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everolimus (Rx)Brand and Other Names:Afinitor, Zortress, more...Afinitor Disperz

 
 
 

Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet (Afinitor)

  • 2.5mg
  • 5mg
  • 7.5mg
  • 10mg

tablet for oral suspension (Afintior Disperz)

  • 2mg
  • 3mg
  • 5mg

tablet (Zortress)

  • 0.25mg
  • 0.5mg
  • 0.75mg
more...

Breast Cancer

Afinitor: 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 consistently with or without food (also see dosage modifications)

Renal Cell Carcinoma

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

10 mg PO qDay consistently with or without food (also see dosage modifications)

Renal Angiomyolipomas with TSC

Afinitor: 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 consistently with or without food (also see dosage modifications)

Advanced Neuroendocrine Tumors

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 consistently with or without food (also see dosage modifications)

Dosage Modifications (Breast Cancer, PNET, RCC, Renal Angiomyolipoma)

Concomitant strong CYP3A4 inducers: May increase dose by 5-mg increments; not to exceed 20 mg/day

Avoid strong CYP3A4 inhibitors

If moderate CYP3A4 and/or PgP inhibitors required: Decrease dose to 2.5 mg/day; if tolerated, may increase up to 5 mg/day

Treatment interruption, discontinuation, and/or dose reduction to 5 mg/day may be required to manage adverse drug effects (see manufacturer’s prescribing information)

Hepatic impairment

  • Mild (Child-Pugh class A): Decrease dose to 7.5 mg qDay; dose may be decreased further to 5 mg qDay if not well tolerated
  • Moderate (Child-Pugh class B): Decrease dose to 5 mg qDay; dose may be decreased further to 2.5 mg qDay if not well tolerated
  • Severe hepatic impairment (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

Subependymal Giant Cell Astrocytoma with TSC

Afinitor and Afinitor Disperz: Indicated for SEGA associated with tuberous sclerosis complex that cannot be treated with surgery

Do not combine Afinitor tablets with Afinitor Disperz to achieve desired total dose

Initial: 4.5 mg/m² PO qDay

Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5-15 ng/mL

Dosage modifications (SEGA)

  • Avoid strong CYP3A4 inducers if other therapy is available
  • If coadministration with strong CYP3A4 inducer required, double initial dose; base subsequent doses on serum concentration; readjust dose if strong CYP3A4 inducer is discontinued
  • Avoid strong CYP3A4 inhibitors
  • Coadministration with moderate CYP3A4 and/or PgP inhibitors: Reduce dose by 50%; administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL
  • Severe hepatic impairment (Child-Pugh class C): Reduce dose by 50%; base subsequent doses on serum concentrations
  • Mild-to-moderate hepatic impairment: Adjustment to the recommended starting dose may not be needed; however, subsequent dosing should be based on therapeutic drug monitoring
  • Reduce dose or withhold for severe or intolerable adverse reactions; reduce dose by ~50%; if dose reduction required while receiving lowest available strength, administer every other day

Therapeutic drug monitoring (SEGA)

  • Monitor whole blood trough concentrations
  • Assess trough concentrations approximately 2 weeks after commencing treatment, a change in dose, a change in coadministration of CYP3A4 and/or PGP inducers or inhibitors, changes in hepatic function, or a change in dosage form between tablets and tablets for oral suspension
  • Once a stable dose is attained, monitor trough concentrations every 3-6 months in patients with changing body surface area or every 6-12 months in patients with stable body surface area for the duration of treatment
  • Titrate dose to attain trough concentration between 5-15 ng/mL
  • -Trough concentrations <5 ng/mL: Increase daily dose by 2.5 mg (Afinitor) or 2 mg (Afinitor Disperz)
  • -Trough Concentrations >15 ng/mL: Reduce daily dose by 2.5 mg (Afinitor) or 2 mg (Afinitor Disperz)
  • -If dose reduction required for patients receiving the lowest available strength, administer every other day

Dosage considerations (SEGA)

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

Kidney Transplant Rejection (Zortress)

Zortress: 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

Moderate hepatic impairment: Reduce daily dose by 50% and monitor blood concentrations

Administer as soon as possible after kidney transplantation

Liver Transplant Rejection (Zortress)

Zortress: 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)

Therapeutic Drug Monitoring (Zortress)

Optimally, dose adjustments should be based on trough concentrations obtained 4 or 5 days after a previous dosing change

Trough concentration <3 ng/mL: Double total dialy dose using the available tablet strenghts (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

Orphan Indications (Orphan)

Diffuse large B-cell lymphoma

Gastric cancer

Waldenstrom macroglobulinemia (also known as lymphoplasmacytic lymphoma)

Orphan indication 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

Renal Impairment

No clinical studies were conducted in patients with decreased renal function

Renal impairment is not expected to result in dosage adjustment

Dosage Forms & Strengths

tablet (Afinitor)

  • 2.5mg
  • 5mg
  • 7.5mg
  • 10mg

tablet for oral suspension (Afintior Disperz)

  • 2mg
  • 3mg
  • 5mg
more...

