everolimus

Action

Binds to intracellular proteins, resulting in an inhibitory (Afinitor) or immunosuppressive (Zortress) complex resulting in inhibition of mTOR kinase

Availability

Tablets (Afinitor): 2.5 mg, 5 mg, 7.5 mg, 10 mg

Tablets (Zortress): 0.25 mg, 0.5 mg, 0.75 mg

Indications and dosages

➣ Metastatic, locally advanced, or unresectable progressive neuroendocrine tumors of pancreatic origin; advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; renal angiomyolipoma and tuberous sclerosis complex

Adults: 10 mg (Afinitor) P.O. daily continued as long as clinical benefit is observed or until unacceptable toxicity occurs

➣ Subependymal giant cell astrocytoma (SEGA) requiring intervention in patients who aren't candidates for surgical intervention

Adults and children age 3 and older with body surface area (BSA) of 2.2 m² or more: 7.5 mg (Afinitor) P.O. daily

Adults and children age 3 and older with BSA of 1.3 to 2.1 m²: 5 mg (Afinitor) P.O. daily

Adults and children age 3 and older with BSA of 0.5 to 1.2 m²: 2.5 mg (Afinitor) P.O. daily

➣ Prophylaxis of organ rejection in kidney transplant patients at low-to-moderate immunologic risk

Adults: Initially, 0.75 mg (Zortress) P.O. b.i.d. in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and corticosteroids. Adjust maintenance dosage to achieve Zortress trough concentration within 3- to 8-ng/ml target range at 4- to 5-day intervals. Start doses as soon as possible after transplant.

Dosage adjustment

• Moderate hepatic impairment (Zortress)

• Mild, moderate, or severe hepatic impairment; change in hepatic status during therapy (Afinitor)

• Patients with SEGA who have severe hepatic impairment (Afinitor not recommended)

• Concurrent use of CYP3A4 inducers or inhibitors (Afinitor, Zortress)

• Concurrent use of moderate inhibitors of CYP3A4 or p-glycoprotein (PgP) (Afinitor)

• Strong CYP3A4 inducers (Afinitor)

• When switching cyclosporine formulations or when cyclosporine dosage is reduced according to recommended target concentrations (Zortress)

• Possible dosage adjustment based on everolimus blood concentrations achieved, tolerability, individual response, and change in concomitant medications (Afinitor, Zortress)

Contraindications

• Hypersensitivity to drug, other rapamycin derivatives, or any of its components

Precautions

Afinitor

Use cautiously in:

• moderate hepatic impairment, renal failure

• severe hepatic impairment (use not recommended)

• noninfectious pneumonitis, infection, oral ulceration

• concurrent use of strong CYP3A4 inhibitors or inducers (avoid use)

• concurrent use of moderate CYP3A4 or PgP inhibitors

• concurrent use of live vaccines, close contact with those who have received live vaccines (avoid use)

• grapefruit, grapefruit juice, other foods known to inhibit CYP450 and PgP activity, St. John's wort

• pregnant or breastfeeding patients

• children with SEGA younger than age 3 or with BSA less than 0.58 m² (safety and efficacy not established).

Zortress

Use cautiously in:

• moderate hepatic impairment, renal dysfunction

• noninfectious pneumonitis, infection, oral ulceration

• lymphoma, other malignancies

• rare hereditary problems of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption (avoid use)

• wound healing, fluid accumulation, hyperlipidemia, proteinuria, polyoma virus infections, noninfectious pneumonitis, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, new-onset diabetes, male infertility

• prolonged exposure to ultraviolet light and sunlight (avoid use)

• concurrent use of CYP3A4 and CYP2D6 substrates with narrow therapeutic index

• concurrent use of strong CYP3A4 inducer rifampin (not recommended)

• concurrent use of ACE inhibitors

• concurrent use of standard doses of cyclosporine (avoid use)

• concurrent use of HMG-CoA reductase inhibitors (such as simvastatin, lovastatin) in transplant patients receiving cyclosporine

• concurrent use of live vaccines, close contact with those who have received live vaccines (avoid use)

• pregnant or breastfeeding patients

• children younger than age 18 (safety and efficacy not established).

Administration

• Administer tablets whole with a glass of water and food (not grapefruit juice or grapefruit products) or give consistently without food.

• Administer Zortress consistently approximately 12 hours apart to minimize variability in absorption and at same time as cyclosporine.

• For patient unable to swallow Afinitor tablets: Immediately before administering, disperse tablets completely in a glass of water (containing approximately 30 ml) by gently stirring. Rinse glass with same volume of water and have patient completely swallow rinse to ensure entire dose is administered.

