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  • CLASSES

    Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors
    Small Molecule Antineoplastic Mammallian Target of Rapamycin (mTOR) Inhibitors

    BOXED WARNING

    Fungal infection, infection

    Everolimus has immunosuppressive properties and may make patients more susceptible to infection. For Zortress, infection is a black box warning. Patients receiving immunosuppressants are at increased risk of developing bacterial, viral, fungal, and protozoal infections including opportunistic infections. Cautious use of combination immunosuppressant therapy is advised, as an overly immunosuppressed immune system can cause increased infection susceptibility. The incidence of serious infections has been reported at a higher frequency in pediatric patients younger than 6 years of age. Bacterial and fungal infections have occurred during everolimus treatment. Some cases have resulted in respiratory failure or death. Pre-existing invasive fungal infections should be resolved prior to treatment with Afinitor. If an invasive fungal infection is diagnosed while the patient is receiving treatment with Afinitor, discontinue everolimus until the infection is resolved.

    Immunosuppression, lymphoma, new primary malignancy, skin cancer, sunlight (UV) exposure

    Zortress has a black box warning for new primary malignancy such as lymphoma and skin cancer due to immunosuppression. Only physicians experienced in the management of systemic immunosuppressant therapy and organ transplant should use Zortress, and the physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Patients with increased risk for skin cancer should limit sunlight (UV) exposure by wearing protective clothing and using a sunscreen with a high protection factor. The risk of malignancy development appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Patients receiving everolimus (Zortress) should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.

    Nephrotoxicity, renal impairment

    Elevations in serum creatinine and proteinuria have been reported in patients receiving Afinitor. Use Afinitor with caution in patients with renal impairment. Clinical studies have not been conducted in patients with renal impairment; however, no dosage adjustments are recommended in these patients by the FDA-approved product labeling. Monitor renal function prior to Afinitor initiation and annually thereafter; monitor renal function at least every 6 months in patients who may have additional risk factors for renal dysfunction. Zortress has a black box warning about the risk of nephrotoxicity due to the concomitant use of cyclosporine. Use of standard doses of cyclosporine with everolimus can lead to increased nephrotoxicity and a lower glomerular filtration rate. In order to reduce renal dysfunction, use reduced cyclosporine doses in combination with everolimus and monitor the cyclosporine and everolimus whole blood trough concentrations. Also, monitor renal function, and consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to be drug related.

    Renal artery thrombosis, renal graft thrombosis, renal vein thrombosis

    Zortress has a black box warning for the risk of renal graft thrombosis. An increased risk of renal artery thrombosis and renal vein thrombosis that resulted in graft loss was reported among everolimus (Zortress) recipients mostly within the first 30 days after transplantation.

    Heart transplant, mortality

    Increased mortality within the first 3 months post-transplantation was reported in patients who received everolimus (Zortress) with or without induction therapy in de novo heart transplant patients in a clinical trial. Many deaths were associated with serious infections. Zortress is not indicated or recommended for use in heart transplant patients.

    DEA CLASS

    Rx

    DESCRIPTION

    Macrolide immunosuppressant analog of sirolimus; inhibits the mammalian target of rapamycin (mTOR), a serine-threonine kinase
    Afinitor is used for advanced renal cell carcinoma, subependymal giant cell astrocytoma associated with tuberous sclerosis complex (TSC), advanced neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal angiomyolipoma and TSC, TSC-associated partial-onset seizures, and hormone receptor-positive, HER2-negative advanced breast cancer; Zortress is used for kidney transplant and liver transplant rejection prophylaxis
    May increase risk for infection

    COMMON BRAND NAMES

    Afinitor, Afinitor DISPERZ, Zortress

    HOW SUPPLIED

    Afinitor DISPERZ Oral Tab for Susp: 2mg, 3mg, 5mg
    Afinitor/Everolimus/Zortress Oral Tab: 0.25mg, 0.5mg, 0.75mg, 1mg, 2.5mg, 5mg, 7.5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of patients with advanced renal cell cancer (RCC).
    For the treatment of patients with advanced renal cell cancer who have failed treatment with sunitinib or sorafenib.
    Oral dosage (Afinitor only)
    Adults

    10 mg orally once daily. Continue treatment for as long as clinical benefit is observed or until unacceptable toxicity develops. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of Afinitor. Dose adjustment is necessary if Afinitor is coadministered with some CYP3A4 inhibitors or inducers. Avoid concomitant use with strong CYP3A4 inhibitors.

