Everolimus

Everolimus is used to treat breast cancer, renal cell carcinoma, advanced neuroendocrine tumors, renal angiomyolipoma, subependymal giant cell astrocytoma, partial-onset seizures, kidney transplant rejection, and liver transplant rejection.

Everolimus is available under the following different brand names: Afinitor, Zortress, and Afinitor Disperz.

Dosages of Everolimus

Adult and pediatric:

Tablet (Afinitor)

• 2.5 mg
• 5 mg
• 7.5 mg
• 10 mg

Tablet for oral suspension (Afinitor Disperz)

• 2 mg
• 3 mg
• 5 mg

Adult only:

Tablet (Zortress)

• 0.25 mg
• 0.5 mg
• 0.75 mg

Dosage Considerations - Should Be Given as Follows

Afinitor only

• Indicated in postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole
• 10 mg orally once/day with or without food; continue until disease progression or unacceptable toxicity

Renal Cell Carcinoma

Afinitor only

• Indicated for advanced renal cell carcinoma (RCC) after failure with sunitinib or sorafenib
• 10 mg orally once/day with or without food; continue until disease progression or unacceptable toxicity

Advanced Neuroendocrine Tumors

Afinitor only

• Indicated for progressive neuroendocrine tumors (PNET) located in the pancreas that is not surgically resectable or is metastatic; also indicated for well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung
• 10 mg orally once/day with or without food; continue until disease progression or unacceptable toxicity

Renal Angiomyolipoma

Afinitor only

• Indicated for the treatment of noncancerous kidney tumors (renal angiomyolipomas) with tuberous sclerosis complex (TSC) in patients not requiring immediate surgery
• 10 mg orally once/day with or without food; continue until disease progression or unacceptable toxicity

Subependymal Giant Cell Astrocytoma

Afinitor and Afinitor Disperz

• Indicated in patients with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected
• Initial dose: 4.5 mg/m² orally once/day with or without food; continue until disease progression or unacceptable toxicity

Partial Onset Seizures

Afinitor Disperz Only

• Indicated for the adjunctive treatment of patients with TSC-associated partial-onset seizures
• Initial dose: 5 mg/m² orally once/day consistently with or without food; continue until disease progression or unacceptable toxicity

Kidney Transplant Rejection

Zortress only

• Indicated for prophylaxis of organ rejection in patients with low-moderate immunologic risk
• Use in combination with reduced doses of cyclosporine, as well as basiliximab and corticosteroids
• Starting dose: 0.75 mg orally every 12 hours initially; adjust maintenance dose to achieve through whole blood concentrations of 3-8 ng/mL target range
• Initiate oral prednisone once the oral medication is tolerated; further taper steroid doses on an individualized basis depending on the clinical status of the patient and function of graft
• Administer as soon as possible after kidney transplantation

Liver Transplant Rejection

Zortress only

• Indicated for prophylaxis of allograft rejection in adult liver transplant recipients in combination with reduced doses of tacrolimus and with corticosteroids
• Starting dose (30 days posttransplant): 1 mg orally every 12 hours initially; adjust maintenance dose to achieve through whole blood concentrations of 3-5 ng/mL by 3 weeks after the first dose of everolimus and through 12 months
• Do not administer until at least 30 days post-liver transplant (earlier administration associated with hepatic artery thrombosis, graft loss, and death)

Dosing Modifications

Coadministration of P-gp and CYP3A4 inhibitors

• Avoid concomitant use of P-gp and strong CYP3A4 inhibitors
• Avoid grapefruit and grapefruit juice
• Breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma
  • Reduce dose to 2.5 mg once/day; may increase the dose to 5 mg once/day if tolerated
  • Resume dose administered before inhibitor initiation, once inhibitor is discontinued for 3 days
• TSC-associated SEGA and partial-onset seizures
  • Reduce daily dose by 50%; change to every other day dosing if the reduced dose is lower than the lowest available strength
  • Resume dose administered before inhibitor initiation, once the inhibitor is discontinued for 3 days
  • Assess trough concentrations when initiating and discontinuing inhibitor

Coadministration of P-gp and CYP3A4 inducers

• Avoid concomitant use of St John's Wort
• Breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma
  • Avoid coadministration when alternatives are available; if coadministration cannot be avoided, double daily dose in 5 mg or fewer increments; multiple increments may be required
  • Resume dose administered before inducer initiation, once an inducer is discontinued for 5 days
• TSC-associated SEGA and partial-onset seizures
  • The double daily dose in 5 mg or fewer increments; multiple increments may be required
  • The 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 inducer
  • Resume dose administered before starting any inducer, once all inducers are discontinued for 5 days