• Before starting Afinitor, obtain CBC, renal function tests (including BUN, serum creatinine, or urinary protein), and fasting serum glucose and lipid profile (when possible ensure optimal glucose and lipid control).

See Discontinue Afinitor therapy in patients with signs and symptoms of severe noninfectious pneumonitis.

See Before starting Afinitor, complete treatment of preexisting invasive fungal infections. During treatment, be vigilant for signs and symptoms of infection. If diagnosis of infection is made, institute appropriate treatment promptly and consider interrupting or discontinuing therapy. If diagnosis of invasive systemic fungal infection is made, discontinue drug and treat with appropriate antifungal therapy.

• Be aware that Afinitor isn't recommended for use in patients with SEGA who have severe hepatic impairment.

• Be aware that patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption shouldn't take Zortress as this may result in diarrhea and malabsorption of drug.

Adverse reactions

Afinitor

CNS: headache, migraine headache, fatigue, malaise, asthenia, dizziness, insomnia, paresthesia, personality change, somnolence, anxiety, seizures

CV: hypertension, tachycardia, deep vein thrombosis, cardiac arrest, congestive heart failure

EENT: eyelid edema, conjunctivitis, ocular hyperemia, otitis media, otitis externa, nasopharyngitis, rhinitis, allergic rhinitis, epistaxis, sinusitis, oropharyngeal pain, pharyngolaryngeal pain, rhinorrhea, pharyngitis, pharyngeal inflammation, nasal congestion

GI: nausea, vomiting, diarrhea, abdominal pain, stomatitis, oral ulcers, constipation, dry mouth, anorexia, hemorrhoids, dysphagia, gastroenteritis, gastric infection, gastritis

GU: urinary tract infection, proteinuria, nephrotoxicity, acute renal failure

Hematologic: anemia, decreased hemoglobin, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia, hemorrhage

Hepatic: hepatic failure

Metabolic: hyperglycemia, increased ALP, hypercholesterolemia, decreased bicarbonate, hypophosphatemia, increased AST and ALT, hypertriglyceridemia, hypocalcemia, hypokalemia, hyperkalemia, hyponatremia, increased serum creatinine, decreased albumin, increased bilirubin, new-onset exacerbation of preexisting diabetes mellitus

Musculoskeletal: arthralgia, back pain, extremity pain, muscle spasms, jaw pain

Respiratory: cough, upper respiratory tract infection, dyspnea, exertional dyspnea, pneumonia, noninfectious pneumonitis, acute respiratory distress, pulmonary embolus, respiratory failure, pleural effusion

Skin: rash, nail disorders, pruritus, dry skin, impaired wound healing, erythema, skin lesion, acneiform dermatitis, cellulitis, tinea, skin infection, contact dermatitis, acne, excoriation, pityriasis rosea

Other: mucosal inflammation, edema, peripheral edema, fluid accumulation, dehydration, fever, infections, weight loss, decreased appetite, dysgeusia, chest pain, chills, abnormal chest Xray, palmar-plantar erythrodysesthesia syndrome, sepsis, death (cause unknown), hypersensitivity reactions (including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, angioedema)

Zortress

CNS: fatigue, headache, tremor, insomnia

CV: hypertension

GI: nausea, vomiting, constipation, diarrhea, abdominal pain, dyspepsia

GU: urinary tract infection, proteinuria, male infertility, hematuria, dysuria

Hematologic: anemia, leukopenia, graft thrombosis, thrombotic microangiopathy, TTP, hemolytic uremic syndrome

Hepatic: increased hepatic enzymes and bilirubin

Metabolic: hyperlipidemia, increased serum creatinine, new-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperkalemia, hypokalemia, hypercholesterolemia, dyslipidemia, hypomagnesemia, hypophosphatemia, hyperglycemia

Musculoskeletal: back pain, extremity pain

Respiratory: cough, upper respiratory tract infection, noninfectious pneumonitis

Skin: impaired wound healing

Other: peripheral edema, incision and procedural pain, fluid accumulation, fever, serious infections, polyoma virus infections, lymphomas and other malignancies, angioedema, hypersensitivity

Interactions

Afinitor

Drug-drug. Depot octreotide: increased octreotide C_min

Moderate CYP3A4 and PgP inhibitors (such as amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil): significantly increased everolimus exposure

Strong CYP3A4 inducers (such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine): decreased everolimus exposure

Strong CYP3A4 inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): significantly increased everolimus exposure

Drug-diagnostic tests. ALP, ALT, AST, blood glucose, cholesterol, serum bilirubin, serum creatinine, lipids, triglycerides, urine proteins: increased levels