    For the treatment of advanced renal cell cancer (RCC) in combination with lenvatinib, following one prior anti-angiogenic therapy.
    Oral dosage (Afinitor only)
    Adults

    5 mg orally once daily, in combination with lenvatinib 18 mg by mouth once daily; continue until disease progression or unacceptable toxicity. In a multicenter, open-label, phase 2 clinical trial, patients with advanced or metastatic renal cell carcinoma (RCC) who had received prior anti-angiogenic therapy were randomized to treatment with lenvatinib plus everolimus (combination therapy, n = 51), or everolimus monotherapy (10 mg per day, n = 50). The primary outcome of investigator-assessed median progression-free survival (PFS) was significantly improved in patients receiving combination therapy compared with everolimus monotherapy (14.6 months vs. 5.5 months; HR 0.37; 95% CI, 0.22 to 0.62); this was supported by a retrospective independent review of radiographs with an observed hazard ratio of 0.43 (95% CI, 0.24 to 0.75). Additionally, the median overall survival was 25.5 months with combination therapy compared with 15.4 months in patients treated with everolimus monotherapy (HR 0.67; 95% CI, 0.42 to 1.08) and the objective response rate was 37% versus 6%, respectively; all but one response (in a patient who received combination therapy) were partial responses.

    For kidney transplant rejection prophylaxis in patients at low-moderate immunologic risk.
    NOTE: The safety and efficacy of everolimus have not been established in patients at high immunologic risk.
    Oral dosage (Zortress only)

    NOTE: Everolimus is FDA-approved for use with Cyclosporine, USP Modified formulation only; everolimus has not been evaluated in clinical trials with other formulations of cyclosporine. Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or intravenous administration of cyclosporine cannot be avoided. Cyclosporine and everolimus interact, so both the cyclosporine dose and the target range for whole blood trough concentrations are to be reduced when cyclosporine is given with everolimus. Avoid standard doses of cyclosporine with everolimus to reduce the risk of nephrotoxicity.

    Adults

    Initially, 0.75 mg orally every 12 hours (1.5 mg per day) in combination with basiliximab induction and concurrently with reduced doses of cyclosporine, USP modified and corticosteroids; administer as soon as possible after transplantation. Therapeutic drug monitoring of everolimus and cyclosporine is recommended for all patients. If needed, adjust everolimus dose at 4 to 5 day intervals. The everolimus dose may need adjustment based on blood concentrations, tolerability, individual response, concomitant medication change, or clinical situation. Initiate cyclosporine as soon as possible and no later than 48 hours after reperfusion of the graft, and adjust the cyclosporine dose to target whole blood trough concentrations from day 5 onwards. In a clinical trial, the mean cyclosporine starting dose was 5.2 mg/kg per day. Initiate oral prednisone once oral medication is tolerated. According to guidelines, use of everolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so significant reduction in the cyclosporine dosage is advised. If everolimus is used, guidelines recommend that it should not be started until graft function is established and surgical wounds are healed.

    For the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) in patients who require therapeutic intervention but are not candidates for curative surgical resection.
    Oral dosage (Afinitor only)
    Adults

