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
Contraindicated (0)
Serious - Use Alternative (162)
- abametapir
abametapir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.
- adalimumab
adalimumab and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- alefacept
alefacept and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- amiodarone
amiodarone will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
- amobarbital
amobarbital will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- anakinra
anakinra and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- anthrax vaccine
everolimus decreases effects of anthrax vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- antithymocyte globulin equine
antithymocyte globulin equine and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- antithymocyte globulin rabbit
antithymocyte globulin rabbit and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- apalutamide
apalutamide will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.
- aprepitant
aprepitant will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- armodafinil
armodafinil will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- artemether/lumefantrine
artemether/lumefantrine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- atazanavir
atazanavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- atorvastatin
atorvastatin will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
- azathioprine
azathioprine and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- basiliximab
basiliximab and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- BCG vaccine live
everolimus decreases effects of BCG vaccine live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- bosentan
bosentan will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- bremelanotide
bremelanotide will decrease the level or effect of everolimus by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.
- brigatinib
brigatinib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Brigatinib induces CYP3A4 in vitro. Coadministration with CYP3A4 substrates, particularly those with a narrow therapeutic index, can result in decreased concentrations and loss of efficacy. If unable to avoid coadministration, monitor CYP3A4 substrate levels and adjust dose as needed.
- budesonide
budesonide will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- butabarbital
butabarbital will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- butalbital
butalbital will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- canakinumab
canakinumab and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- carbamazepine
carbamazepine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- chloramphenicol
chloramphenicol will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- cimetidine
cimetidine will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- clarithromycin
clarithromycin will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
clarithromycin will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - clotrimazole
clotrimazole will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
- cobicistat
cobicistat will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- conivaptan
conivaptan will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- cortisone
cortisone will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- darifenacin
darifenacin will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- darunavir
darunavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- dasatinib
dasatinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- deferiprone
deferiprone, everolimus. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; if an alternative is not possible, monitor absolute neutrophil count more frequently.
- dexamethasone
dexamethasone will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- DHEA, herbal
DHEA, herbal will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- diphtheria & tetanus toxoids
everolimus decreases effects of diphtheria & tetanus toxoids by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- diphtheria & tetanus toxoids/ acellular pertussis vaccine
everolimus decreases effects of diphtheria & tetanus toxoids/ acellular pertussis vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine
everolimus decreases effects of diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- dronedarone
dronedarone will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
dronedarone will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - efavirenz
efavirenz will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- enzalutamide
enzalutamide will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- erdafitinib
erdafitinib will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index.
- erythromycin base
erythromycin base will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
erythromycin base will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - erythromycin ethylsuccinate
erythromycin ethylsuccinate will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
erythromycin ethylsuccinate will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - erythromycin lactobionate
erythromycin lactobionate will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
erythromycin lactobionate will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - erythromycin stearate
erythromycin stearate will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
erythromycin stearate will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - eslicarbazepine acetate
eslicarbazepine acetate will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- etanercept
etanercept and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- etravirine
etravirine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- felodipine
felodipine will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
- fexinidazole
fexinidazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.
- fluconazole
fluconazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- fluvoxamine
fluvoxamine will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- fosamprenavir
fosamprenavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- fosphenytoin
fosphenytoin will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
fosphenytoin will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - glatiramer
everolimus and glatiramer both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- golimumab
everolimus and golimumab both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- grapefruit
grapefruit will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- griseofulvin
griseofulvin will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- hepatitis A vaccine inactivated
everolimus decreases effects of hepatitis A vaccine inactivated by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- hepatitis a/b vaccine
everolimus decreases effects of hepatitis a/b vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- hepatitis a/typhoid vaccine
everolimus decreases effects of hepatitis a/typhoid vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- hepatitis b vaccine
everolimus decreases effects of hepatitis b vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- human papillomavirus vaccine, nonavalent
everolimus decreases effects of human papillomavirus vaccine, nonavalent by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines.