Bicarbonates, calcium, hemoglobin, platelets, serum albumin, serum phosphorus, sodium, WBCs: decreased levels

Potassium: decreased or increased level

Drug-food. Grapefruit, grapefruit juice, other foods known to inhibit CYP450 and PgP: increased everolimus exposure

Drug-herbs. St. John's wort: decreased everolimus exposure

Zortress

Drug-drug. CYP3A substrates (such as cyclosporine) and CYP2D6 substrates with narrow therapeutic indices: potentially increased concentrations of these drugs

CYP3A4 and PgP substrates (verapamil): significantly increased everolimus C_max and area under the curve

Moderate CYP3A4 and PgP inhibitors (such as amprenavir, diltiazem, fluconazole, indinavir, macrolide antibiotics, nicardipine): increased everolimus blood concentration

PgP inhibitors (such as cyclosporine, digoxin): increased everolimus blood concentration

Strong CYP3A4 inducers (such as carbamazepine, efavirenz, nevirapine, phenobarbital, phenytoin, rifampin): decreased everolimus exposure

Strong CYP3A4 inhibitors (such as clarithromycin, itraconazole, ketoconazole, ritonavir, telithromycin, voriconazole): significantly increased everolimus exposure

Drug-diagnostic tests. Blood glucose, cholesterol, lipids, magnesium, hepatic enzymes, serum bilirubin, serum creatinine, serum phosphorus: increased levels

Hemoglobin, platelets: decreased levels

Potassium: decreased or increased level

Drug-food. Grapefruit, grapefruit juice: increased everolimus exposure

Drug-herbs. St. John's wort: decreased everolimus exposure

Patient monitoring

• Closely monitor CBC with differential.

See Monitor renal function, including BUN, urinary protein, and serum creatinine, closely.

• Closely monitor drug blood concentration in patients with hepatic impairment; during concomitant administration of CYP3A4 inducers/inhibitors, or PgP substrates; when switching cyclosporine formulations; and when cyclosporine dosage is reduced according to recommended target concentrations.

• Watch for increases in serum cholesterol, triglyceride, and blood glucose levels.

See Closely monitor patients for hypersensitivity reactions, serious infections, respiratory or cardiac signs and symptoms, signs or symptoms of bleeding or thrombosis, seizures, and palmar-plantar erythrodysesthesia.

• Be aware that patients are at increased risk for delayed wound healing and fluid accumulation; particularly monitor incision sites to minimize complications.

Patient teaching

• Tell patient to take drug at same time each day with a whole glass of water, either consistently with food or without food.

• For patient taking Afinitor: Instruct patient to swallow tablets whole and not to chew or crush them. Tell patient unable to swallow tablets to disperse drug completely (by gently stirring) in a glass of water (containing approximately 1 ounce) immediately before drinking, then rinse with same volume of water and completely swallow rinse to ensure entire dose is taken.

• Tell patient to avoid grapefruit juice and grapefruit products during therapy.

• Inform patient of the need to monitor blood chemistry and hematologic values before starting therapy and periodically thereafter.

See Instruct patient to immediately seek medical attention for difficulty breathing or new or worsening respiratory signs or symptoms, flushing, chest pain, swelling of airway or tongue, fever or other signs or symptoms of infection, urinary problems, or bleeding.

• For patient taking Afinitor: Instruct patient to report signs and symptoms of palmar-plantar erythrodysesthesia (such as redness, swelling, tenderness, or tingling of palms of hands or soles of feet).

See For patient taking Zortress: Inform patient of increased risk of developing lymphomas and other malignancies, particularly of the skin. Tell patient to avoid prolonged exposure to ultraviolet light and sunlight during therapy.

See For patient taking Zortress: Inform patient of risk of a clot in the blood vessels of the transplanted kidney and to immediately seek medical attention if pain in the groin, lower back, side, or abdomen; change in urination; blood in urine or dark-colored urine; fever; nausea; or vomiting occurs.

• Advise patient to manage oral ulcerations with mouthwashes (without alcohol or peroxide) and topical treatments, as prescribed.

• Instruct patient to tell prescriber about all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with everolimus.

• Tell patient to avoid live vaccines and close contact with those who have received live vaccines during therapy.

• Advise patient to avoid use of St. John's wort during therapy.

• For patient taking Zortress: Advise female patient of childbearing age that drug may cause fetal harm and to use an effective method of contraception during therapy and for 8 weeks after treatment ends.

• For patient taking Afinitor: Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of the drug for her treatment.

• For patient taking Zortress: Advise female patient of childbearing age to avoid breastfeeding during therapy.

• For patient taking Zortress: Inform male patient of potential risk of infertility with therapy.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.