e-ver-OH-li-mus

Therapeutic Classification: antineoplastics, Immunosuppressant agents

Pharmacologic Classification: kinase inhibitors

Afinitor:

• • Advanced renal cell carcinoma that has failed treatment with sunitinib or sorafenib.
  • Subependymal giant cell astrocytoma associated with tuberous sclerosis complex in patients who are not candidates for curative surgical resection.
  • Tuberous sclerosis complex–associated partial-onset seizures (adjunctive treatment).
  • Progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced, or metastatic disease.
  • Progressive, well-differentiated, nonfunctional neuroendocrine tumors of GI or lung origin in patients with unresectable, locally advanced, or metastatic disease.
  • Renal angiomyolipoma with tuberous sclerosis complex in patients not requiring immediate surgery.
  • Treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole (in combination with exemestane).

Zortress:

• • Prevention of organ rejection in patients who have received a kidney transplant and are at low to moderate immunologic risk.
  • Prevention of organ rejection in patients who have received a liver transplant.

• Acts as a kinase inhibitor, decreasing cell proliferation.
• Inhibits activation and proliferation of T and B lymphocytes.

• Decreased spread of renal cell carcinoma and breast cancer.
• Improvement in progression-free survival in patients with progressive neuroendocrine tumors
• Decreased volume of subependymal giant cell astrocytoma and angiomyolipoma lesions.
• Prevention of kidney and liver transplant rejection.
• Reduction in seizure frequency.

Absorption: Well absorbed following oral administration.

Distribution: 20% confined to plasma.

Metabolism/Excretion: Mostly metabolized by liver via the CYP3A4 isoenzyme; metabolites are mostly excreted in feces (80%) and urine (5%).

Half-life: 30 hr.

(plasma concentrations)

Contraindicated in:

• Hypersensitivity to everolimus or other rapamycins
• Severe hepatic impairment; use only if benefit exceeds risk for renal cell carcinoma, progressive neuroendocrine tumors, breast cancer, and renal angiomyolipoma with tuberous sclerosis complex
• Heart transplantation (Zortress) (↑ risk of mortality)
• Functional carcinoid tumors
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Mild or moderate hepatic impairment (dose ↓ required)
• Exposure to sunlight/UV light (may ↑ risk of malignant skin changes)
• Patients undergoing radiation treatment before, during, or after therapy (↑ risk of radiation sensitization and radiation recall)
• Women of reproductive potential and men with female partners of reproductive potential
• Pedi: Safety not established in children for indications other than SEGA and TSC-associated partial-onset seizures
• Geri: Older adults may be more sensitive to drug effects; consider age-related ↓ in hepatic function, concurrent disease states, and drug therapy.

CV: peripheral edema.

Derm: delayed wound healing, dry skin, pruritus, rash.

Endo: hyperglycemia.

GI: anorexia, constipation, diarrhea, mouth ulcers, mucositis, nausea, stomatitis, vomiting, HEPATIC ARTERY THROMBOSIS.

GU: ↓fertility, acute renal failure, amenorrhea, kidney arterial/venous thrombosis (Zortress), menstrual irregularities, proteinuria.

Hemat: anemia, leukopenia, thrombocytopenia, HEMOLYTIC UREMIC SYNDROME, THROMBOTIC MICROANGIOPATHY, THROMBOTIC THROMBOCYTOPENIC PURPURA.

Metab: hyperlipidemia, hypertriglyceridemia.

MS: extremity pain.

Neuro: fatigue, weakness, dysgeusia, headache.

Resp: cough, dyspnea, pulmonary embolism, INTERSTITIAL LUNG DISEASE, PULMONARY HYPERTENSION.
Misc: fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS AND ANGIOEDEMA), INFECTION (INCLUDING ACTIVATION OF LATENT VIRAL INFECTIONS SUCH AS BK VIRUS-ASSOCIATED NEPHROPATHY), (ZORTRESS)LYMPHOMA/SKIN CANCER .

Drug-Drug:

• P-glycoprotein (P-gp) inhibitors and strong CYP3A4 inhibitors, including atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, and voriconazole, significantly ↑ levels and the risk of toxicity; avoid concurrent use.
• P-gp inhibitors and moderate CYP3A4 inhibitors, including aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil, may ↑ levels and the risk of toxicity; ↓ dose of everolimus (Afinitor).
• P-gp inducers and strong CYP3A4 inducers, including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, and rifampin, may ↓ levels and effectiveness; avoid concurrent use, if possible. If concurrent use unavoidable, ↑ dose of everolimus may be required.
• ↑risk of nephrotoxicity with aminoglycosides, amphotericin B, cisplatin, or cyclosporine.
• ACE inhibitors may ↑ risk of angioedema.
• May ↓ antibody formation and ↑ risk of adverse reactions from live-virus vaccines; avoid use of live-virus vaccines during treatment.
• Cannabidiol may ↑ levels and risk of toxicity; consider ↓ everolimus dose.

Drug-Natural Products:

• St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

• Grapefruit juice may ↑ levels and the risk of toxicity; avoid concurrent use.

