everolimus (Rx)

Brand and Other Names:Afinitor, Zortress, more...Afinitor Disperz
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet (Afinitor)

  • 2.5mg
  • 5mg
  • 7.5mg
  • 10mg

tablet for oral suspension (Afinitor Disperz)

  • 2mg
  • 3mg
  • 5mg

tablet (Zortress)

  • 0.25mg
  • 0.5mg
  • 0.75mg

Breast Cancer

Afinitor only

Indicated in postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole

10 mg PO qDay with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Renal Cell Carcinoma

Afinitor only

Indicated for advanced renal cell carcinoma (RCC) after failure with sunitinib or sorafenib

10 mg PO qDay with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Advanced Neuroendocrine Tumors

Afinitor only

Indicated for progressive neuroendocrine tumors (PNET) located in the pancreas that are not surgically resectable or are metastatic; also indicated for well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung

10 mg PO qDay with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Renal Angiomyolipoma

Afinitor only

Indicated for the treatment of noncancerous kidney tumors (renal angiomyolipomas) with tuberous sclerosis complex (TSC) in patients not requiring immediate surgery

10 mg PO qDay with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Subependymal Giant Cell Astrocytoma

Afinitor and Afinitor Disperz

Indicated in patients with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected

Initial dose: 4.5 mg/m² PO qDay with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Partial Onset Seizures

Afinitor Disperz only

Indicated for the adjunctive treatment of patients with TSC-associated partial onset seizures

Initial dose: 5 mg/m² PO qDay consistently with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Kidney Transplant Rejection

Zortress only

Indicated for prophylaxis of organ rejection in patients with low-moderate immunologic risk

Use in combination with reduced doses of cyclosporine, as well as basiliximab and corticosteroids

Starting dose: 0.75 mg PO q12hr initially; adjust maintenance dose to achieve trough whole blood concentrations of 3-8 ng/mL target range

Initiate oral prednisone once oral medication is tolerated; further taper steroid doses on an individualized basis depending on the clinical status of patient and function of graft

Administer as soon as possible after kidney transplantation

Liver Transplant Rejection

Zortress only

Indicated for prophylaxis of allograft rejection in adult liver transplant recipients in combination with reduced doses of tacrolimus and with corticosteroids

Starting dose (30 days posttransplant): 1 mg PO q12hr initially; adjust maintenance dose to achieve trough whole blood concentrations of 3-5 ng/mL by 3 weeks after first dose of everolimus and through 12 months

Do not administer until at least 30 days post liver transplant (earlier administration associated with hepatic artery thrombosis, graft loss, and death)

Dosage Modifications

Coadministration of P-gp and CYP3A4 inhibitors

  • Avoid concomitant use of P-gp and strong CYP3A4 inhibitors
  • Avoid grapefruit and grapefruit juice
  • Breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma
    • Reduce dose to 2.5 mg qDay; may increase dose to 5 mg qDay if tolerated
    • Resume dose administered prior to inhibitor initiation, once inhibitor is discontinued for 3 days
  • TSC-associated SEGA and partial-onset seizures
    • Reduce daily dose by 50%; change to every other day dosing if reduced dose is lower than the lowest available strength
    • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days
    • Assess trough concentrations when initiating and discontinuing inhibitor

Coadministration of P-gp and CYP3A4 inducers

  • Avoid concomitant use of St John’s Wort
  • Breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma
    • Avoid coadministration when alternatives are available; if coadministration cannot be avoided, double daily dose ≤5 mg increments; multiple increments may be required
    • Resume dose administered prior to inducer initiation, once an inducer is discontinued for 5 days
  • TSC-associated SEGA and partial-onset seizures
    • Double daily dose ≤5 mg increments; multiple increments may be required
    • Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification
    • Assess trough concentrations when initiating and discontinuing inducer
    • Resume dose administered before starting any inducer, once all inducers are discontinued for 5 days

Noninfectious pneumonitis

  • Grade 1: No dose adjustment required; initiate appropriate monitoring
  • Grade 2: Withhold treatment until symptoms resolve to Grade ≤1; resume at 50% of previous dose; permanently discontinue treatment if toxicity does not resolve or improve to Grade 1 within 4 weeks
  • Grade 3: Withhold treatment until symptoms resolve to Grade ≤1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength; if toxicity recurs at Grade 3, permanently discontinue
  • Grade 4: Permanently discontinue