Noninfectious pneumonitis

• Grade 1: No dose adjustment required; initiate appropriate monitoring
• Grade 2: Withhold treatment until symptoms resolve to Grade less than or equal to 1; resume at 50% of the previous dose; permanently discontinue treatment if toxicity does not resolve or improve to Grade 1 within 4 weeks
• Grade 3: Withhold treatment until symptoms resolve to Grade less than or equal to 1; resume at 50% of the 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

Stomatitis

• Manage with topical analgesic mouth treatments (e.g., benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids (e.g., triamcinolone oral paste)
• Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in the management of stomatitis which may worsen mouth ulcers
• Grade 1: No dosage adjustment required; manage with nonalcoholic or saltwater (0.9%) mouthwash several times a day
• Grade 2: Withhold until improvement to less than or equal to Grade 1; resume at same dose; if recurs at Grade 2, withhold until improvement to less than or equal to Grade 1; resume at 50% of the 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 less than or equal to Grade 1; resume at same dose; resume at 50% of the previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength
• Grade 4: Permanently discontinue

Other nonhematologic toxicities

• Grade 1: No dosage adjustment required
• Grade 2
  • If toxicity is intolerable, withhold until improvement to Grade less than or equal to 1; resume at the same dose
  • If toxicity recurs at Grade 2, withhold until improvement to Grade less than or equal to 1; resume at 50% of the 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 1; resume at same dose; consider resuming at 50% of the 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

Metabolic events (e.g., hyperglycemia, dyslipidemia)

• Grade 1 or 2: No dosage adjustment is required
• Grade 3: Withhold until improvement to less than or equal to Grade 2; resume at same dose; resume at 50% of the previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength
• Grade 4: Discontinue treatment

Thrombocytopenia

• Grade 1 (less than 75,000/mm³): No dosage adjustment is required
• Grade 2 (50,000-75,000/mm³): Interrupt dose until recovery at Grade less than or equal to 1; reinitiate treatment at the same dose
• Grade 3 or 4 (less than 50,000/mm³): Interrupt dose until recovery at Grade less than or equal to 1; resume at 50% of the previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength

Neutropenia

• Grade 1 or 2 (1,000-1,500/mm³): No dosage adjustment required
• Grade 3 (500-1,000/mm³): Interrupt dose until recovery at Grade less than or equal to 2; reinitiate treatment at the same dose
• Grade 4 (less than 500/mm³): Interrupt dose until recovery at Grade less than or equal to 2; resume at 50% of the previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength

Febrile neutropenia

• Grade 3 (ANC less than 1,000/mm³ single temperature >38.3ºC (101ºF) or a sustained temperature of greater than or equal to 38ºC (100.4ºF) for more than 1hr): Interrupt dose until recovery at Grade less than or equal to 2 and no fever; resume at 50% of the previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength
• Grade 4 (Life-threatening consequences): Permanently discontinue

Therapeutic drug monitoring and dose titration

• Titrate dose to attain trough concentrations of 5-15 ng/mL
• Monitor everolimus whole blood through concentrations
• Adjust dose using the following equation: new dose = current dose x (target concentration divided by current concentration); not exceed increments of 5 mg/dose
• Recommended timing of drug monitoring
  • Initiation, modification, and switch between Afinitor and Afinitor Disperz: 1-2 weeks
  • Initiation or discontinuation of P-gp and moderate CYP3A inhibitor, P-gp and strong CYP3A inducer, hepatic function changes: 2 weeks
  • Stable dose with change body surface area (BSA): Every 3-6 months
  • Stable dose with stable BSA: Every 6-12 months

Renal impairment

• No clinical studies were conducted in patients with decreased renal function

Hepatic impairment (Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma)

• Mild (Child-Pugh class A): Decrease dose to 7.5 mg once/day; may further be decreased to 5 mg once/day if not well tolerated
• Moderate (Child-Pugh class B): Decrease dose to 5 mg once/day; may further decrease to 2.5 mg once/day if not well tolerated
• Severe (Child-Pugh class C): Decrease dose to 2.5 mg once/day; administer only if the desired benefit outweighs the risk; not to exceed 2.5 mg once/day
• Adjust dose if status changes during treatment

Hepatic impairment (TSC-associated SEGA and partial-onset seizures)

• Mild-to-moderate (Child-Pugh class A or B): No dosage adjustment is necessary
• Severe (Child-Pugh class C): 2.5 mg/m²: orally once/day