    4.5 mg/m2/dose PO once daily initially, then titrate dose to achieve a target trough concentration of 5 to 15 ng/mL. Continue therapy until disease progression or unacceptable toxicity; the optimal duration of therapy is unknown. Adjust dose at 1 to 2-week intervals based on trough concentrations, tolerability, clinical response, change in hepatic function, and concomitant drug changes. Adjust the dose using the equation: new dose = current dose x (target concentration divided by current concentration). The maximum dose increment at any titration must not exceed 5 mg; multiple dose titrations may be required. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy. Consider alternate day dosing if dose reduction is needed in a patient receiving the lowest available strength. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with everolimus (median dose intensity, 5.9 mg/m2/day; median duration of therapy, 41.9 weeks) resulted in a significantly improved subependymal giant cell astrocytoma (SEGA) response rate compared with placebo (35% vs. 0%; p less than 0.0001) in patients with progressive SEGA associated with tuberous sclerosis complex (TSC) in a multinational, randomized, double-blind, placebo-controlled, phase III trial (the EXIST-1 trial; n = 117). Patients aged 0 to 65 years were eligible for study enrollment and all patients had 2 or more main features of TSC; the median age in 78 patients who received everolimus was 9.5 years (range, 1 to 23.9 years). A SEGA response rate was defined as at least a 50% total volume reduction from baseline in all target SEGA without evidence of 1) worsening non-target SEGA, 2) new lesions (1 cm or more in diameter), or 3) new or worsening hydrocephalus; confirmation of response was required 8 to 12 weeks later. At a median follow-up time of 9.7 months, the estimated 6-month progression-free rate was significantly improved with everolimus therapy (100% vs. 86%; p = 0.0002). After 24 weeks of treatment, the median seizure frequency per 24 hours was unchanged from baseline with either everolimus or placebo. At a median follow-up time of 3.9 years (range, 0.2 to 4.9 years), the SEGA response rate was 57.7% and the median time to response was 5.3 months (range, 2.5 to 33.1 months) in patients who received everolimus on study or after crossing over from the placebo group (median duration of therapy 3.9 years). Treatment with everolimus (3 mg/m2/day PO initially, then titrated to trough concentrations of 5 to 15 ng/mL) led to a significant reduction in SEGA volume from baseline (p less than 0.001) and seizure frequency (p = 0.02) at 6 months compared with baseline in 28 patients (median age, 11 years; range, 3 to 34 years) with SEGA associated with TSC in a phase I-II study. At 6 months, the median dose of everolimus was 5.6 mg/m2/day (range, 1.5 to 10.5 mg/m2/day). Additionally, a SEGA volume reduction of 30% or more was achieved in 75% of patients and of 50% or more was achieved in 32% of patients. At 60 months, a SEGA volume reduction of 30% or more and of 50% or more occurred in 60.9% and 52.2% of patients, respectively, who received everolimus (median duration of therapy, 67.8 months; range, 4.7 to 83.2 months) in an extension trial (n = 23). At 60 months, daily seizures were reported in 11.1% of patients who received everolimus compared with 26.9% of patients at baseline.

    Children and Adolescents

    4.5 mg/m2/dose PO once daily initially, then titrate dose to achieve a target trough concentration of 5 to 15 ng/mL. Continue therapy until disease progression or unacceptable toxicity; the optimal duration of therapy is unknown. Adjust dose at 1 to 2-week intervals based on trough concentrations, tolerability, clinical response, change in hepatic function, and concomitant drug changes. Adjust the dose using the equation: new dose = current dose x (target concentration divided by current concentration). The maximum dose increment at any titration must not exceed 5 mg; multiple dose titrations may be required. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy. Consider alternate day dosing if dose reduction is needed in a patient receiving the lowest available strength. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with everolimus (median dose intensity, 5.9 mg/m2/day; median duration of therapy, 41.9 weeks) resulted in a significantly improved subependymal giant cell astrocytoma (SEGA) response rate compared with placebo (35% vs. 0%; p less than 0.0001) in patients with progressive SEGA associated with tuberous sclerosis complex (TSC) in a multinational, randomized, double-blind, placebo-controlled, phase III trial (the EXIST-1 trial; n = 117). Patients aged 0 to 65 years were eligible for study enrollment and all patients had 2 or more main features of TSC; the median age in 78 patients who received everolimus was 9.5 years (range, 1 to 23.9 years). A SEGA response rate was defined as at least a 50% total volume reduction from baseline in all target SEGA without evidence of 1) worsening non-target SEGA, 2) new lesions (1 cm or more in diameter), or 3) new or worsening hydrocephalus; confirmation of response was required 8 to 12 weeks later. At a median follow-up time of 9.7 months, the estimated 6-month progression-free rate was significantly improved with everolimus therapy (100% vs. 86%; p = 0.0002). After 24 weeks of treatment, the median seizure frequency per 24 hours was unchanged from baseline with either everolimus or placebo. At a median follow-up time of 3.9 years (range, 0.2 to 4.9 years), the SEGA response rate was 57.7% and the median time to response was 5.3 months (range, 2.5 to 33.1 months) in patients who received everolimus on study or after crossing over from the placebo group (median duration of therapy 3.9 years). Treatment with everolimus (3 mg/m2/day PO initially, then titrated to trough concentrations of 5 to 15 ng/mL) led to a significant reduction in SEGA volume from baseline (p less than 0.001) and seizure frequency (p = 0.02) at 6 months compared with baseline in 28 patients (median age, 11 years; range, 3 to 34 years) with SEGA associated with TSC in a phase I-II study. At 6 months, the median dose of everolimus was 5.6 mg/m2/day (range, 1.5 to 10.5 mg/m2/day). Additionally, a SEGA volume reduction of 30% or more was achieved in 75% of patients and of 50% or more was achieved in 32% of patients. At 60 months, a SEGA volume reduction of 30% or more and of 50% or more occurred in 60.9% and 52.2% of patients, respectively, who received everolimus (median duration of therapy, 67.8 months; range, 4.7 to 83.2 months) in an extension trial (n = 23). At 60 months, daily seizures were reported in 11.1% of patients who received everolimus compared with 26.9% of patients at baseline.

