dose by approximately 50% to maintain trough concentrations of 5 to 10 ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, consider alternate day dosing. Subsequent dosing should be individualized based on therapeutic drug monitoring. Everolimus trough concentrations should be assessed approximately 2 weeks after the addition of a moderate CYP3A4 and/or PgP inhibitor. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4 and/or PgP inhibitor and the everolimus trough concentration should be re-assessed approximately 2 weeks later.1

Strong CYP3A4 Inducers

Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). For patients requiring a concomitant strong CYP3A4 inducer, double the Afinitor dose. Subsequent dosing should be individualized based on therapeutic drug monitoring. If the strong inducer is discontinued, the Afinitor dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer and the everolimus trough concentrations should be assessed approximately 2 weeks later.

Grapefruit, grapefruit juice and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. St. John's Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided.1

Important Safety Information

Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Renal function, blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Please see additional Important Safety Information on the right.
Please see full Prescribing Information for Afinitor.
 

References

  1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010.
  2. Clinical Study Report CRAD001C2485. Data on file; Novartis Pharmaceuticals Corporation.

A helpful tool to determine the recommended starting dose for Afinitor

The Afinitor Starting Dose Calculator is a tool that physicians and healthcare providers can use to help determine the appropriate starting daily dose of Afinitor
for each patient based on their body surface area. Calculate dose.

AFINITOR is indicated for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection.

The effectiveness of AFINITOR is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated.

Important Safety Information

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

Non-infectious Pneumonitis: Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. If symptoms are severe, AFINITOR therapy should be discontinued. Under both circumstances, corticosteroids may be indicated and AFINITOR may be re-initiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances.

Infections: AFINITOR 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, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Treatment of pre-existing invasive fungal infections should be completed prior to starting treatment. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

Oral Ulceration: Oral ulcerations (i.e., mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with AFINITOR. In the SEGA study, 86% of AFINITOR-treated patients developed stomatitis which was mostly CTCAE grade 1 or 2. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes 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.

Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Renal function, blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Drug-drug Interactions: Avoid co-administration with strong CYP3A4 inhibitors. Use caution and reduce the AFINITOR dose if co-administration with a moderate CYP3A4 and/or PgP inhibitor is required. Avoid co-administration with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if co-administration is required, increase the AFINITOR dose.

Hepatic Impairment: AFINITOR should not be used in patients with severe hepatic impairment. Exposure of everolimus was increased in patients with moderate hepatic impairment. In these patients, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring.

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of AFINITOR therapy.

Use in Pregnancy: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment.

Adverse Reactions: The most common adverse reactions (incidence ≥30%, all grades) were stomatitis (86%), upper respiratory tract infection (82%), sinusitis (39%), otitis media (36%), and pyrexia (32%). The most common grade 3 adverse reactions (incidence ≥3%) were convulsion (7%), sinusitis (4%), pneumonia (4%), viral bronchitis (4%), tooth infection (4%), stomatitis (4%), aspiration (4%), cyclic neutropenia (4%), sleep apnea syndrome (4%), vomiting (4%), dizziness (4%), white blood cell count decreased (4%), and neutrophil count decreased (4%). A grade 4 convulsion (4%) was reported.

Laboratory Abnormalities: The most common laboratory abnormalities (incidence ≥50%, all grades) were elevations in aspartate transaminase (AST) concentrations (89%), total cholesterol (68%), and reductions in white blood cell counts (54%). Grade 3 laboratory abnormalities were elevated AST concentrations (4%) and low absolute neutrophil count (4%).

Please see full Prescribing Information for Afinitor.