Hepatic impairment (Zortress)

• Mild (Child-Pugh class A): Reduce initial daily dose by approximately 1/3 of the recommended daily dose
• Moderate-to-severe (Child-Pugh class B or C): Reduce initial daily dose by approximately 1/2 of the recommended daily dose
• Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus is not within the target trough concentration range of 3-8 ng/mL

Therapeutic drug monitoring and dosage modifications (Zortress)

• Optimally, dose adjustments should be based on trough concentrations obtained 4 or 5 days after a previous dosing change
• Recommended therapeutic range of 3- 8 ng/mL is based on an LC/MS/MS assay method; currently, in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies
• Trough concentration less than 3 ng/mL: Double total daily dose using the available tablet strengths (i.e., 0.25 mg, 0.5 mg, 0.75 mg)
• Trough concentration greater than 8 ng/mL on 2 consecutive measurements: Decrease dose by 0.25 mg twice daily

Dosing Considerations

Do not combine the 2 dosage forms (Afinitor and Afinitor Disperz) to achieve the desired dose; use 1 dosage form or the other

Zortress only

• Limitations of use: Safety and efficacy have not been established in kidney transplant patients at high immunologic risk and recipients of transplanted organs other than kidney or liver

Common side effects of Everolimus include:

• Inflammation of the mouth and lips
• Constipation
• Infections
• Weakness/lethargy
• Fatigue
• Cough
• Diarrhea
• Rash
• Anemia
• Nausea
• Weight loss
• Swelling of extremities
• Shortness of breath
• Fever
• Vomiting
• Headache
• Nosebleed
• Decreased lymphocytes, Grade 3
• Increased glucose, Grade 3
• Pneumonitis
• Itching
• Dry skin
• Decreased Hgb, Grade 3
• Menstrual irregularities

Less common side effects of everolimus include:

• Changes in taste
• High blood pressure (hypertension), including hypertensive crisis
• Bleeding
• Fast heart rate
• Congestive heart failure

Postmarketing side effects of everolimus reported include:

• Angioedema
• Pancreatitis
• Cholelithiasis
• Arterial thrombotic events
• Reflex sympathetic dystrophy
• Pulmonary embolism
• Male infertility with mTOR inhibitors (including everolimus)
• Gingivitis
• Ovarian cyst
• Renal angiomyolipoma with tuberous sclerosis complex
• Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event
• Hypotension
• Deep vein thrombosis
• Hypothyroidism
• Abdominal hernia
• Ascites
• Gastritis
• Bile duct stenosis
• Cytomegalovirus
• Increase in blood creatinine
• Nocturia
• Osteoarthritis
• Hypokalemia
• Hypomagnesemia
• Phlebitis
• Ecchymosis
• Sepsis and septic shock

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Everolimus has serious interactions with at least 155 different drugs.
• Everolimus has moderate interactions with at least 62 different drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

• This medication contains everolimus. Do not take Afinitor, Zortress, or Afinitor Disperz if you are allergic to everolimus or any ingredients contained in this drug.

Black Box Warnings

Zortress only

Malignancies and serious infections

• Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress Patients should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources
• Increased susceptibility to infection and possible development of malignancies (eg, lymphoma, skin cancer) may result from immunosuppression

Renal function

• Coadministration with standard doses of cyclosporine may increase nephrotoxicity; reduced cyclosporine dose
• Monitor cyclosporine and everolimus whole blood trough concentrations

Kidney graft thrombosis

• Increased risk of kidney arterial and venous thrombosis resulting in graft loss, typically within the first 30 days post-transplantation

Heart transplantation

• Increased mortality, often associated with serious infections, reported within the first 3 months post-transplantation
• Not recommended for use in heart transplantation

Contraindications

• Hypersensitivity to everolimus or rapamycin (sirolimus) derivatives

Effects of Drug Abuse

• No information is available.

Short-Term Effects

• See "What Are Side Effects Associated with Using Everolimus?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Everolimus?"