- human papillomavirus vaccine, quadrivalent
everolimus decreases effects of human papillomavirus vaccine, quadrivalent by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines.
- hydroxychloroquine sulfate
everolimus and hydroxychloroquine sulfate both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- idelalisib
idelalisib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates
- indinavir
indinavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
indinavir will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - infliximab
everolimus and infliximab both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- influenza virus vaccine quadrivalent
everolimus decreases effects of influenza virus vaccine quadrivalent by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- influenza virus vaccine quadrivalent, cell-cultured
everolimus decreases effects of influenza virus vaccine quadrivalent, cell-cultured by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- influenza virus vaccine quadrivalent, intranasal
everolimus decreases effects of influenza virus vaccine quadrivalent, intranasal by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- influenza virus vaccine trivalent
everolimus decreases effects of influenza virus vaccine trivalent by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- isoniazid
isoniazid will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- itraconazole
itraconazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Not recommended during and 2 weeks after itraconazole.
itraconazole will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Not recommended during and 2 weeks after itraconazole. - ivosidenib
ivosidenib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternate therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
- Japanese encephalitis virus vaccine
everolimus decreases effects of Japanese encephalitis virus vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- ketoconazole
ketoconazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
ketoconazole will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - lapatinib
lapatinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
lapatinib will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - leflunomide
everolimus and leflunomide both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- lopinavir
lopinavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- loratadine
loratadine will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- lovastatin
lovastatin will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
- lumacaftor/ivacaftor
lumacaftor/ivacaftor will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Lumacaftor is a strong inducer of CYP3A. Avoid coadministration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index.
- lumefantrine
lumefantrine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- marijuana
marijuana will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- measles (rubeola) vaccine
everolimus decreases effects of measles (rubeola) vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- measles mumps and rubella vaccine, live
everolimus decreases effects of measles mumps and rubella vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- measles, mumps, rubella and varicella vaccine, live
everolimus decreases effects of measles, mumps, rubella and varicella vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- mefloquine
mefloquine increases levels of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- meningococcal A C Y and W-135 polysaccharide vaccine combined
everolimus decreases effects of meningococcal A C Y and W-135 polysaccharide vaccine combined by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- metronidazole
metronidazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- miconazole vaginal
miconazole vaginal will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- mifepristone
mifepristone will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- mobocertinib
mobocertinib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If use is unavoidable, increase CYP3A4 substrate dosage in accordance with its prescribing information.
- modafinil
modafinil will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- muromonab CD3
everolimus and muromonab CD3 both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- mycophenolate
everolimus and mycophenolate both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- nafcillin
nafcillin will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- nefazodone
nefazodone will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
nefazodone will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - nelfinavir
nelfinavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- nevirapine
nevirapine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- nicardipine
nicardipine will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
- nifedipine
nifedipine will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
nifedipine will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - nilotinib
nilotinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
nilotinib will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - oxcarbazepine
oxcarbazepine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- pentobarbital
pentobarbital will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- pexidartinib
pexidartinib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of pexidartinib (a CYP3A4 inducer) with sensitive CYP3A substrates may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.
- phenobarbital
phenobarbital will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
phenobarbital will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - phenytoin
phenytoin will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
phenytoin will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - pneumococcal vaccine 13-valent
everolimus decreases effects of pneumococcal vaccine 13-valent by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- pneumococcal vaccine heptavalent
everolimus decreases effects of pneumococcal vaccine heptavalent by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- pneumococcal vaccine polyvalent
everolimus decreases effects of pneumococcal vaccine polyvalent by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- posaconazole
posaconazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- pregabalin
everolimus, pregabalin. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Coadministration results in additive risk of developing angioedema of face, mouth, and neck. Angioedema may result in respiratory compromise.
- primidone
primidone will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- quercetin
quercetin will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- quinidine
quinidine will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- quinupristin/dalfopristin
quinupristin/dalfopristin will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rabies vaccine
everolimus decreases effects of rabies vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants may interfere with development of active immunity.