    For the treatment of patients with unresectable, locally advanced, or metastatic malignant neuroendocrine tumor (NET) or carcinoid tumors.
    For the treatment of progressive malignant neuroendocrine tumor (NET) of pancreatic origin (also known as PNET) in patients with unresectable, locally advanced or metastatic disease.
    Oral dosage
    Adults

    10 mg orally once daily. Continue treatment for as long as clinical benefit is observed or until unacceptable toxicity develops. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind, placebo-controlled clinical trial of patients with locally advanced or metastatic advanced pancreatic neuroendocrine tumors (PNET) and disease progression within the prior 12 months, treatment with everolimus (n = 207) significantly improved both investigator-assessed progression-free survival (PFS) (11 months vs. 4.6 months) and PFS by central review (13.7 months vs. 5.7 months) compared with placebo (n = 203). Overall survival was not significantly different between study arms, however, 85% of patients treated with placebo crossed over to receive everolimus following radiologic progression.

    For the treatment of progressive, well-differentiated, non-functional malignant neuroendocrine tumor (NET) of gastrointestinal or lung origin (also known as carcinoid) in patients with unresectable, locally advanced or metastatic disease.
    NOTE: Everolimus is not indicated for the treatment of patients with functional carcinoid tumors.
    Oral dosage
    Adults

    10 mg orally once daily. Continue treatment for as long as clinical benefit is observed or until unacceptable toxicity develops. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind, placebo-controlled clinical trial of patients with unresectable, locally advanced or metastatic, well differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (excluding pancreatic) or lung origin and disease progression within the prior 6 months, treatment with everolimus (n = 205) significantly improved progression-free survival (PFS) per independent radiological review (11 months vs. 3.9 months); the overall response rate was 2% in patients treated with Afinitor compared with 1% of those who received placebo. At the time of the planned interim analysis, there was not a significant difference in overall survival (OS). Everolimus is not indicated for the treatment of patients with functional carcinoid tumors. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, patients with advanced or metastatic functional carcinoid tumors were treated with depot octreotide in combination with Afinitor (n = 429) or placebo; 67% of patients in the placebo group crossed over to receive Afinitor after progression. Combination therapy with Afinitor and depot octreotide did not improve PFS (primary outcome), and overall survival was better in patients who were treated with octreotide alone.

    For the treatment of breast cancer.
    For the treatment of hormone receptor-positive, HER2-negative advanced breast cancer in postmenopausal women who have failed treatment with letrozole or anastrozole, in combination with exemestane.
    Oral dosage (Afinitor only)
    Postmenopausal females

    10 mg PO once daily in combination with exemestane 25 mg PO once daily. Continue treatment for as long as clinical benefit is observed or until unacceptable toxicity develops. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Everolimus plus exemestane significantly improved progression-free survival compared with everolimus alone in postmenopausal women with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer refractory to letrozole or anastrozole in a randomized, double-blind phase 3 clinical trial.