Cautions

• Non-infectious pneumonitis is a class effect on rapamycin derivatives; non-infectious pneumonitis was reported in up to 19% of patients treated with Afinitor/Afinitor Disperz in clinical trials, some cases were reported with pulmonary hypertension (e.g., pulmonary arterial hypertension) as a secondary
• For Grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue therapy based on severity; corticosteroids may be indicated until clinical symptoms resolve; administer prophylaxis when concomitant use of corticosteroids or other immunosuppressive agents required; the development of pneumonitis has been reported even at a reduced dose
• Continue therapy without dose alteration in patients who develop radiological changes
• Elicits immunosuppressive effects and may increase the risk for infections; some of the infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal; incidence of Grade 3 and 4 infections up to 10% and up to 3%, respectively reported; incidence of serious infections was reported at a higher frequency in patients less than 6 years of age; monitor for signs and symptoms and treat promptly
• Pneumocystis jiroveci pneumonia, some with a fatal outcome, reported; this may be associated with concomitant use of corticosteroids or other immunosuppressive agents
• Hypersensitivity reactions observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment); permanently discontinue therapy if clinically significant hypersensitivity occurs
• Stomatitis (e.g., mouth ulcers and oral mucositis) reported at an incidence ranging from 44-78% across clinical trials; stomatitis most often occurs within the first 8 weeks of treatment
• Complete treatment of preexisting invasive fungal infections before starting treatment; monitor for signs and symptoms of an infection; withhold or permanently discontinue therapy based on the severity of infection
• Do not administer antifungal agents, unless a fungal infection has been diagnosed
• May delay wound healing and increase wound-related complications (e.g., dehiscence, wound infection, incisional hernia, lymphocele, and seroma)
• Cases of renal failure (including acute renal failure), some fatal, have been observed; monitor renal function before starting therapy and annually thereafter; monitor renal function at least every 6 months in patients who have additional risk factors for renal failure
• May cause angioedema and fluid accumulation
• Decreases Hgb, lymphocytes, ANC, platelets; increases cholesterol, TG, glucose, creatinine
• In the BOLERO-2 study, the incidence of deaths due to any cause within 28 days of the last everolimus dose was 6% in patients 65 years and older compared to 2% in patients under 65 years; adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients 65 years and older compared to 17% in patients under 65 years; careful monitoring and appropriate dose adjustments for adverse reactions are recommended
• Can cause fetal harm when administered to pregnant women
• Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia at an incidence up to 75%, 86%, and 73%, respectively; in diabetic patients, monitor fasting serum glucose more frequently as clinically indicated; monitor lipid profile before starting treatment and annually thereafter; when possible, achieve optimal glucose and lipid control before starting treatment; for Grade 3-4 metabolic events, withhold or permanently discontinue treatment based on the severity
• Anemia, lymphopenia, neutropenia, and thrombocytopenia reported; monitor complete blood count before starting therapy every 6 months for the first year of treatment and annually thereafter; withhold or permanently discontinue treatment based on the severity

Zortress only

• See Black Box Warnings
• Polyomavirus infections in transplant patients may have serious, and sometimes fatal, outcomes
• Rapamycin (mTOR) inhibitors are associated with increased hepatic artery thrombosis; reported cases mostly have occurred within the first 30 days post-transplant and most also lead to graft loss or death
• An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, usually within the first 30 days post-transplantation
• Use of Zortress in transplant patients has been associated with increased proteinuria; risk of proteinuria increased with higher everolimus whole blood trough concentrations; monitor
• Increase the risk of new-onset diabetes mellitus after transplant; closely monitor blood glucose concentrations
• Increase risk of acute organ rejection reported with complete elimination of calcineurin inhibition

Drug interaction overview

• Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)
• Caution when coadministered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem, grapefruit juice)
• Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, rifabutin, rifapentine, phenobarbital, St John's wort); may decrease blood concentrations and require an increase in the dose (typically double the dose)
• Not for administration to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption as this may result in diarrhea and malabsorption
• Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations before initiating therapy; avoid the use of live vaccines during treatment and close contact with live vaccine recipients
• Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema
• Due to an interaction with cyclosporine, clinical studies of Zortress with cyclosporine conducted in kidney transplant patients strongly discouraged patients from receiving HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin)

Pregnancy and Lactation

• Based on animal studies and mechanism of action everolimus therapy can cause fetal harm when administered to the pregnant woman; there are limited case reports of use in pregnant women. These reports are not sufficient to inform about risks of birth defects or miscarriage; pregnant women should be advised of the potential risk to the fetus.
• Female patients of reproductive potential are advised to use effective contraception during treatment and for 8 weeks after the last dose. The pregnancy status of females of reproductive potential should be verified before starting treatment with everolimus.
• Based on findings in animal reproduction studies, male patients with female partners of reproductive potential are advised to use effective contraception during treatment and for 4 weeks after the last dose.
• There are no data on the presence of everolimus in human milk, effects on breastfed infants, or milk production. The drug and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, lactating women are advised not to breastfeed during treatment and for 2 weeks after the last dose.