Stomatitis

  • Manage with topical analgesic mouth treatments (eg, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (eg, triamcinolone oral paste)
  • Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis which may worsen mouth ulcers
  • Grade 1: No dosage adjustment required; manage with nonalcoholic or salt water (0.9%) mouthwash several times a day
  • Grade 2: Withhold until improvement to ≤Grade 1; resume at same dose; if recurs at Grade 2, withhold until improvement to ≤Grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
  • Grade 3: Withhold until improvement to ≤Grade 1; resume at same dose; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
  • Grade 4: Permanently discontinue

Other nonhematologic toxicities

  • Grade 1: No dosage adjustment required
  • Grade 2
    • If toxicity is intolerable, withhold until improvement to Grade ≤1; resume at same dose
    • If toxicity recurs at Grade 2, withhold until improvement to Grade ≤1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
  • Grade 3
    • Withhold until improvement to ≤Grade 1; resume at same dose; consider resuming at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
    • If recurs at Grade 3, permanently discontinueGrade 4: Permanently discontinue
  • Grade 4: Permanently discontinue

Metabolic events (eg, hyperglycemia, dyslipidemia)

  • Grade 1 or 2: No dosage adjustment required
  • Grade 3: Withhold until improvement to ≤Grade 2; resume at same dose; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
  • Grade 4: Discontinue treatment

Thrombocytopenia

  • Grade 1 (<75,000/mm³): No dosage adjustment required
  • Grade 2 (50,000-75,000/mm³): Interrupt dose until recovery at Grade ≤1; reinitiate treatment at same dose
  • Grade 3 or 4 (<50,000/mm³): Interrupt dose until recovery at Grade ≤1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength

Neutropenia

  • Grade 1 or 2 (1,000-1,500/mm³): No dosage adjustment required
  • Grade 3 (500-1,000/mm³): Interrupt dose until recovery at Grade ≤2; reinitiate treatment at same dose
  • Grade 4 (<500/mm³): Interrupt dose until recovery at Grade ≤2; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength

Febrile neutropenia

  • Grade 3 (ANC <1,000/mm³ single temperature >38.3ºC (101ºF) or a sustained temperature of ≥38ºC (100.4ºF) for >1hr): Interrupt dose until recovery at Grade ≤2 and no fever; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than the lowest available strength
  • Grade 4 (Life-threatening consequences): Permanently discontinue

Therapeutic drug monitoring and dose titration

  • Titrate dose to attain trough concentrations of 5-15 ng/mL
  • Monitor everolimus whole blood trough concentrations
  • Adjust dose using the following equation: new dose = current dose x (target concentration divided by current concentration); not exceed increments of 5 mg/dose
  • Recommended timing of drug monitoring
    • Initiation, modification, and switch between Afinitor and Afinitor Disperz: 1-2 weeks
    • Initiation or discontinuation of P-gp and moderate CYP3A inhibitor, P-gp and strong CYP3A inducer, hepatic function changes: 2 weeks
    • Stable dose with change body surface area (BSA): Every 3-6 months
    • Stable dose with stable BSA: Every 6-12 months

Renal impairment

  • No clinical studies were conducted in patients with decreased renal function

Hepatic impairment (Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma)

  • Mild (Child Pugh class A): Decrease dose to 7.5 mg qDay; may further decreased to 5 mg qDay if not well tolerated
  • Moderate (Child Pugh class B): Decrease dose to 5 mg qDay; may further decreased to 2.5 mg qDay if not well tolerated
  • Severe (Child Pugh class C): Decrease dose to 2.5 mg qDay; administer only if desired benefit outweighs risk; not to exceed 2.5 mg qDay
  • Adjust dose if status changes during treatment

Hepatic impairment (TSC-associated SEGA and partial-onset seizures)

  • Mild-to-moderate (Child Pugh class A or B): No dosage adjustment necessary
  • Severe (Child Pugh class C): 2.5 mg/m&sup2: PO qDay

Hepatic impairment (Zortress)

  • Mild (Child Pugh class A): Reduce initial daily dose by ~1/3 of the recommended daily dose
  • Moderate-to-severe (Child Pugh class B or C): Reduce initial daily dose by ~1/2 of the recommended daily dose
  • Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus is not within the target trough concentration range of 3-8 ng/mL

Therapeutic drug monitoring and dosage modifications (Zortress)

  • Optimally, dose adjustments should be based on trough concentrations obtained 4 or 5 days after a previous dosing change
  • Recommended therapeutic range of 3- 8 ng/mL is based on an LC/MS/MS assay method; currently in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies
  • Trough concentration <3 ng/mL: Double total daily dose using the available tablet strengths (ie, 0.25 mg, 0.5 mg, 0.75 mg)
  • Trough concentration >8 ng/mL on 2 consecutive measurement: Decrease dose by 0.25 mg BID

