everolimus (Rx)

>10%

Stomatitis (44%)

Constipation (38%)

Infections (37%)

Asthenia (33%)

Fatigue (31%)

Cough (30%)

Diarrhea (30%)

Rash (29%)

Anemia (26%)

Nausea (26%)

Anorexia (25%)

Edema, peripheral (25-45%)

Dyspnea (24%)

Pyrexia (20%)

Vomiting (20%)

Headache (19%)

Epistaxis (18%)

Decreased lymphocytes, Grade 3 (16%)

Increased glucose, Grade 3 (15%)

Pneumonitis (14%)

Pruritus (14%)

Dry skin (13%)

Decreased Hgb, Grade 3 (12%)

Menstrual irregularities (11%)

1-10% (selected)

Dysgeusia (10%)

Hypertension, including hypertensive crisis (4%)

Hemorrhage (3%)

Tachycardia (3%)

CHF (1%)

Postmarketing Reports

Angioedema

Pancreatitis

Cholelithiasis

Cholecystitis

Arterial thrombotic events

Reflex sympathetic dystrophy

Pulmonary embolism

Male infertility with mTOR inhibitors (including everolimus)

Gengivitis

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

Echymosis

Sepsis and septic shock

Thrombotic microangiopathy

Radiation sensitization and radiation recall

Contraindications

Hypersensitivity to everolimus or rapamycin (sirolimus) derivatives

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 (eg, pulmonary arterial hypertension) as a secondary (see Dosage Modifications)

For Grade 2 to 4 non-infectious 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

Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) reported in patients treated with radiation prior to, during, or subsequent to treatment; monitor patients closely when therapy administered during or sequentially with radiation treatment

Continue therapy without dose alteration in patients who develop radiological changes

Elicits immunosuppressive effects and may increase risk for infections; some of 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 (eg, swelling of the airways or tongue, with or without respiratory impairment) (see Contraindications); permanently discontinue therapy if clinically significant hypersensitivity occurs

Stomatitis (eg, mouth ulcers and oral mucositis) reported at an incidence ranging from 44-78% across clinical trials; stomatitis most often occurs within first 8 weeks of treatment (see Dosage Modifications)

Complete treatment of preexisting invasive fungal infections prior to starting treatment; monitor for signs and symptoms of infection; withhold or permanently discontinue therapy based on severity of infection

Do not administer antifungal agents, unless fungal infection has been diagnosed

May delay wound healing and increase wound-related complications (eg, dehiscence, wound infection, incisional hernia, lymphocele, and seroma); withhold therapy for at least 1 week prior to elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing; safety of resumption of treatment upon resolution of wound healing complications has not been established

Cases of renal failure (including acute renal failure), some fatal, have been observed; monitor renal function prior to 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 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 compared to 2% in patients <65 years; adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥65 years compared to 17% in patients <65 year; careful monitoring and appropriate dose adjustments for adverse reactions are recommended

Can cause fetal harm when administered to pregnant women (see Pregnancy)

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 prior to starting treatment and annually thereafter; when possible, achieve optimal glucose and lipid control prior to starting treatment (see Dosage Modifications); for Grade 3-4 metabolic events, withhold or permanently discontinue treatment based on severity

Anemia, lymphopenia, neutropenia, and thrombocytopenia reported (see Dosage Modifications); monitor complete blood count prior to starting therapy every 6 months for the first year of treatment and annually thereafter; withhold or permanently discontinue treatment based on severity

Zortress only

• See Black Box Warnings
• Polyoma virus 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 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

• See Dosage Modifications
• Avoid use of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)
• Caution when coadministered with moderate CYP3A4 and/or PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem, grapefruit juice)
• Avoid use of concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, dexamethasone, rifampin, rifabutin, rifapentine, phenobarbital, St John's wort); may decrease blood concentrations and require an increase in 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 prior to initiating therapy; avoid 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 with receiving HMG-CoA reductase inhibitors (eg, simvastatin, lovastatin)

Pregnancy

Based on animal studies and mechanism of action therapy can cause fetal harm when administered to pregnant woman; there are limited case reports of use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage; advise pregnant women of potential risk to fetus

Contraception

• Females

  • Advise female patients of reproductive potential to use effective contraception during treatment and for 8 weeks after last dose
  • Verify the pregnancy status of females of reproductive potential prior to starting treatment

• Males

  • Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after last dose

Infertility

• Females

  • Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients receiving therapy; based on these clinical findings and findings in animals, female fertility may be compromised by treatment with drug