- rabies vaccine chick embryo cell derived
everolimus decreases effects of rabies vaccine chick embryo cell derived by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- ranolazine
ranolazine will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
- rifabutin
rifabutin will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rifampin
rifampin will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
rifampin will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - rifapentine
rifapentine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- rilonacept
everolimus and rilonacept both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- ritonavir
ritonavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
ritonavir will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - rotavirus oral vaccine, live
everolimus decreases effects of rotavirus oral vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- rubella vaccine
everolimus decreases effects of rubella vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- rufinamide
rufinamide will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- saquinavir
saquinavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- secobarbital
secobarbital will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- sirolimus
everolimus and sirolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- smallpox (vaccinia) vaccine, live
everolimus decreases effects of smallpox (vaccinia) vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- sotorasib
sotorasib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the CYP3A4 substrate for dosage modifications
sotorasib will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications. - St John's Wort
St John's Wort will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
St John's Wort will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated. - temsirolimus
everolimus and temsirolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- tepotinib
tepotinib will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.
- tetanus toxoid adsorbed or fluid
everolimus decreases effects of tetanus toxoid adsorbed or fluid by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- tick-borne encephalitis vaccine
everolimus decreases effects of tick-borne encephalitis vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- tipranavir
tipranavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- tocilizumab
tocilizumab and everolimus both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- tofacitinib
everolimus, tofacitinib. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- tongkat ali
everolimus and tongkat ali both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- topiramate
topiramate will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- travelers diarrhea and cholera vaccine inactivated
everolimus decreases effects of travelers diarrhea and cholera vaccine inactivated by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- tucatinib
tucatinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.
- typhoid polysaccharide vaccine
everolimus decreases effects of typhoid polysaccharide vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- typhoid vaccine live
everolimus decreases effects of typhoid vaccine live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- ustekinumab
everolimus and ustekinumab both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- varicella virus vaccine live
everolimus decreases effects of varicella virus vaccine live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- venetoclax
venetoclax will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. In vitro data suggest venetoclax may inhibit P-gp substrates at therapeutic dose levels in the gut. Avoid coadministration of narrow therapeutic index P-gp substrates with venetoclax. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hr before venetoclax.
- verapamil
verapamil will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Concomitant use of a moderate 3A4 inhibitor such as verapamil may significantly increase the plasma concentrations of everolimus following oral administration.
verapamil will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Everolimus prescribing information lists indication-specific dosing recommendations.
verapamil, everolimus. Either increases levels of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: With concomitant use of mTOR inhibitors, consider appropriate dose reductions of both medications. - voriconazole
voriconazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- voxelotor
voxelotor will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.
- yellow fever vaccine
everolimus decreases effects of yellow fever vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
- zafirlukast
zafirlukast will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- zoster vaccine live
everolimus decreases effects of zoster vaccine live by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.
Monitor Closely (74)
- astragalus
everolimus increases and astragalus decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.
- belatacept
belatacept and everolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor.
- belzutifan
belzutifan will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If unable to avoid coadministration of belzutifan with sensitive CYP3A4 substrates, consider increasing the sensitive CYP3A4 substrate dose in accordance with its prescribing information.
- benazepril
benazepril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- berotralstat
berotralstat will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.
berotralstat will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor or titrate substrate dose when berotralstat is coadministered with narrow therapeutic index drugs that are CYP3A substrates. - betrixaban
everolimus increases levels of betrixaban by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Decrease betrixaban dose to 80 mg PO once, then 40 mg PO qDay if coadministered with a P-gp inhibitor.
- cannabidiol
cannabidiol will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Therapeutic drug monitoring and dose reduction of P-gp substrates should be considered when given orally and concurrently with cannabidiol
- captopril
captopril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- cenobamate
cenobamate will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.
- cholera vaccine
everolimus decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.