    For the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer in postmenopausal women with secondary aromatase inhibitor resistance, in combination with tamoxifen†.
    Oral dosage (Afinitor only)
    Postmenopausal females

    10 mg PO once daily plus tamoxifen 20 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized phase 2 study, clinical benefit rate, time to progression, and overall survival were significantly improved with everolimus plus tamoxifen compared with tamoxifen alone.

    For the treatment of HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with vinorelbine and trastuzumab†.
    Oral dosage (Afinitor only)
    Adults

    5 mg PO once daily plus vinorelbine 25 mg/m2 IV weekly and trastuzumab 4 mg/kg IV once followed by 2 mg/kg IV weekly until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Everolimus plus vinorelbine and trastuzumab significantly improved progression-free survival compared with placebo plus vinorelbine and trastuzumab in patients with HER2-positive, trastuzumab-resistant advanced breast cancer in patients who had received prior taxane therapy; objective response rate and overall survival were not significantly improved.

    For the treatment of renal angiomyolipoma and tuberous sclerosis complex not requiring immediate surgery.
    Oral dosage (Afinitor only)
    Adults

    10 mg orally once daily. Continue treatment for as long as clinical benefit is observed or until unacceptable toxicity develops. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of Afinitor. Dose adjustment is necessary if Afinitor is coadministered with some CYP3A4 inhibitors or inducers. Avoid concomitant use with strong CYP3A4 inhibitors. The confirmed response rate was 42% with everolimus therapy (median treatment duration, 38 weeks) compared with 0% with placebo (p < 0.0001) in a randomized, double-blind, phase III trial in adult patients with renal angiomyolipoma as a feature of tuberous sclerosis complex (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). Response was defined as a reduction in angiomyolipoma volume of 50% or more relative to baseline and absence of angiomyolipoma progression. The median time to response in the everolimus arm was 2.9 months; all responses lasted between 10 and 85 weeks. The median time to progression was not reached in the everolimus arm and 11.4 months in the placebo arm. Additionally, the 6-month progression-free rates were 98% and 83% in the everolimus and placebo arms, respectively; the 12-month progression-free rates were 92% and 25%, respectively.

    For liver transplant rejection prophylaxis.
    Oral dosage
    Adults

    Initially, 1 mg orally twice daily started at least 30 days after transplantation in combination with reduced dose tacrolimus and corticosteroids. Steroid doses may be further tapered based on the patient's clinical status and graft function. Therapeutic drug monitoring of everolimus and tacrolimus is recommended. In a trial, patients received tacrolimus plus corticosteroids with or without mycophenolate mofetil for the first 30 days and then tacrolimus (target trough concentration 3 to 5 ng/mL) and everolimus (target trough concentration 3 to 8 ng/mL) plus corticosteroids.

    For the treatment of tuberous sclerosis complex (TSC)-associated partial seizures.
    Oral dosage (Afinitor Disperz only)
    Adults

    5 mg/m2/dose PO once daily, then titrate dose to achieve a target trough concentration of 5 to 15 ng/mL. Continue therapy until disease progression or unacceptable toxicity; the optimal duration of therapy is unknown. Adjust dose at 1 to 2-week intervals based on trough concentrations, tolerability, clinical response, change in hepatic function, and concomitant drug changes. Adjust the dose using the equation: new dose = current dose x (target concentration divided by current concentration). The maximum dose increment at any titration must not exceed 5 mg; multiple dose titrations may be required. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy. Consider alternate day dosing if dose reduction is needed in a patient receiving the lowest available strength. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children and Adolescents 2 years and older

    5 mg/m2/dose PO once daily, then titrate dose to achieve a target trough concentration of 5 to 15 ng/mL. Continue therapy until disease progression or unacceptable toxicity; the optimal duration of therapy is unknown. Adjust dose at 1 to 2-week intervals based on trough concentrations, tolerability, clinical response, change in hepatic function, and concomitant drug changes. Adjust the dose using the equation: new dose = current dose x (target concentration divided by current concentration). The maximum dose increment at any titration must not exceed 5 mg; multiple dose titrations may be required. Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy. Consider alternate day dosing if dose reduction is needed in a patient receiving the lowest available strength. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the treatment of relapsed or refractory Waldenstrom macroglobulinemia†.
    Oral dosage
    Adults

    10 mg orally daily was evaluated in a single-arm, phase II trial (n = 60; the RAD001 trial). Each cycle consisted of 4 weeks of treatment. Patients with stable disease or better after 6 cycles continued treatment per physician discretion until progression or unacceptable toxicity.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Zortress: Maximum dosage is based on everolimus trough concentrations (target of 3 to 8 ng/mL).
    Afinitor: 10 mg/day for advanced hormone receptor-positive breast cancer, advanced renal cell carcinoma, and renal angiomyolipoma with tuberous sclerosis complex (TSC); maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC.
    Afinitor Disperz: Maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of SEGA and partial seizures associated with TSC.

