everolimus

Everolimus is a medication used in the treatment of certain types of benign tumors and advanced cancers and to prevent rejection after solid organ transplants.

In the treatment of tumors and cancers, everolimus prevents the growth and proliferation of cells as well as the growth of new blood vessels in the tumor microenvironment. Everolimus is an immunosuppressant that helps prevent transplant rejection by inhibiting the activation and proliferation of immune cells.

Everolimus is a derivative of rapamycin, another macrolide drug with antitumor and immunosuppressive properties, and works similarly. Everolimus works by inhibiting the activity of a protein known as the mammalian or mechanistic target of rapamycin (mTOR). The mTOR protein is involved in several cell functions including cell division and survival. Some types of tumors and cancers grow due to unregulated mTOR activity and blocking the mTOR pathway helps control the proliferation of tumor cells, as well as T and B types of immune cells.

Everolimus works in the following ways:

• Binds to FK binding protein-12 (FKBP-12), an intracellular protein, and forms a complex that inhibits mTOR activity and cell proliferation.
• Reduces the activity of S6 ribosomal protein kinase (S6k1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, and reduces protein synthesis.
• Reduces the growth of new blood vessels (angiogenesis) in the tumor environment by inhibiting vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1).
• Reduces the growth of fatty lumps (lipomas), caused by mTOR dysregulation.
• Inhibits the activation and proliferation of immune cells T and B lymphocytes, preventing them from attacking transplanted organs and causing graft rejection.

The Afinitor and Afinitor Disperz brands of everolimus are used in the treatment of certain types of metastatic cancers and tuberous sclerosis complex, a rare genetic disorder that causes benign tumors to grow in various organs including the brain, kidneys, heart, lungs, eyes, and skin. Zortress brand of everolimus is used to prevent transplant organ rejection, and the brands are not interchangeable. The uses of everolimus include:

FDA-approved:

Adult:

Afinitor

• Hormone receptor-positive, HER2-negative breast cancer
• Advanced progressive neuroendocrine tumors of pancreatic origin
• Advanced renal cell carcinoma
• Tuberous sclerosis complex (TSC)-associated renal angiomyolipoma

Zortress

• Prevention of kidney transplant rejection
• Prevention of liver transplant rejection

Adult and Pediatric:

Afinitor and Afinitor Disperz

• Tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA)

Afinitor Disperz

• Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures

Off-label:

Adult:

• Advanced, progressive carcinoid tumors
• Relapsed or refractory Hodgkin lymphoma
• Advanced, refractory thymoma and thymic carcinomas
• Relapsed or refractory Waldenstrom macroglobulinemia