Advanced Renal Cell Carcinoma, Advanced Progressive Neuroendocrine Tumors, Advanced Neuroendocrine Tumors, Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, and Renal Angiomyolipoma with Tuberous Sclerosis Complex (Afinitor)

• PO (Adults): 10 mg once daily until disease progression or unacceptable toxicity; Concurrent use of P-gp inhibitor and moderate CYP3A4 inhibitor: 2.5 mg once daily until disease progression or unacceptable toxicity; Concurrent use of P-gp inducer and strong CYP3A4 inducer:↑ dose in 5 mg increments up to 20 mg once daily; continue until disease progression or unacceptable toxicity.

Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex (Afinitor)

• PO (Adults and Children 1 yr): 4.5 mg/m² once daily. Titrate, as needed, at 2-wk intervals to achieve recommended whole blood trough concentration. Continue until disease progression or unacceptable toxicity; Concurrent use of P-gp inhibitor and moderate CYP3A4 inhibitor: 2.25 mg/m² once daily. Titrate, as needed, at 2-wk intervals to achieve recommended whole blood trough concentration. Continue until disease progression or unacceptable toxicity; Concurrent use of P-gp inducer and strong CYP3A4 inducer: 9 mg/m² once daily. Titrate, as needed, at 2-wk intervals to achieve recommended whole blood trough concentration. Continue until disease progression or unacceptable toxicity.

Tuberous Sclerosis Complex-Associated Partial-Onset Seizures (Afinitor)

• PO (Adults and Children 2 yr): 5 mg/m² once daily. Titrate, as needed, at 2-wk intervals to achieve recommended whole blood trough concentration. Continue until disease progression or unacceptable toxicity; Concurrent use of P-gp inhibitor and moderate CYP3A4 inhibitor: 2.5 mg/m² once daily. Titrate, as needed, at 2-wk intervals to achieve recommended whole blood trough concentration. Continue until disease progression or unacceptable toxicity; Concurrent use of P-gp inducer and strong CYP3A4 inducer: 10 mg/m² once daily. Titrate, as needed, at 2-wk intervals to achieve recommended whole blood trough concentration. Continue until disease progression or unacceptable toxicity.

Kidney Transplantation (Zortress)

• PO (Adults): 0.75 mg twice daily (with reduced-dose cyclosporine); titrate to achieve recommended whole blood trough concentration.

Liver Transplantation (Zortress)

• PO (Adults): 1 mg twice daily (with reduced-dose tacrolimus) (start 30 days post-transplant); titrate to achieve recommended whole blood trough concentration.

(Generic available)

• Tablets (Afinitor): 2.5 mg; 5 mg; 7.5 mg; 10 mg;
• Tablets for oral suspension (Afinitor Disperz): 2 mg; 3 mg; 5 mg;
• Tablets (Zortress): 0.25 mg; 0.5 mg; 0.75 mg; 1 mg;

• Assess for symptoms of noninfectious pneumonitis (hypoxia, pleural effusion, cough, dyspnea) during therapy. If symptoms are mild, therapy may continue. If Grade 2 pneumonitis occurs: hold therapy until Grade 0–1; reinitiate everolimus at 50% of previous dose. Permanently discontinue if does not resolve or improve to Grade 1 within 4 wk. If Grade 3 pneumonitis occurs: hold therapy until Grade 0–1; resume at 50% of previous dose. Change to every other day if dose is lower than lowest available strength. Permanently discontinue if Grade 3 pneumonitis recurs. If Grade 4 pneumonitis occurs: permanently discontinue.
• Assess for mouth ulcers, stomatitis, or oral mucositis; usually occurs within first 8 wk of therapy. Begin dexamethasone alcohol-free oral solution as a swish-and-spit mouthwash when starting therapy to reduce incidence and severity of stomatitis. Topical treatments may be used; avoid peroxide-containing mouthwashes and antifungals unless fungal infection has been diagnosed. If Grade 2 stomatitis occurs: hold therapy until Grade 0–1; resume at previous dose. If Grade 2 recurs, withhold until Grade 0–1; resume at 50% of previous dose. Change to every other day if dose is lower than lowest available strength. If Grade 3 stomatitis occurs: hold therapy until Grade 0–1; hold until Grade 0–1; resume at 50% of previous dose. Change to every other day if dose is lower than lowest available strength. If Grade 4 stomatitis occurs: discontinue permanently.
• Assess for signs and symptoms of systemic fungal infections (fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness with or without concomitant shock). Withhold therapy until infection has been diagnosed and adequately treated.
• Monitor for signs and symptoms of hypersensitivity reactions (anaphylaxis, dyspnea, flushing, chest pain, angioedema) during therapy. Permanently discontinue therapy if severe reactions occur.

