everolimus (Rx)

Brand and Other Names:Afinitor, Zortress, more...Afinitor Disperz

Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet (Afinitor)

  • 2.5mg
  • 5mg
  • 7.5mg
  • 10mg

tablet for oral suspension (Afinitor Disperz)

  • 2mg
  • 3mg
  • 5mg

tablet (Zortress)

  • 0.25mg
  • 0.5mg
  • 0.75mg
  • 1mg

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
    • <18 years of age

Orphan Designations

Diffuse large B-cell lymphoma

Gastric cancer

Waldenstrom macroglobulinemia (also known as lymphoplasmacytic lymphoma)

Sponsor

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

Tuberous Sclerosis Topical Treatment (Orphan)

Everolimus ointment

Orphan designation for topical treatment of tuberous sclerosis

Sponsor

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

Dosage Forms & Strengths

tablet (Afinitor)

  • 2.5mg
  • 5mg
  • 7.5mg
  • 10mg

tablet for oral suspension (Afinitor Disperz)

  • 2mg
  • 3mg
  • 5mg

Subependymal Giant Cell Astrocytoma

Afinitor and Afinitor Disperz

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

<1 year: Safety and efficacy not established

≥1 year

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

Partial-Onset Seizures

Afinitor Disperz only

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

<2 years: Safety and efficacy not established

≥2 years

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

Dosage Modifications

Coadministration of P-gp and CYP3A4 inhibitors

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

Coadministration of P-gp and CYP3A4 inducers

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

Therapeutic drug monitoring and dose titration

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

Dosing Considerations

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

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

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Interactions

Interaction Checker

and everolimus

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              Serious - Use Alternative (167)

              • 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.

              • fosaprepitant

                fosaprepitant 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.

              • hydrocortisone

                hydrocortisone will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • 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.

              • levoketoconazole

                levoketoconazole will increase the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.

                levoketoconazole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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.

              • 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.

              • nirmatrelvir/ritonavir

                nirmatrelvir/ritonavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • olutasidenib

                olutasidenib will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of olutasidenib (a CYP3A4 inducer) with sensitive CYP3A substrates unless otherwise instructed in substrates prescribing information. If unavoidable, monitor for loss of therapeutic effect of sensitive CYP3A4 substrates.

              • oxcarbazepine

                oxcarbazepine will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • pacritinib

                pacritinib will increase 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.

              • ropeginterferon alfa 2b

                ropeginterferon alfa 2b, everolimus. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression.

              • 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 (90)

              • 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.

              • elranatamab

                elranatamab will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Elranatamab causes cytokine release syndrome (CRS) that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates. This is more likely to occur from initiation of elranatamab step-up dosing up to 14 days after the first treatment dose and during and after CRS.

              • 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.

              • epcoritamab

                epcoritamab, everolimus. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Epcoritamab causes release of cytokines that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates. For certain CYP substrates, minimal changes in their concentration may lead to serious adverse reactions. If needed, modify therapy as recommended in the substrate's prescribing information. .

              • 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.

              • glofitamab

                glofitamab, everolimus. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glofitamab causes release of cytokines that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates. For certain CYP substrates, minimal changes in their concentration may lead to serious adverse reactions. If needed, modify therapy as recommended in the substrate's prescribing information. .

              • 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.

              • isavuconazonium sulfate

                isavuconazonium sulfate will increase the level or effect of everolimus by Other (see comment). Use Caution/Monitor. Isavuconazonium sulfate, an inhibitor of P-gp and CYP3A4, may increase the effects or levels of sensitive P-gp or CYP3A4 substrates, which may require dose adjustment.

              • 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.

              • lenacapavir

                lenacapavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lencapavir (a moderate CYP3A4 inhibitor) may increase CYP3A4 substrates initiated within 9 months after last SC dose of lenacapavir, which may increase potential risk of adverse reactions of CYP3A4 substrates.

              • 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.

              • lonapegsomatropin

                lonapegsomatropin decreases effects of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substrates.

              • 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.

              • omaveloxolone

                omaveloxolone will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Omaveloxolone may reduce systemic exposure of sensitive CYP3A4 substrates. Check prescribing information of substrate if dosage modification is needed.

              • 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.

              • pirtobrutinib

                pirtobrutinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Pirtobrutinib (a CYP3A4 inhibitor) may increase plasma concentrations of sensitive CYP3A4 substrate which may increase the risk of adverse reactions related to these substrates.

              • 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.

              • ritlecitinib

                ritlecitinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Ritlecitinib inhibits CYP3A4 substrates; coadministration increases AUC and peak plasma concentration sensitive substrates, which may increase risk of adverse reactions. Additional monitoring and dosage adjustment may be needed in accordance with product labeling of CYP3A substrates.

              • 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.

              • somapacitan

                somapacitan decreases effects of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substrates.

              • somatrogon

                somatrogon decreases effects of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substrates.