Zortress

• Lung transplantation
• Heart transplantation

• Do not administer everolimus to patients with hypersensitivity to everolimus, sirolimus, other rapamycin derivatives, or any component of the everolimus formulation.
• Specific warnings for Zortress brand of everolimus include:
  • Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress. Patients should be managed in facilities equipped with adequate medical resources.
  • Immunosuppression can increase susceptibility to infection and possible development of malignancies such as lymphoma and skin cancer. Prolonged exposure to ultraviolet light or sunlight should be avoided.
  • Use of cyclosporine in combination with Zortress, can increase the risk for kidney toxicity (nephrotoxicity and proteinuria). Reduce the doses of cyclosporine to prevent kidney toxicity and monitor patient’s kidney function.
  • An increased incidence of blood clot block (thrombosis) in the blood vessels in the kidneys and liver, which may result in graft loss, has been reported.
  • Concomitant use of cyclosporine and Zortress may increase the risk of thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Monitor patient’s hematologic parameters.
  • Zortress is not recommended for patients with heart transplant because of increased risk of serious infection and mortality.
  • Do not administer Zortress earlier than 30 days after liver transplant.
  • Zortress may increase the risk of new-onset diabetes mellitus, and monitor blood glucose levels in patients.
  • Patients receiving immunosuppressants, including everolimus are at an increased risk for opportunistic infections that include polyoma virus infections, with serious and sometimes fatal outcomes. BK virus infection can affect the kidney and lead to graft loss. Reduced immunosuppression may be considered in patients with BK virus-associated nephropathy.
• Everolimus can cause non-infectious pneumonitis and interstitial lung disease. Monitor patients for symptoms and withhold or discontinue everolimus based on the severity, and treat appropriately.
• Everolimus increases the risk for infections. Monitor patients for symptoms and withhold or discontinue everolimus based on the severity, and treat the infection promptly. Treat any existing infections before initiating everolimus. Antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia and for cytomegalovirus (CMV) are recommended in transplant patients.
• Patients taking angiotensin-converting enzyme (ACE) inhibitor class of medications are at an increased risk for developing angioedema. Discontinue everolimus permanently if a patient develops angioedema.
• Permanently discontinue everolimus in case of significant hypersensitivity reactions, which may include anaphylaxis, shortness of breath (dyspnea), and angioedema.
• Everolimus therapy can cause mouth inflammation (stomatitis) and mouth ulcers. Initiate dexamethasone alcohol-free mouthwash when starting everolimus therapy.
• Kidney failure has been reported in some patients. Evaluate kidney function prior to treatment and monitor annually thereafter. Patients with additional risk factors for kidney failure should be monitored at least every 6 months. Use with caution if other drugs that can cause nephrotoxicity are used concurrently.
• Everolimus may delay wound healing and increase wound-related complications. Monitor patients and treat them promptly.
• Everolimus may cause generalized fluid accumulation including peripheral edema, pericardial and pleural effusions, and ascites.
• Monitor geriatric patients for adverse reactions and adjust the dosage.
• Everolimus treatment can lead to hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. Evaluate the patient’s glucose and lipid levels before initiating treatment and monitor periodically thereafter. Withhold or discontinue everolimus permanently if glucose and lipid levels get unacceptably high.
• There have been reports of bone marrow suppression with anemia, lymphopenia, neutropenia, and thrombocytopenia. Monitor blood counts closely and withhold or discontinue everolimus based on severity.
• Do not administer live vaccines to patients receiving everolimus, because of the increased risk for infection and reduced immune response with vaccination. Complete routine childhood vaccinations before initiating therapy.
• Do not administer everolimus to pregnant women, it may cause fetal harm.
  • Advise women patients of pregnancy potential and male patients with women partners to practice effective contraception during treatment and for 4 weeks after the last dose.
  • If pregnancy occurs during treatment apprise the patient of the hazards to the fetus.
• Everolimus can cause male and menstrual irregularities in females.
• Closely monitor everolimus blood concentrations if administered concurrently with strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), the enzyme that metabolizes the drug. They can increase or decrease the drug concentration.
• Advise patients to avoid grapefruit and grapefruit juice during everolimus therapy. Grapefruit inhibits CYP3A4 and P-glycoprotein (P-gp) activity and can increase drug concentrations.
• Do not administer everolimus to patients with rare hereditary problems such as galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, it may result in diarrhea and malabsorption.

Common side effects of everolimus include:

• Oral inflammation (stomatitis)
• Constipation
• Diarrhea
• Nausea
• Vomiting
• Loss of appetite (anorexia)
• Taste disorder (dysgeusia)
• Severe hypersensitivity reactions
• Infections
• Fatigue
• Weakness (asthenia)
• High temperature (pyrexia)
• Headache
• Cough
• Shortness of breath (dyspnea)
• Lung inflammation (pneumonitis)
• Rash
• Dry skin
• Itching (pruritus)
• Bone marrow suppression (myelosuppression)
• Low red blood cell count (anemia)
• Decrease in lymphocyte immune cells
• Decrease in hemoglobin
• Peripheral edema
• Nasal bleeding (epistaxis)
• Increase in blood glucose levels
• Menstrual irregularities
• Impaired wound healing
• Kidney failure
• Hemorrhage
• High blood pressure (hypertension) including hypertensive crisis
• Congestive heart failure
• Rapid heart rate (tachycardia)

Less common side effects of everolimus include:

• Swelling beneath the skin and mucous membranes (angioedema)
• Swelling due to build-up of lymph fluid (lymphedema)
• Fluid collection in the abdomen (ascites)
• Gum inflammation (gingivitis)
• Gallbladder inflammation (cholecystitis)
• Gallstones (cholelithiasis)
• Narrowing (stenosis) of bile duct
• Inflammation of the pancreas (pancreatitis)
• Gastritis
• Abdominal hernia
• Blood clot in veins (deep vein thrombosis/DVT)
• Arterial thrombotic events
• Blood clot in lungs (pulmonary embolism)
• Vein inflammation (phlebitis)
• Bruising (ecchymosis)
• Microscopic blood clots in small blood vessels (thrombotic microangiopathy)
• Low blood pressure (hypotension)
• Cardiac failure with pulmonary hypertension
• Renal angiomyolipoma with tuberous sclerosis complex
• Increase in blood creatinine levels
• Frequent nighttime urination (nocturia)
• Ovarian cyst
• Male infertility
• Underactive thyroid (hypothyroidism)
• Osteoarthritis
• Reflex sympathetic dystrophy (RSD)
• Low blood potassium (hypokalemia)
• Low magnesium in blood (hypomagnesemia)
• Cytomegalovirus
• Sepsis and septic shock
• Radiation sensitization and radiation recall syndrome, an inflammatory reaction to certain anticancer drugs when administered after radiation

