everolimus (e-ver-oh-li-mus) Afinitor, Afinitor Disperz, Certican, Zortress

 Indications

Afinitor. Advanced renal cell carcinoma that has failed

treatment with sunitinib or sorafenib. Subependymal giant

cell astrocytoma (SEGA) associated with tuberous

sclerosis complex (TSC) in patients who are not candidates

for curative surgical resection. Progressive neuroendocrine

tumors of pancreatic origin (PNET) in patients

with unresectable, locally advanced, or metastatic

disease. Progressive, well-differentiated, non-functional

neuroendocrine tumors (NET) of GI or lung origin in

patients with unresectable, locally advanced, or metastatic

disease. Renal angiomyolipoma with TSC in patients

not requiring immediate surgery. Treatment of

postmenopausal women with advanced hormone receptor-

positive, HER2-negative breast cancer in combination

with exemestane, after failure of treatment with

letrozole or anastrozole. 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.

Action

Acts as a kinase inhibitor, decreasing cell proliferation.

Inhibits activation and proliferation of T and B lymphocytes.

Therapeutic Effects: Decreased spread of

renal cell carcinoma. Improvement in progression-free

survival in patients with PNET. Decreased volume of

SEGA and angiomyolipoma lesions. Prevention of kidney

and liver transplant rejection.

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: 20% confined to plasma.

Metabolism and Excretion: Mostly metabolized

by liver and other systems (CYP3A4 and P-gp; metabolites

are mostly excreted in feces [80%] and urine

[5%]).

Half-life: 30 hr.

TIME/ACTION PROFILE (blood levels))

ROUTE ONSET PEAK DURATION

PO unknown 1–2 hr 24 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity to everolimus

or other rapamycins; Severe hepatic impairment

(Child-Pugh class C); use only if benefit exceeds risk

for renal cell carcinoma, PNET, breast cancer, and renal

angiomyolipoma with TSC; Concurrent use with

strong CYP3A4 inhibitors (i.e., ketoconazole, itraconazole,

clarithromycin, atazanavir, nefazodone, saquinavir,

ritonavir, indinavir, nelfinavir, voriconazole); Heart

transplantation (Zortress) (qrisk of mortality); Functional

carcinoid tumors; OB: May cause fetal harm;

avoid use during pregnancy (Afinitor); use only if benefit

to mother outweighs risk to fetus (Zortress); Lactation:

Avoid breast feeding.

Use Cautiously in: Mild or moderate hepatic impairment

(Child-Pugh class A or B); doseprequired;

Concurrent use of moderate CYP3A4 and/or P-gp inhibitors;

doseprequired; Exposure to sunlight/UV light

(mayqrisk of malignant skin changes); Geri: May be

more sensitive to drug effects; consider age-relatedpin

hepatic function, concurrent disease states and drug

therapy; Pedi: Safety not established for indications

other than SEGA.

Adverse Reactions/Side Effects

CNS: fatigue, weakness, headache. CV: peripheral

edema. Resp: INTERSTITIAL LUNG DISEASE, PULMONARY

HYPERTENSION, cough, dyspnea, pulmonary embolism.

GI: HEPATIC ARTERY THROMBOSIS, anorexia, constipation,

diarrhea, mucositis, mouth ulcers, nausea, stomatitis,

vomiting, dysgeusia. GU: acute renal failure, infertility,

proteinuria. Derm: delayed wound healing, dry

skin, pruritus, rash. Hemat: HEMOLYTIC UREMIC SYNDROME,

THROMBOTIC MICROANGIOPATHY, THROMBOTIC

THROMBOCYTOPENIC PURPURA, anemia, leukopenia,

thrombocytopenia.Metab: hyperlipidemia, hypergly cemia, hypertriglyceridemia. MS: extremity pain.

Misc: ANGIOEDEMA, fever, hypersensitivity reactions including

ANAPHYLAXIS, infection (including activation of

latent viral infections such as BK virus-associated nephropathy),

kidney arterial/venous thrombosis (Zortress),

qrisk of lymphoma/skin cancer (Zortress).

Interactions

Drug-Drug: Strong CYP3A4 inhibitors, including

atazanavir, clarithromycin, indinavir, itraconazole,

ketoconazole, nefazodone, nelfinavir, ritonavir,

saquinavir, or voriconazoleqlevels and the

risk of toxicity; avoid concurrent use. Moderate inhibitors

of CYP3A4, including aprepitant, diltiazem,

erythromycin, fluconazole, fosamprenavir, and

verapamilqlevels and the risk of toxicity;pdose of

everolimus (Afinitor). Avoid concurrent use with strong

CYP3A4 inducers including carbamazepine, dexamethasone,

phenobarbital, phenytoin, rifabutin,

and rifampin;qdose of everolimus may be required.

Cyclosporine, aprepitant, diltiazem, verapamil,

fluconazole, and fosamprenavir mayqlevels.qrisk

of nephrotoxicity with aminoglycosides, amphotericin

B, cisplatin, or cyclosporine. ACE inhibitors

mayqrisk of angioedema. Maypantibody formation

andqrisk of adverse reactions from live-virus vaccines;

avoid use of live-virus vaccines during treatment.

Drug-Natural Products: St. John’s wort mayp

levels and efficacy; avoid concurrent use.

Drug-Food:qblood levels and risk of toxicity with

grapefruit juice; avoid concurrent use.

Route/Dosage

Advanced Renal Cell Carcinoma, Advanced

PNET, Advanced NET, Advanced

Hormone Receptor-Positive, HER2-Negative

Breast Cancer, and Renal Angiomyolipoma

with TSC

PO (Adults): 10 mg once daily; Concurrent use of

moderate inhibitors of CYP3A4 and/or P-gp—pdose

to 2.5 mg daily; Concurrent use of strong inducers of

CYP3A4—qdose in 5 mg increments up to 20 mg/

daily.

Hepatic Impairment

PO (Adults): Mild hepatic impairment (Child–Pugh

Class A)—7.5 mg once daily; may bepto 5 mg once

daily if not well tolerated; Moderate hepatic impairment

(Child–Pugh Class B)—5 mg once daily; may

bepto 2.5 mg once daily if not well tolerated; Severe

hepatic impairment (Child–Pugh Class C)—2.5 mg

once daily.

SEGA with TSC

PO (Adults and Children 1 yr): 4.5 mg/m2. Titrate,

as needed, at 2-wk intervals to achieve recommended

whole blood trough concentration. Concurrent use of

moderate inhibitors of CYP3A4 and/or P-glycoprotein—

2.25 mg/m2; Concurrent use of strong inducers

of CYP3A4—9 mg/m2.

Hepatic Impairment

PO (Adults and Children 1 yr): Severe hepatic

impairment (Child–Pugh Class C)—2.5 mg/m2.

Kidney Transplantation

PO (Adults): 0.75 mg twice daily (with reduced-dose

cyclosporine); titrate to achieve recommended whole

blood trough concentration.

Hepatic Impairment

PO (Adults): Mild hepatic impairment (Child–Pugh

Class A)—pdaily dose by 33%; Moderate or severe

hepatic impairment (Child–Pugh Class B or C)—p

daily dose by 50%.

Liver Transplantation

PO (Adults): 1 mg twice daily (with reduced-dose tacrolimus)

(start 30 days post-transplant); titrate to

achieve recommended whole blood trough concentration.

Hepatic Impairment

PO (Adults): Mild hepatic impairment (Child–Pugh

Class A)—pdaily dose by 33%; Moderate or severe

hepatic impairment (Child–Pugh Class B or C)—p

daily dose by 50%.

Availability

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.