• Verify negative pregnancy test before starting therapy.
  • Monitor renal function prior to and periodically during therapy. May cause ↑ BUN, serum creatinine, and proteinuria.
  • Monitor fasting serum glucose and lipid profile prior to and periodically during therapy. May cause ↑ cholesterol, triglycerides, glucose. Attempt to achieve optimal glucose and lipid control prior to therapy. If Grade 3 metabolic events (hyperglycemia, dyslipidemia) occur: hold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose. Change to every other day if dose is lower than lowest available strength.
  • Monitor CBC prior to and every 6 mo for 1st yr of therapy and annually thereafter; may cause ↓ hemoglobin, lymphocytes, neutrophils, and platelets. If Grade 2 thrombocytopenia occurs: hold dose until Grade 0–1; resume at same dose. If Grade 3 or 4 thrombocytopenia occurs: hold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose. Change to every other day if dose is lower than lowest available strength. If Grade 3 neutropenia occurs: hold dose until Grade 0–1; resume at same dose. If Grade 4 neutropenia occurs: hold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose. Change to every other day if dose is lower than lowest available strength. If Grade 3 febrile neutropenia occurs: hold until improvement to Grade 0, 1, or 2 and no fever. Resume at 50% of previous dose. Change to every other day if dose is lower than lowest available strength. If Grade 4 febrile neutropenia occurs: discontinue permanently.
  • May cause ↑ AST, ALT, phosphate, and bilirubin.
  • Afinitor: Monitor Afinitor trough levels 2 wk after initiation of therapy, a change in dose, a change in coadministration of CYP3A4 and/or P-gp inducers or inhibitors, change in hepatic function, or change in dose form between everolimus tablets and Disperz. Once at a stable dose, monitor trough concentrations every 3–6 mo in patients with changing body surface area or every 6–12 mo in patients with stable body surface area for duration of treatment. Therapeutic blood concentrations are 5–15 ng/mL (Afinitor). If trough concentration <5 ng/mL, ↑ daily dose by 2.5 mg in patients taking tablets and 2 mg for Disperz. If trough concentration >15 ng/mL, ↓ daily dose by 2.5 mg in patients taking tablets and 2 mg for Disperz. If dose ↓ is required with lowest dose, administer every other day. Do not combine dose forms to achieve dose.
  • Zortress: Therapeutic blood concentrations are 3–8 ng/mL via the LCMSMS assay (Zortress). Base dose adjustments of Zortress on trough concentrations obtained 4 or 5 days after a previous dosing change. Adjust dose if trough concentration <3 ng/mL by doubling dose using available tablet strengths (0.25 mg, 0.5 mg or 0.75 mg). If trough concentration >8 ng/mL on two consecutive measures, ↓ dose of Zortress by 0.25 mg twice daily.

• May impair wound healing. Hold everolimus for 1 wk before and 2 wk after elective surgery to ensure adequate wound healing.
• PO: Administer at the same time each day consistently with or without food, followed by a whole glass of water. DNC: Swallow tablets whole; do not break, crush, or chew.
  • Do not combine the two dose forms (Afinitor Tablets and Afinitor Disperz) to achieve the desired total dose. Use one dose form or the other.
  • Administer Disperz, dispersible tablet, as a suspension only. Wear gloves to avoid possible contact with everolimus when preparing suspensions for another person. Place dose in 10 mL syringe; do not exceed 10 mg/syringe. If higher dose required, use additional syringe. Do not break or crush tablets. Draw 5 mL water and 4 mL of air into syringe. Place filled syringe into container (tip up) for 3 min until tablets are in suspension. Invert syringe five times immediately prior to administration. Administer immediately after preparation; discard suspension if not administered within 60 min after preparation. After administration, draw 5 mL of water and 4 mL of air into same syringe, and swirl contents to suspend remaining particles. Administer entire contents of syringe. Can also be dispersed using same technique and 25 mL water in small glass.

• Instruct patient to take everolimus at the same time each day as directed. Take missed doses as soon as remembered up to 6 hr after time of normal dose. If more than 6 hr after normal dose, omit dose for that day and take next dose next day; do not take two doses to make up missed dose. Do not eat grapefruit or drink grapefruit juice during therapy. Advise patient to read Patient Information prior to beginning therapy and with each Rx refill in case of new information.
• Advise patient to report worsening respiratory symptoms or signs of infection (new or worsening cough, shortness of breath, chest pain, difficulty breathing or wheezing, fever, chills, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stool or dark urine, yellowing of the skin, pain in upper right side) or severe allergic reaction (rash, itching, hives, flushing, trouble breathing or swallowing, chest pain, dizziness, trouble breathing, swelling of tongue, mouth, or throat) to health care professional promptly.
• Inform patient that mouth sores may occur. Consult health care professional for treatment if pain, discomfort, or open sores in mouth occur. May require special mouthwash or gel.
• Instruct patient to avoid use of live vaccines and close contact with those who have received live vaccines.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
• Notify health care professional of everolimus therapy before treatment or surgery. May require temporarily stopping everolimus.
• May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for up to 8 wk after last dose, male patients with female partners of reproductive potential to use effective contraception during and for up to 4 wk after last dose, and to notify health care professional if pregnancy is planned or suspected. Advise female patients to avoid breastfeeding during and for 2 wk after last dose. May impair fertility in female and male patients.
• Emphasize the importance of routine blood tests to determine effectiveness and side effects.

• Decreased spread of tumor. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.
• Prevention of kidney or liver transplant rejection.
• Reduced seizure frequency.

Afinitor, Afinitor Disperz, Zortress