Everolimus

Trade Names:
Afinitor
- Tablet 5 mg
- Tablet 10 mg

Pharmacology

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Inhibitor of mammalian target of rapamycin (mTOR), which is a serine-threonine kinase. Everolimus binds to an intracellular protein, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity.

Pharmacokinetics

Absorption

T _max is 1 to 2 h. C _max is dose-proportional between 5 and 10 mg. Steady-state is achieved within 2 wk with once-daily dosing. High-fat meals reduce C _max and AUC by 60% and 16%, respectively.

Distribution

Protein binding is approximately 74%.

Metabolism

Everolimus is a substrate for CYP3A4 and P-glycoprotein (Pgp). Six metabolites have been identified and are approximately 100 times less active than everolimus.

Elimination

Elimination half-life is approximately 30 h. Recovery in the feces and urine is 80% and 5%, respectively.

Special Populations

No influence of CrCl (25 to 178 mL/min) has been detected.

The average AUC in subjects with moderate hepatic function impairment is twice that found in subjects with healthy hepatic function. Dose reduction is recommended in patients with moderate hepatic function impairment. Administration is not recommended in patients with severe hepatic function impairment.

No effect of age on pharmacokinetics has been observed.

No effect of gender on pharmacokinetics has been observed.

Average exposure is higher in Japanese patients compared with non-Japanese patients. Oral Cl is 20% higher in black patients compared with white patients. The importance of these differences in safety and efficacy has not been established.

Indications and Usage

Treatment of advanced renal cell carcinoma after failure of sunitinib or sorafenib.

Contraindications

Hypersensitivity to rapamycin derivatives or any component of the product.

Dosage and Administration

PO 10 mg once daily.

PO

Temporarily reduce dosage to 5 mg once daily.

Reduce dosage to 5 mg once daily in patients with moderate hepatic function impairment. Do not use in patients with severe hepatic function impairment.

Consider increasing dose in 5 mg increments to 20 mg once daily. However, no clinical data are available.

General Advice

• Administer at the same time each day.
• May be taken without regard to meals.
• Do not chew or crush tablets.

Storage/Stability

Store at 59° to 86°F. Protect from light and moisture.

Drug Interactions

Ketoconazole, a strong CYP3A4 inhibitor and Pgp inhibitor, increases everolimus C _max and AUC by 3.9- and 15-fold, respectively. Moderate CYP3A4 inhibitors and Pgp inhibitors (eg, erythromycin, verapamil) increase everolimus C _max and AUC by approximately 2- and 4-fold, respectively.

Everolimus C _max and AUC may be reduced. Strong CYP3A4 inducers may reduce everolimus C _max and AUC by approximately 60%.

High-fat meals reduce the C _max and AUC; however, everolimus may be taken without regard to meals.

Avoid taking live vaccines during use of everolimus.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (4%); tachycardia (3%); CHF (1%).

CNS

Asthenia (33%); fatigue (31%); pyrexia (20%); headache (19%); insomnia (9%); dizziness (7%); paresthesia (5%); dysphagia (4%).

Dermatologic

Rash (29%); pruritus (14%); dry skin (13%); hand-foot syndrome, nail disorder (5%); erythema, onychoclasis, skin lesion (4%); acniform dermatitis (3%).

EENT

Epistaxis (18%); eyelid edema, pharyngolaryngeal pain (4%); rhinorrhea (3%); conjunctivitis (2%).

GI

Stomatitis (44%); diarrhea (30%); nausea (26%); anorexia (25%); vomiting (20%), dysgeusia (10%); abdominal pain (9%); dry mouth (8%); hemorrhoids (5%).

Hematologic-Lymphatic

Hemorrhage (3%).

Lab Tests

Decreased hemoglobin (92%); increased cholesterol (77%); increased triglycerides (73%); increased glucose (57%); decreased lymphocytes (51%); increased creatinine (50%); decreased phosphate (37%); increased AST (25%); increased ALT, decreased platelets (23%); decreased neutrophils (14%); increased bilirubin (3%).

Metabolic-Nutritional

Peripheral edema (25%); weight decrease (9%); exacerbation of preexisting diabetes mellitus (2%).

Musculoskeletal

Extremity pain (10%); jaw pain (3%).

Respiratory

Cough (30%); dyspnea (24%); pneumonitis (14%); pleural effusion (7%).

Miscellaneous

Infections and infestations (37%); mucosal inflammation (19%); chest pain (5%); chills (4%); renal failure (3%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

No overall differences in safety or efficacy have been observed in patients 65 yr of age and older compared with younger subjects.

Renal Function

Renal function impairment is not expected to alter drug exposure and no dosage adjustment is recommended.

Hepatic Function

Dosage reduction in patients with moderate hepatic function impairment is recommended. Because use in patients with severe hepatic function impairment has not been evaluated, avoid administration.

Infections

Because everolimus has immunosuppressive properties, patients may be predisposed to infections, especially from opportunistic pathogens.

Noninfectious pneumonitis

May occur. Consider the possibility in patients who present with nonspecific respiratory signs and symptoms.

Oral ulcerations

Mouth ulcers, oral mucositis, and stomatitis may occur.

Overdosage

Symptoms

Clinical experience is limited.

Patient Information

• Instruct patients to promptly report any new or worsening respiratory symptoms, or signs or symptoms of infection.
• Advise patients to avoid the use of live vaccines and to avoid close contact with persons who have received live vaccines.
• Advise women of childbearing potential to use an effective method of contraception during therapy and for 8 wk after ending treatment.
• Instruct patients to take everolimus at the same time each day.
• Instruct patient that product may be taken without regard to meals.
• Instruct patient not to chew or crush the tablets.

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