              • somatropin

                somatropin decreases effects of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substrates.

              • 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.

              • talquetamab

                talquetamab will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Talquetamab causes cytokine release syndrome (CRS) that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates. This is more likely to occur from initiation of talquetamab step-up dosing up to 14 days after the first treatment dose and during and after CRS.

              • tazemetostat

                tazemetostat will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • teclistamab

                teclistamab will increase the level or effect of everolimus by altering metabolism. Use Caution/Monitor. Teclistamab causes release of cytokines that may suppress activity of CYP450 enzymes, resulting in increased exposure of CYP substrates. Monitor for increased concentrations or toxicities of sensitive CYP substrates. Adjust dose of CYP substrate drug as needed.

              • 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.

              • trofinetide

                trofinetide will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor CYP3A4 substrates for which a small increase in plasma concentration may lead to serious toxicities if coadministered with trofinetide (a weak CYP3A4 inhibitor).

              • 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.

              • turmeric

                turmeric will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • 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 (4)

              • acetazolamide

                acetazolamide will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • anastrozole

                anastrozole will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • cyclophosphamide

                cyclophosphamide will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • larotrectinib

                larotrectinib will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

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              Adverse Effects

              >10%

              Stomatitis (44%)

              Constipation (38%)

              Infections (37%)

              Asthenia (33%)

              Fatigue (31%)

              Cough (30%)

              Diarrhea (30%)

              Rash (29%)

              Anemia (26%)

              Nausea (26%)

              Anorexia (25%)

              Edema, peripheral (25-45%)

              Dyspnea (24%)

              Pyrexia (20%)

              Vomiting (20%)

              Headache (19%)

              Epistaxis (18%)

              Decreased lymphocytes, Grade 3 (16%)

              Increased glucose, Grade 3 (15%)

              Pneumonitis (14%)

              Pruritus (14%)

              Dry skin (13%)

              Decreased Hgb, Grade 3 (12%)

              Menstrual irregularities (11%)

              1-10% (selected)

              Dysgeusia (10%)

              Hypertension, including hypertensive crisis (4%)

              Hemorrhage (3%)

              Tachycardia (3%)

              CHF (1%)

              Postmarketing Reports

              Angioedema

              Pancreatitis

              Cholelithiasis

              Cholecystitis

              Arterial thrombotic events

              Lymphedema

              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

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              Warnings

              Black Box Warnings

              Zortress only

              Malignancies and serious infections

              • Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress
              • Patients should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources
              • Physician responsible for maintenance therapy should have complete information requisite for follow-up of the patient
              • 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; reduce 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

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

              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 noninfectious 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 (eg, 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; antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia and prophylaxis for cytomegalovirus (CMV) recommended in transplant recipients

              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; concomitant use with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors may increase risk of developing angioedema

              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; consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if dysfunction is thought to be drug-related; caution should be exercised when using other drugs which are known to impair renal function

              May cause angioedema and fluid accumulation; generalized fluid accumulation, including peripheral edema (eg, lymphoedema) and other types of localized fluid collection, such as pericardial and pleural effusions and ascites also reported

              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)

              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

              Interstitial lung disease

              • A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled out through appropriate investigations
              • Cases of ILD, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some reported with pulmonary hypertension [including pulmonary arterial hypertension (PAH)] as a secondary event, have occurred in patients receiving rapamycins, and their derivatives, including this drug; most cases generally resolve on drug interruption with or without glucocorticoid therapy; however, fatal cases have also occurred

              Hyperlipidemia

              • Increased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, reported to occur following initiation of therapy and risk of hyperlipidemia is increased with higher everolimus whole blood trough concentrations; use of anti-lipid therapy may not normalize lipid levels in patients receiving everolimus
              • If hyperlipidemia detected, interventions, such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines; the risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen containing everolimus; similarly, the risk/benefit of continued therapy should be reevaluated in patients with severe refractory hyperlipidemia; everolimus has not been studied in patients with baseline cholesterol levels greater than 350 mg/dL
              • 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

              Zortress only

              • See Black Box Warnings
              • Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes; these include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multiple leukoencephalopathy (PML); patient monitoring may help detect patients at risk for polyoma virus-associated nephropathy (PVAN); reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML; physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft
              • 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
              • Therapy should not be administered earlier than 30 days after liver transplant
              • 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)
              • Concomitant use with cyclosporine may increase risk of thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome; monitor hematologic parameters
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              Pregnancy & Lactation

              Pregnancy

              Based on animal studies and mechanism of action therapy can cause fetal harm when administered to pregnant woman; there are limited case reports of use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage; advise pregnant women of potential risk to fetus

              Contraception

              • Females
                • Advise female patients of reproductive potential to use effective contraception during treatment and for 8 weeks after last dose
                • Verify the pregnancy status of females of reproductive potential prior to starting treatment
              • Males
                • Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after last dose