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet (Afinitor)

• 2.5 mg
• 5 mg
• 7.5 mg
• 10 mg

Tablet For Oral Suspension (Afinitor Disperz)

• 2 mg
• 3 mg
• 5 mg

Tablet (Zortress)

• 0.25 mg
• 0.5 mg
• 0.75 mg
• 1 mg

Adult:

Breast Cancer

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 daily with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Renal Cell Carcinoma

Afinitor only

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

Advanced Neuroendocrine Tumors

Afinitor only

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

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 daily with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Subependymal Giant Cell Astrocytoma (SEGA)

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 daily with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

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 daily consistently with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

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 trough whole blood concentrations of 3-8 ng/mL target range
• Initiate oral prednisone once oral medication is tolerated; further taper steroid doses on an individualized basis depending on the clinical status of 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 trough whole blood concentrations of 3-5 ng/mL by 3 weeks after 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)

Dosage 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 daily; may increase the dose to 5 mg once daily if tolerated
  • Resume dose administered prior to 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 prior to 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 5 mg or lower increments; multiple increments may be required
  • Resume dose administered prior to inducer initiation, once an inducer is discontinued for 5 days
• TSC-associated SEGA and partial-onset seizures
  • Double daily dose 5 mg or lower increments; 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 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 1 or below; resume at 50% of 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 1 or below; resume at 50% of previous dose; change to every other day dosing if 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 management of stomatitis which may worsen mouth ulcers
• Grade 1: No dosage adjustment required; manage with nonalcoholic or salt water (0.9%) mouthwash several times a day
• Grade 2: Withhold until improvement to Grade 1 or below; resume at same dose; if recurs at Grade 2, withhold until improvement to Grade 1 or below; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
• Grade 3: Withhold until improvement to Grade 1 or below; resume at same dose; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
• Grade 4: Permanently discontinue

Other nonhematologic toxicities

• Grade 1: No dosage adjustment is required
• Grade 2
  • If toxicity is intolerable, withhold until improvement to Grade 1 or below; resume at the same dose
  • If toxicity recurs at Grade 2, withhold until improvement to Grade 1 or below; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
• Grade 3
  • Withhold until improvement to Grade 1 or below; 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 it recurs at Grade 3, permanently discontinue
• Grade 4: Permanently discontinue

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

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

Thrombocytopenia

• Grade 1 (below 75,000/mm³): No dosage adjustment required
• Grade 2 (50,000-75,000/mm³): Interrupt dose until recovery at Grade 1 or below; reinitiate treatment at same dose
• Grade 3 or 4 (below 50,000/mm³): Interrupt dose until recovery at Grade 1 or below; resume at 50% of previous dose; change to every other day dosing if 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 2 or below; reinitiate treatment at same dose
• Grade 4 (below 500/mm³): Interrupt dose until recovery at Grade 2 or below; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength

Febrile neutropenia

• Grade 3 (ANC below 1,000/mm³ single temperature above 38.3ºC (101ºF) or a sustained temperature of 38ºC (100.4ºF) or above for longer than 1 hour): Interrupt dose until recovery at Grade 2 or below 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 (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 trough 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 daily; may further decrease to 5 mg once daily if not well tolerated
• Moderate (Child Pugh class B): Decrease dose to 5 mg once daily; may further decrease to 2.5 mg once daily if not well tolerated
• Severe (Child Pugh class C): Decrease dose to 2.5 mg once daily; administer only if desired benefit outweighs risk; not to exceed 2.5 mg once daily
• 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 necessary
• Severe (Child Pugh class C): 2.5 mg/m²: orally once daily

Hepatic impairment (Zortress)