- crizotinib
crizotinib increases levels of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- cyclosporine
cyclosporine will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Everolimus is a CYP3A4 and P-gp substrate. Prescribing information for coadministration with cyclosporine (a CYP3A4 and P-gp strong inhibitor) depends on everolimus indication and brand. Avoid coadministration if used for renal cell carcinoma (Afinitor). If used for kidney transplant immunosuppression (Zortress), reduce cyclosporine dose and use target serum concentration to reduce nephrotoxicity.
- dabrafenib
dabrafenib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- deferasirox
deferasirox will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- dengue vaccine
everolimus decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.
- denosumab
everolimus, denosumab. Other (see comment). Use Caution/Monitor. Comment: Caution should be taken in patients on concomitant immunosuppressants or with impaired immune systems because of increased risk for serious infections.
- dichlorphenamide
dichlorphenamide and everolimus both decrease serum potassium. Use Caution/Monitor.
dichlorphenamide, everolimus. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Both drugs can cause metabolic acidosis. - diltiazem
diltiazem will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Dose adjustment is based on indication. In breast cancer, PNET, renal cell cancer, or renal angiomyolipoma w/ TSC patents, decrease everolimus dose to 2.5-5 mg/day; decrease everolimus dose 50% and monitor levels in SEGA patients.
- duvelisib
duvelisib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.
- echinacea
everolimus increases and echinacea decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.
- elagolix
elagolix will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
elagolix decreases levels of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed. - eliglustat
eliglustat increases levels of everolimus by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.
- eluxadoline
eluxadoline increases levels of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Caution when CYP3A substrates that have a narrow therapeutic index are coadministered with eluxadoline.
- enalapril
enalapril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- encorafenib
encorafenib, everolimus. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.
- fedratinib
fedratinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.
- ferric maltol
ferric maltol, everolimus. Either increases levels of the other by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Coadministration of ferric maltol with certain oral medications may decrease the bioavailability of either ferric maltol and some oral drugs. For oral drugs where reductions in bioavailability may cause clinically significant effects on its safety or efficacy, separate administration of ferric maltol from these drugs. Duration of separation may depend on the absorption of the medication concomitantly administered (eg, time to peak concentration, whether the drug is an immediate or extended release product).
- fingolimod
everolimus increases effects of fingolimod by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects. .
- fosinopril
fosinopril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- glecaprevir/pibrentasvir
glecaprevir/pibrentasvir will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- glycerol phenylbutyrate
glycerol phenylbutyrate will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.
- haemophilus influenzae type b vaccine
everolimus decreases effects of haemophilus influenzae type b vaccine by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Avoid vaccination during chemotherapy or radiation therapy if possible because antibody response might be suboptimal. Patients vaccinated within a 14-day period before starting or during immunosuppressive therapy should be revaccinated =3 months after therapy is discontinued if immune competence has been restored.
- influenza virus vaccine quadrivalent, recombinant
everolimus decreases effects of influenza virus vaccine quadrivalent, recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immune response to vaccine may be decreased in immunocompromised individuals.
- influenza virus vaccine trivalent, recombinant
everolimus decreases effects of influenza virus vaccine trivalent, recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immune response to vaccine may be decreased in immunocompromised individuals.
- istradefylline
istradefylline will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.
istradefylline will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of P-gp substrates in clinical trials. Consider dose reduction of sensitive P-gp substrates. - ivacaftor
ivacaftor increases levels of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.
- letermovir
letermovir increases levels of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- lisinopril
lisinopril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- lonafarnib
lonafarnib will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Lonafarnib is a weak P-gp inhibitor. Monitor for adverse reactions if coadministered with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. Reduce P-gp substrate dose if needed.
- lorlatinib
lorlatinib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- maitake
everolimus increases and maitake decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.
- mercaptopurine
everolimus and mercaptopurine both increase immunosuppressive effects; risk of infection. Use Caution/Monitor.
- metformin
everolimus decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- mitotane
mitotane decreases levels of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.