              Infertility

              • Females
                • Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients receiving therapy; based on these clinical findings and findings in animals, female fertility may be compromised by treatment with drug
              • Males
                • Based on clinical findings and findings in animals, treatment may impair fertility in male patients; cases of reversible azoospermia reported in male patients receiving therapy; in male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at exposures (AUC) similar to those in patients receiving a dose of 10 mg daily; the fertility index in rats increased when everolimus administration was stopped for a 10-13 week recovery

              Lactation

              There are no data on presence of everolimus in human milk, effects on breastfed infant or on milk production; drug and/or its metabolites passed into milk of lactating rats at a concentration 3.5 times higher than in maternal serum; because of potential for serious adverse reactions in breastfed infants from everolimus, advise lactating women not to breastfeed during treatment and for 2 weeks after last dose

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

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              Pharmacology

              Mechanism of Action

              Afinitor

              • Inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase; in several cancers and tuberous sclerosis complex, the mTOR pathway is dysregulated; everolimus binds to FKBP-12, an intracellular protein and thus inhibiting the mTOR kinase pathway
              • Also, reduces the activity of S6 ribosomal protein kinase (S6k1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR and also involved in protein synthesis; everolimus inhibits the expression of hypoxia-inducible factor and reduces the expression of vascular endothelial growth factor (VEGF)

              Zortress

              • Inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes; binds to cellular cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase; in the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited; consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited

              Absorption

              Peak Plasma Time: 1-2 hr

              High-fat meals reduced systemic exposure to Afinitor 10 mg (as measured by AUC) by 22% and peak plasma concentration by 54%

              High-fat meals reduced Afinitor Disperz AUC by 12% and peak plasma concentration by 60%

              Distribution

              Protein Bound: 74%

              Vd (Zortress): 107-342 L (kidney transplant patients)

              Metabolism

              CYP3A4 substrate

              PgP substrate and moderate inhibitor

              Competitive inhibitor of CYP3A4 and mixed inhibitor of CYP2D6

              Elimination

              Half Life: 30 hr

              Excretion: 80% feces; 5% urine

              Pharmacogenomics

              Rapamycins form complexes with an intracellular immunophillin (FKBP), which bind to a kinase called the mammalian target of rapamycin (mTOR)

              Intrinsic rapamycin resistance may be caused by genetic mutations identified for FKBP and mTOR genes

              Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose; oral clearance is on average 20% higher in black patients than in white patients

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              Administration

              Oral Suspension Preparation

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

              Using an oral syringe

              • Place prescribed dose into a 10-mL syringe; do not exceed a total of 10 mg/syringe; prepare additional syringes if higher doses are required
              • Do not break or crush tablets
              • Draw ~5 mL of water and 4 mL of air into syringe
              • Place filled syringe into a container (tip up) for 3 min, until tablets are in suspension; do not shake syringe
              • Gently invert syringe 5 times immediately prior to administration

              Using a small drinking glass

              • Place prescribed dose into a small drinking glass (up to 100 mL) containing ~25 mL of water; do not exceed a total of 10 mg/glass; prepare additional syringes if higher doses are required
              • Allow 3 minutes for suspension to occur
              • Stir contents gently with a spoon, immediately prior to drinking

              Oral Administration (Afinitor tablets and Afinitor Disperz)

              Administer the same time every day

              Administer consistently with food or consistently without food

              Afinitor tablets

              • Swallow whole, do not break or crush tablets

              Afinitor Disperz

              • Administer as a PO suspension only
              • Administer suspension immediately after preparation; discard suspension if not administered within 60 min after preparation
              • Oral syringe: After administration, draw ~5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles; administer entire contents of the syringe
              • Drinking glass: After administration, add 25 mL of water and stir with same spoon to resuspend remaining particles; administer the entire contents of the glass

              Missed dose

              • ≤6 hr from normal administration time: Take missed dose
              • >6 hr from normal administration time: Skip dose; the next day, administer at its usual time; do not double dose to make up for the missed dose

              Zortress

              Swallow tablets whole, do not chew, crush, or split

              Kidney transplantation

              • Administer as soon as possible after kidney transplantation
              • Routine everolimus and cyclosporine therapeutic drug concentration monitoring is recommended
              • Administer consistently with or without food at the same time as cyclosporine

              Liver transplantation

              • Do not administer until at least 30 days post liver transplant (earlier administration associated with hepatic artery thrombosis, graft loss, and death)
              • Use in combination with reduced doses of tacrolimus and with corticosteroids
              • May continue to taper corticosteroid dose on individual basis
              • Routine everolimus and tacrolimus therapeutic drug concentration monitoring is recommended

              Storage

              Zortress: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); protect from light and moisture

              Afinitor: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); protect from light and moisture

              Afinitor Disperz: Store at room temperature (20-25°C [68-77°F]); protect from light and moisture

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              Formulary

              FormularyPatient Discounts

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

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

              Adding plans allows you to:

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

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

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