Dosing & Uses
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/m²: 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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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
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)
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.
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
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
Images
Patient Handout
Formulary
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