Subependymal Giant Cell Astrocytoma

Afinitor and Afinitor Disperz: Indicated for SEGA associated with tuberous sclerosis that cannot be treated with surgery

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

Dosage modifications (SEGA)

  • Avoid strong CYP3A4 inducers if other therapy is available
  • If coadministration with strong CYP3A4 inducer required, double initial dose to 9 mg/m² initially; base subsequent doses on serum concentration; adjust dose if strong CYP3A4 inducer is discontinued
  • Avoid strong CYP3A4 inhibitors
  • Coadministration with moderate CYP3A4 and/or PgP inhibitors: 2.5 mg/m² initially; base subsequent doses on serum concentration
  • Severe hepatic impairment (Child-Pugh class C): 2.5 mg/m² initially; base subsequent doses on serum concentration
  • Mild-to-moderate hepatic impairment: Adjustment to the recommended starting dose may not be needed; however, subsequent dosing should be based on therapeutic drug monitoring
  • Reduce dose or withhold for severe or intolerable adverse reactions; reduce dose by ~50%; if dose reduction required while receiving lowest available strength, administer every other day

Therapeutic drug monitoring (SEGA)

  • Monitor whole blood trough concentrations
  • Assess trough concentrations approximately 2 weeks after commencing treatment, a change in dose, a change in coadministration of CYP3A4 and/or PGP inducers or inhibitors, changes in hepatic function, or a change in dosage form between tablets and tablets for oral suspension
  • Once a stable dose is attained, monitor trough concentrations every 3-6 months in patients with changing body surface area or every 6-12 months in patients with stable body surface area for the duration of treatment
  • Titrate dose to attain trough concentration between 5-15 ng/mL
  • -Trough concentrations <5 ng/mL: Increase daily dose by 2.5 mg (Afinitor) or 2 mg (Afinitor Disperz)
  • -Trough Concentrations >15 ng/mL: Reduce daily dose by 2.5 mg (Afinitor) or 2 mg (Afinitor Disperz)
  • -If dose reduction required for patients receiving the lowest available strength, administer every other day

Dosage considerations (SEGA)

  • 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

everolimus and

No Results

     
     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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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 (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

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            Warnings

            Black Box Warnings

            Black box warnings for Zortress

            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

            Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema

            Interstitial lung disease/noninfectious pneumonitis; monitor for clinical symptoms or radiological changes; fatal cases have occurred; manage by dose reduction or discontinuation until symptoms resolve, and consider use of corticosteroids; pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event reported

            Elicits immunosuppressive effects and may increase risk for infections; some infections have been severe or fatal; 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

            Mouth ulcers, stomatitis, and oral mucositis are common; management includes mouthwashes (without alcohol or peroxide) and topical treatments

            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

            May cause angioedema and fluid accumulation

            Decreases Hgb, lymphocytes, ANC, platelets; increases cholesterol, TG, glucose, creatinine

            Child-Pugh Class C hepatic impairment

            Avoid use of live vaccines during treatment and close contact with live vaccine recipients

            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

            Can cause fetal harm; advise females of reproductive potential of potential risk to fetus and to use effective contraception during therapy and for 8 weeks after final dose

            Elevations of serum creatinine, urinary protein, blood glucose, and lipids may occur; decreases in hemoglobin, neutrophils, and platelets may also occur; monitor renal function, blood glucose, lipids, and hematologic parameters prior to treatment and periodically thereafter

            May impair male fertility

            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)

            Increased risk of acute organ rejection reported with complete elimination of calcineurin inhibition

            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

            Limit patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor

            May increase risk of new onset diabetes mellitus after transplant; blood glucose concentrations should be monitored closely

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            Pregnancy & Lactation

            Pregnancy Category: D; Can cause fetal harm when administered to a pregnant woman; advise female patients of reproductive potential to use highly effective contraception while receiving everolimus and for up to 8 weeks after ending treatment

            Male infertility: Based on animal studies, may impair male fertility

            Lactation: distribution into breast milk unknown; not recommended

            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.

            more...
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            Pharmacology

            Mechanism of Action

            Afintior: mTOR kinase inhibitor (mammalian target of rapamycin, a serine-threonine kinase, downstream of the PI3K/AKT pathway, which is dysregulated in several human cancers); binds to intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) which inhibits mTOR kinase activity; reduces activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP1); inhibits expression of hypoxia-inducible factor (eg, HIF-1) and reduces expression of vascular endothelial growth factor (VEGF); inhibits of mTOR reduces cell proliferation, angiogenesis, and glucose uptake; constitutive activation of PI3K/Akt/mTOR pathway contributes to endocrine resistance in breast cancer; in vitro studies show sensitivity of estrogen-dependent and HER2+ breast cancer cells to therapy and combination treatment enhances anti-tumor activity of everolimus in a synergistic manner

            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

            Distribution

            Protein Bound: 74%

            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

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            Administration

            Afinitor tablets

            Swallow whole, do not break or crush tablets

            Administer consistently with food or consistently without food

            Afinitor Disperz

            Administer Afinitor Disperz as a PO suspension only

            Administer Afinitor Disperz PO qDay at the same time every day

            Administer consistently with food or consistently without food

            Administer suspension immediately after preparation; discard suspension if not administered within 60 minutes after preparation

            Prepare suspension in water only

            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
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            Images

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            Formulary

            FormularyPatient Discounts

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            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.
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            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.
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