    Geriatric

    Zortress: Maximum dosage is based on everolimus trough concentrations (target of 3 to 8 ng/mL).
    Afinitor: 10 mg/day for advanced hormone receptor-positive breast cancer, advanced renal cell carcinoma, and renal angiomyolipoma with tuberous sclerosis complex (TSC); maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC.
    Afinitor Disperz: Maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of SEGA and partial seizures associated with TSC.

    Adolescents

    Zortress: Safety and efficacy have not been established.
    Afinitor: Maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC).
    Afinitor Disperz: Maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of SEGA and partial seizures associated with TSC.

    Children

    2 to 12 years:
    Zortress: Safety and efficacy have not been established.
    Afinitor: Maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC).
    Afinitor Disperz: Maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of SEGA and partial seizures associated with TSC.
    1 year:
    Zortress: Safety and efficacy have not been established.
    Afinitor/Afinitor Disperz: Maximum dosage is based on everolimus trough concentrations (target of 5 to 15 ng/mL) for the treatment of SEGA associated with TSC.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Advanced hormone receptor-positive, HER2-negative breast cancer, advanced renal cell cancer, pancreatic neuroendocrine tumors, or renal angiomyolipoma with tuberous sclerosis complex
    Mild hepatic impairment (Child-Pugh class A): Afinitor 7.5 mg PO once daily; decrease dose to 5 mg PO once daily if not well tolerated.
    Moderate hepatic impairment (Child-Pugh class B): Afinitor 5 mg PO once daily; decrease dose to 2.5 mg PO once daily if not well tolerated.
    Severe hepatic impairment (Child-Pugh class C): Afinitor 2.5 mg PO once daily may be initiated if the benefits of therapy outweigh the risk of toxicity from increased drug exposure; do not increase dose above 2.5 mg/day.
     
    Subependymal giant cell astrocytoma or partial seizures associated with tuberous sclerosis complex
    Mild or moderate hepatic impairment (Child-Pugh class A or B): No initial Afinitor dose adjustment is necessary; however individualize subsequent dosing based on therapeutic drug monitoring; assess Afinitor concentrations after 2 weeks of a hepatic status change; titrate dose to achieve trough concentrations of 5 to 15 ng/mL.
    Severe hepatic impairment (Child-Pugh class C): Initiate Afinitor at 2.5 mg/m2 PO once daily; individualize subsequent dosing based on therapeutic drug monitoring; assess Afinitor concentrations after 2 weeks and titrate dose to achieve/maintain trough concentrations of 5 to 15 ng/mL.
     
    Renal and liver transplant rejection prophylaxis
    Mild hepatic impairment (Child-Pugh class A): Reduce the initial Zortress daily dosage by approximately one-third; monitor whole blood trough concentrations and adjust dose as necessary. Dose titration is needed if a patient’s whole blood trough concentration as measured by an LC/MS/MS assay is not within the target trough concentration of 3 to 8 ng/mL.
    Moderate hepatic impairment (Child-Pugh class B): Reduce the initial Zortress daily dosage by approximately one-half; monitor whole blood trough concentrations and adjust dose as necessary. Dose titration is needed if a patient’s whole blood trough concentration as measured by an LC/MS/MS assay is not within the target trough concentration of 3 to 8 ng/mL.
    Severe hepatic impairment (Child-Pugh class C): Reduce the initial Zortress daily dosage by approximately one-half; monitor whole blood trough concentrations and adjust dose as necessary. Dose titration is needed if a patient’s whole blood trough concentration as measured by an LC/MS/MS assay is not within the target trough concentration of 3 to 8 ng/mL.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Everolimus should be taken at the same time each day.
    Take consistently either with food or without food.
    Initiate dexamethasone alcohol-free oral solution as a swish and spit mouthwash when starting treatment with Afinitor to reduce the incidence and severity of stomatitis; this has not been studied in pediatric patients.
    Do not combine everolimus tablets with everolimus tablets for oral suspension (Afinitor Disperz) to achieve the desired dose. Use one dosage form or the other. Afinitor Disperz should only be administered as a suspension.
    Follow procedures for proper handling of anticancer drugs. Wear gloves to avoid exposure to crushed tablets when preparing the Afinitor Disperz suspension; wash skin thoroughly if contact occurs.