• Males

  • Based on clinical findings and findings in animals, treatment may impair fertility in male patients; cases of reversible azoospermia reported in male patients receiving therapy; in male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at exposures (AUC) similar to those in patients receiving a dose of 10 mg daily; the fertility index in rats increased when everolimus administration was stopped for a 10-13 week recovery

Lactation

There are no data on presence of everolimus in human milk, effects on breastfed infant or on milk production; drug and/or its metabolites passed into milk of lactating rats at a concentration 3.5 times higher than in maternal serum; because of potential for serious adverse reactions in breastfed infants from everolimus, advise lactating women not to breastfeed during treatment and for 2 weeks after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Afinitor

• Inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase; in several cancers and tuberous sclerosis complex, the mTOR pathway is dysregulated; everolimus binds to FKBP-12, an intracellular protein and thus inhibiting the mTOR kinase pathway
• Also, reduces the activity of S6 ribosomal protein kinase (S6k1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR and also involved in protein synthesis; everolimus inhibits the expression of hypoxia-inducible factor and reduces the expression of vascular endothelial growth factor (VEGF)

Zortress

• Inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes; binds to cellular cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase; in the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited; consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited

Absorption

Peak Plasma Time: 1-2 hr

High-fat meals reduced systemic exposure to Afinitor 10 mg (as measured by AUC) by 22% and peak plasma concentration by 54%

High-fat meals reduced Afinitor Disperz AUC by 12% and peak plasma concentration by 60%

Distribution

Protein Bound: 74%

Vd (Zortress): 107-342 L (kidney transplant patients)

Metabolism

CYP3A4 substrate

PgP substrate and moderate inhibitor

Competitive inhibitor of CYP3A4 and mixed inhibitor of CYP2D6

Elimination

Half Life: 30 hr

Excretion: 80% feces; 5% urine

Pharmacogenomics

Rapamycins form complexes with an intracellular immunophillin (FKBP), which bind to a kinase called the mammalian target of rapamycin (mTOR)

Intrinsic rapamycin resistance may be caused by genetic mutations identified for FKBP and mTOR genes

Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose; oral clearance is on average 20% higher in black patients than in white patients

Oral Suspension Preparation

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

Using an oral syringe

• Place prescribed dose into a 10-mL syringe; do not exceed a total of 10 mg/syringe; prepare additional syringes if higher doses are required
• Do not break or crush tablets
• Draw ~5 mL of water and 4 mL of air into syringe
• Place filled syringe into a container (tip up) for 3 min, until tablets are in suspension; do not shake syringe
• Gently invert syringe 5 times immediately prior to administration

Using a small drinking glass

• Place prescribed dose into a small drinking glass (up to 100 mL) containing ~25 mL of water; do not exceed a total of 10 mg/glass; prepare additional syringes if higher doses are required
• Allow 3 minutes for suspension to occur
• Stir contents gently with a spoon, immediately prior to drinking

Oral Administration (Afinitor tablets and Afinitor Disperz)

Administer the same time every day

Administer consistently with food or consistently without food

Afinitor tablets

• Swallow whole, do not break or crush tablets

Afinitor Disperz

• Administer as a PO suspension only
• Administer suspension immediately after preparation; discard suspension if not administered within 60 min after preparation
• Oral syringe: After administration, draw ~5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles; administer entire contents of the syringe
• Drinking glass: After administration, add 25 mL of water and stir with same spoon to resuspend remaining particles; administer the entire contents of the glass

Missed dose

• ≤6 hr from normal administration time: Take missed dose
• >6 hr from normal administration time: Skip dose; the next day, administer at its usual time; do not double dose to make up for the missed dose

Zortress

Swallow tablets whole, do not chew, crush, or split

Kidney transplantation

• Administer as soon as possible after kidney transplantation
• Routine everolimus and cyclosporine therapeutic drug concentration monitoring is recommended
• Administer consistently with or without food at the same time as cyclosporine

Liver transplantation

• Do not administer until at least 30 days post liver transplant (earlier administration associated with hepatic artery thrombosis, graft loss, and death)
• Use in combination with reduced doses of tacrolimus and with corticosteroids
• May continue to taper corticosteroid dose on individual basis
• Routine everolimus and tacrolimus therapeutic drug concentration monitoring is recommended

Storage

Zortress: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); protect from light and moisture

Afinitor: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); protect from light and moisture

Afinitor Disperz: Store at room temperature (20-25°C [68-77°F]); protect from light and moisture