Dosing Considerations

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

Zortress only

  • Limitations of use
    • Safety and efficacy has not been established in kidney transplant patients at high immunologic risk and recipients of transplanted organs other than kidney or liver

Orphan Designations

Diffuse large B-cell lymphoma

Gastric cancer

Waldenstrom macroglobulinemia (also known as lymphoplasmacytic lymphoma)

Sponsor

  • Novartis Pharmaceuticals Corporation; One Health Plaza; East Hanover, NJ 07936-1080

Tuberous Sclerosis Topical Treatment (Orphan)

Everolimus ointment

Orphan designation for topical treatment of tuberous sclerosis

Sponsor

  • Aucta Pharmaceuticals, LLC; 675 US Highway One; North Brunswick, New Jersey 08902

Dosage Forms & Strengths

tablet (Afinitor)

  • 2.5mg
  • 5mg
  • 7.5mg
  • 10mg

tablet for oral suspension (Afinitor Disperz)

  • 2mg
  • 3mg
  • 5mg

Subependymal Giant Cell Astrocytoma

Afinitor and Afinitor Disperz

Indicated in pediatric patients (≥1 year) with tuberous sclerosis complex TSC for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected

<1 year: Safety and efficacy not established

≥1 year

  • Initial dose based on body surface area with subsequent titration to attain trough concentrations of 5-15 ng/mL
  • 4.5 mg/m² PO qDay with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Partial-Onset Seizures

Afinitor Disperz only

Indicated for the adjunctive treatment of pediatric patients (≥2 years) with TSC-associated partial-onset seizures

<2 years: Safety and efficacy not established

≥2 years

  • Initial dose: 5 mg/m² PO qDay with or without food; continue until disease progression or unacceptable toxicity (see Dosage Modifications)

Dosage Modifications

Coadministration of P-gp and CYP3A4 inhibitors

  • Avoid concomitant use of P-gp and strong CYP3A4 inhibitors
  • Avoid grapefruit and grapefruit juice
  • TSC-associated SEGA and partial-onset seizures
    • Reduce daily dose by 50%; change to every other day dosing if reduced dose is lower than the lowest available strength
    • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days
    • Assess trough concentrations when initiating and discontinuing inhibitor

Coadministration of P-gp and CYP3A4 inducers

  • Avoid concomitant use of St John’s Wort
  • TSC-associated SEGA and partial-onset seizures
    • Double daily dose ≤5 mg increments; multiple increments may be required
    • Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification
    • Assess trough concentrations when initiating and discontinuing inducer
    • Resume dose administered before starting any inducer, once all inducers are discontinued for 5 days

Therapeutic drug monitoring and dose titration

  • Titrate dose to attain trough concentrations of 5-15 ng/mL
  • Monitor everolimus whole blood trough concentrations
  • Adjust dose using the following equation: new dose = current dose x (target concentration divided by current concentration); not exceed increments of 5 mg/dose
  • Recommended timing of drug monitoring
    • Initiation, modification, and switch between Afinitor and Afinitor Disperz: 1-2 weeks
    • Initiation or discontinuation of P-gp and moderate CYP3A inhibitor, P-gp and strong CYP3A inducer, hepatic function changes: 2 weeks
    • Stable dose with change body surface area (BSA): Every 3-6 months
    • Stable dose with stable BSA: Every 6-12 months

Dosing Considerations

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

In a randomized advanced hormone receptor positive, HER2-negative breast cancer study, no overall differences in safety or effectiveness were observed between these elderly patients and younger patients during clinical trials

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Interactions

Interaction Checker

and everolimus

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      Serious - Use Alternative

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            Adverse Effects

            >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

            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

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            Warnings

            Black Box Warnings

            Zortress only

            Malignancies and serious infections

            • Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress Patients should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources
            • Increased susceptibility to infection and possible development of malignancies (eg, lymphoma, skin cancer) may result from immunosuppression

            Renal function

            • Coadministration with standard doses of cyclosporine may increase nephrotoxicity; reduced cyclosporine dose
            • Monitor cyclosporine and everolimus whole blood trough concentrations

            Kidney graft thrombosis

            • Increased risk of kidney arterial and venous thrombosis resulting in graft loss, typically within the first 30 days post-transplantation

            Heart transplantation

            • Increased mortality, often associated with serious infections, reported within the first 3 months post-transplantation
            • Not recommended for use in heart transplantation

            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

            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)

            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)
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            Pregnancy & Lactation

            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.

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            Pharmacology

            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

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            Administration

            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

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
            Additional Offers
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.