• Mild (Child Pugh class A): Reduce initial daily dose by 1/3 of the recommended daily dose
• Moderate-to-severe (Child Pugh class B or C): Reduce initial daily dose by 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 below 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 above 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
  • Safety and efficacy not established in patients below 18 years of age

Geriatric:

• In a randomized advanced hormone receptor-positive, HER2-negative breast cancer study, no overall differences in safety or effectiveness were observed between these elderly patients and younger patients during clinical trials

Pediatric:

Subependymal Giant Cell Astrocytoma

Afinitor and Afinitor Disperz

• Indicated in pediatric patients (1 year and above) with tuberous sclerosis complex TSC for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected
• Children below 1 year: Safety and efficacy not established
• Children 1 year and above
  • Initial dose based on body surface area with subsequent titration to attain trough concentrations of 5-15 ng/mL
  • 4.5 mg/m² orally once daily with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Partial-Onset Seizures

Afinitor Disperz only

• Indicated for the adjunctive treatment of pediatric patients (2 years and above) with TSC-associated partial-onset seizures
• Children below 2 years: Safety and efficacy not established
• Children 2 years and above
• Initial dose: 5 mg/m² orally once daily with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Dosage Modifications

Coadministration of P-gp and CYP3A4 inhibitors

• Avoid concomitant use of P-gp and strong CYP3A4 inhibitors
• Avoid grapefruit and grapefruit juice
• TSC-associated SEGA and partial-onset seizures
  • Reduce daily dose by 50%; change to every other day dosing if 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 inhibitor

Coadministration of P-gp and CYP3A4 inducers

• Avoid concomitant use of St John’s Wort
• TSC-associated SEGA and partial-onset seizures
  • Double daily dose 5 mg or lower increments; 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 inducer
  • Resume dose administered before starting any inducer, once all inducers are discontinued for 5 days

Therapeutic drug monitoring and dose titration

• Titrate dose to attain trough concentrations of 5-15 ng/mL
• Monitor everolimus whole blood trough 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

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

Overdose

• There is limited experience of everolimus overdose in humans.
• Animal studies showed a low acute toxicity potential for everolimus, and no lethality or severe toxicity. Overdose may be treated with supportive and symptomatic care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Everolimus has no listed severe interactions with other drugs.
• Everolimus has serious interactions with at least 167 different drugs.
• Everolimus has moderate interactions with at least 77 different drugs.
• Mild interactions of everolimus include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • larotrectinib

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no adequate and well-controlled studies on the safety of everolimus use in pregnant women, however, animal reproductive studies show everolimus can cause fetal harm if administered during pregnancy.
• Everolimus should be used in pregnancy only if maternal benefits clearly outweigh potential risks to the fetus.
• Women of pregnancy potential and men with women partners of child-bearing age should practice effective contraception.
• Everolimus may cause menstrual irregularities in women and infertility in men.
• There is no information on the presence of everolimus in breastmilk, however, the drug is excreted in animal milk. There is no information on the drug’s effects on milk production or on the breastfed infant, 
• Nursing mothers should not breastfeed during everolimus therapy and for 2 weeks following the last dose of everolimus, because of the potential for serious adverse effects in the breastfed infant.

• Take everolimus exactly as prescribed. You may also be prescribed a mouthwash to reduce the risk of mouth ulcers and sores from the treatment. Follow the directions for use. Do not interchange different brands of everolimus.
• Do not consume grapefruit or grapefruit juice while on everolimus treatment. it can increase the drug concentrations to toxic levels.
• Inform your healthcare provider immediately if you develop:
  • Lung or breathing problems including, new or worsening cough, shortness of breath, chest pain, difficulty breathing or wheezing
  • Symptoms of infections (including hepatitis B reactivation) such as fever, chills, tiredness, skin rash, joint pain and inflammation, nausea, pale stools or dark urine, loss of appetite, and/or abdominal pain
  • Severe hypersensitivity symptoms which may include rash, hives, itching, flushing, swelling of tongue, mouth, or throat, trouble breathing or swallowing, chest pain or dizziness
  • Symptoms of kidney failure
• Inform your healthcare provider if you notice problems with the healing of your surgical incision/wound, or if the incision is warm, red, and painful, develops swelling and pus, or opens up.
• You will need periodic tests while you are on everolimus therapy. Do not miss your appointments.
• Store everolimus safely out of reach of children,
• In case of overdose, seek medical help immediately or contact Poison Control.