    Oral Solid Formulations

    Swallow Afinitor and Zortress tablets whole with a full glass of water; do not break or crush tablets.
    For Zortress, administer every 12 hours and at the same time as cyclosporine.
    If an Afinitor dose is missed, take within 6 hours of missing the dose. If more than 6 hours have passed, skip the dose of the day and take the Afinitor dose the next day at the scheduled time.

    Extemporaneous Compounding-Oral

    Give Afinitor DISPERZ (everolimus tablets for oral suspension) as a suspension only; do not swallow whole.
    Prepare suspension in water only.
    Do not combine the 2 dosage forms (Afinitor tablets and Afinitor DISPERZ) to achieve the desired dose; use one dosage form or the other.
    If an Afinitor DISPERZ dose is missed, take within 6 hours of missing the dose. If more than 6 hours have passed, skip the dose of the day and take the Afinitor dose the next day at the scheduled dose.
     
    Preparation using an oral syringe:
    Add the prescribed dose of Afinitor DISPERZ into a 10-mL syringe; prepare an additional syringe if the dose exceeds 10 mg per syringe.
    Draw approximately 5 mL of water and 4 mL of air into the syringe.
    Place the filled syringe into a container (tip up) for 3 minutes, until the Afinitor DISPERZ tablets are in suspension.
    Administration using an oral syringe:
    Gently invert the syringe 5 times immediately prior to administration.
    After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles; give the entire contents of the syringe.
    Administer the suspension immediately after preparation; discard if not used within 60 minutes of preparation.
     
    Preparation using a small drinking glass:
    Add the prescribed dose of Afinitor DISPERZ into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water; prepare an additional glass if the total dose exceeds 10 mg per glass.
    Allow 3 minutes for suspension to occur.
    Administration using a small drinking glass:
    Stir the contents gently with a spoon, immediately prior to drinking.
    After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend remaining particles; give the entire contents of the glass.
    Administer the suspension immediately after preparation; discard if not used within 60 minutes of preparation.

    STORAGE

    Afinitor :
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container
    Afinitor DISPERZ:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container
    Zortress :
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Hypersensitivity reactions to everolimus have occurred. Reaction symptoms include, but are not limited to, anaphylactic reactions, angioedema, chest pain, dyspnea, and flushing. Afinitor is contraindicated for use by patients with a hypersensitivity to everolimus, any of its excipients, or any other rapamycin derivatives. Zortress is contraindicated for use by patients with a hypersensitivity to everolimus, sirolimus, or to components of the drug product.

    Pleural effusion, pneumonitis, pulmonary fibrosis

    Non-infectious pneumonitis and/or non-infectious pulmonary fibrosis has been observed in clinical trials of everolimus (both Afinitor and Zortress) and is a class effect of rapamycin derivatives. Some cases of pneumonitis have been reported with pulmonary hypertension, including pulmonary arterial hypertension, as a secondary event. Fatalities due to pneumonitis have occurred. Signs and symptoms may include hypoxia, dyspnea, cough, and pleural effusion. Patients who develop radiological changes suggestive of pneumonitis without accompanying symptomatology may continue to receive everolimus without dose modification; initiate appropriate monitoring in these patients. Afinitor therapy may need to be withheld and/or dose reduced in patients who develop moderate to severe noninfectious pneumonitis. In patients with life-threatening pneumonitis (ventilatory support indicated), discontinue everolimus treatment. Steroids may be indicated in patients with moderate to severe noninfectious pneumonitis. If corticosteroids or other immunosuppressive agents are used, administer concurrent prophylaxis for pneumocystis jiroveci pneumonia (PJP). PJP, sometimes with fatal outcome, has been observed in patients taking everolimus; these cases may be associated with concomitant use of everolimus with corticosteroids or other immunosuppressants.