- moexipril
moexipril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- ofatumumab SC
ofatumumab SC, everolimus. Either increases effects of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with coadministration. When switching from therapies with immune effects, take into account the duration and mechanism of action of these therapies when initiating ofatumumab SC.
- palbociclib
palbociclib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced if coadministered with palbociclib
- perindopril
perindopril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- pitolisant
pitolisant will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Pitolisant is a borderline/weak inducer of CYP3A4. Monitor sensitive CYP3A4 substrates for reduced effectiveness if coadministered.
- poliovirus vaccine inactivated
everolimus decreases effects of poliovirus vaccine inactivated by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Avoid vaccination during chemotherapy or radiation therapy if possible because antibody response might be suboptimal. Patients vaccinated within a 14-day period before starting or during immunosuppressive therapy should be revaccinated =3 months after therapy is discontinued if immune competence has been restored. .
- ponatinib
ponatinib increases levels of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- quinapril
quinapril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- ramipril
ramipril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- ribociclib
ribociclib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Caution if ribociclib is coadministered with sensitive CYP3A4 substrates that have a narrow therapeutic index. Dose reduction for sensitive CYP3A4 substrates may be needed.
- rucaparib
rucaparib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.
- sarecycline
sarecycline will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.
- siponimod
siponimod and everolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- sipuleucel-T
everolimus decreases effects of sipuleucel-T by pharmacodynamic antagonism. Modify Therapy/Monitor Closely.
- sofosbuvir/velpatasvir
sofosbuvir/velpatasvir will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Velpatasvir inhibits P-gp. Closely monitor P-gp substrates, particularly those with a narrow therapeutic index. Modify dose if needed.
sofosbuvir/velpatasvir increases levels of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Velpatasvir inhibits CYP3A4. Caution if coadministered with drugs with narrow therapeutics indexes. - stiripentol
stiripentol, everolimus. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.
stiripentol will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol. - tacrolimus
tacrolimus and everolimus both increase nephrotoxicity and/or ototoxicity. Modify Therapy/Monitor Closely. If used for liver transplant immunosuppression (Zortress), reduce tacrolimus dose and use target serum concentration to reduce nephrotoxicity.
- tazemetostat
tazemetostat will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- tecovirimat
tecovirimat will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.
- telotristat ethyl
telotristat ethyl will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Telotristat ethyl induces CYP3A4 and may reduce systemic exposure of sensitive CYP3A4 substrates. Monitor for suboptimal efficacy and consider increasing the dose of the CYP3A4 substrate.
- trandolapril
trandolapril, everolimus. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration increases risk of angioedema.
- trastuzumab
trastuzumab, everolimus. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .
- trastuzumab deruxtecan
trastuzumab deruxtecan, everolimus. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .
- trazodone
trazodone will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- tucatinib
tucatinib will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.
- ustekinumab
ustekinumab, everolimus. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.
- vemurafenib
vemurafenib increases levels of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- verapamil
everolimus will increase the level or effect of verapamil by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Everolimus prescribing information lists indication-specific dosing recommendations.
- voclosporin
voclosporin, everolimus. Either increases toxicity of the other by nephrotoxicity and/or ototoxicity. Modify Therapy/Monitor Closely. Coadministration with drugs associated with nephrotoxicity may increase the risk for acute and/or chronic nephrotoxicity.
- zoster vaccine recombinant
everolimus decreases effects of zoster vaccine recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressive therapies may reduce the effectiveness of zoster vaccine recombinant.
Minor (0)
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
Cholecystitis
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
Thrombotic microangiopathy
Radiation sensitization and radiation recall
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
Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) reported in patients treated with radiation prior to, during, or subsequent to treatment; monitor patients closely when therapy administered during or sequentially with radiation treatment
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); withhold therapy for at least 1 week prior to elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing; safety of resumption of treatment upon resolution of wound healing complications has not been established
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
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Formulary
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