Dosing and uses of Afinitor, Zortress (everolimus)
Adult dosage forms and 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
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
Pediatric dosage forms and strengths
tablet (Afinitor)
- 2.5mg
- 5mg
- 7.5mg
- 10mg
tablet for oral suspension (Afintior Disperz)
- 2mg
- 3mg
- 5mg
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
Geriatric dosage forms and strengths
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
Afinitor, Zortress (everolimus) adverse (side) 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
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
Pregnancy and 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.
Pharmacology of Afinitor, Zortress (everolimus)
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
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