    Fungal infection, infection

    Everolimus has immunosuppressive properties and may make patients more susceptible to infection. For Zortress, infection is a black box warning. Patients receiving immunosuppressants are at increased risk of developing bacterial, viral, fungal, and protozoal infections including opportunistic infections. Cautious use of combination immunosuppressant therapy is advised, as an overly immunosuppressed immune system can cause increased infection susceptibility. The incidence of serious infections has been reported at a higher frequency in pediatric patients younger than 6 years of age. Bacterial and fungal infections have occurred during everolimus treatment. Some cases have resulted in respiratory failure or death. Pre-existing invasive fungal infections should be resolved prior to treatment with Afinitor. If an invasive fungal infection is diagnosed while the patient is receiving treatment with Afinitor, discontinue everolimus until the infection is resolved.

    Immunosuppression, lymphoma, new primary malignancy, skin cancer, sunlight (UV) exposure

    Zortress has a black box warning for new primary malignancy such as lymphoma and skin cancer due to immunosuppression. Only physicians experienced in the management of systemic immunosuppressant therapy and organ transplant should use Zortress, and the physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Patients with increased risk for skin cancer should limit sunlight (UV) exposure by wearing protective clothing and using a sunscreen with a high protection factor. The risk of malignancy development appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Patients receiving everolimus (Zortress) should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.

    Nephrotoxicity, renal impairment

    Elevations in serum creatinine and proteinuria have been reported in patients receiving Afinitor. Use Afinitor with caution in patients with renal impairment. Clinical studies have not been conducted in patients with renal impairment; however, no dosage adjustments are recommended in these patients by the FDA-approved product labeling. Monitor renal function prior to Afinitor initiation and annually thereafter; monitor renal function at least every 6 months in patients who may have additional risk factors for renal dysfunction. Zortress has a black box warning about the risk of nephrotoxicity due to the concomitant use of cyclosporine. Use of standard doses of cyclosporine with everolimus can lead to increased nephrotoxicity and a lower glomerular filtration rate. In order to reduce renal dysfunction, use reduced cyclosporine doses in combination with everolimus and monitor the cyclosporine and everolimus whole blood trough concentrations. Also, monitor renal function, and consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to be drug related.

    Renal artery thrombosis, renal graft thrombosis, renal vein thrombosis

    Zortress has a black box warning for the risk of renal graft thrombosis. An increased risk of renal artery thrombosis and renal vein thrombosis that resulted in graft loss was reported among everolimus (Zortress) recipients mostly within the first 30 days after transplantation.

    Diabetes mellitus, hyperglycemia, hyperlipidemia, hypertriglyceridemia

    Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have occurred during treatment with everolimus. Use everolimus with caution in patients with diabetes mellitus, hyperlipidemia, or hypertriglyceridemia. Monitor fasting blood glucose and lipid profile prior to treatment with everolimus and annually thereafter; more frequent blood glucose monitoring is recommended in diabetic patients or if everolimus is co-administered with other medications that may cause hyperglycemia. If possible, blood glucose and lipids should be adequately controlled prior to treatment with everolimus. Consider the risks versus benefits of everolimus in patients with established hyperlipidemia before starting everolimus and during everolimus receipt for patients with severe, refractory hyperlipidemia. Everolimus has not been studied in patients with baseline cholesterol concentrations greater than 350 mg/dL.

    Hepatic disease

    Everolimus exposure is increased in patients with hepatic impairment. Adjustment of the dose of everolimus is recommended in patients with hepatic disease.

    Vaccination

    Vaccination with live vaccines should be avoided during treatment with everolimus (Zortress; Afinitor). Additionally, close contact with people who have received live vaccines should avoided. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. Consider completing recommended childhood vaccines prior to starting Afinitor therapy in pediatric patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who do not require immediate treatment. Use of an accelerated vaccination schedule may be necessary in these patients.

    Heart transplant, mortality

    Increased mortality within the first 3 months post-transplantation was reported in patients who received everolimus (Zortress) with or without induction therapy in de novo heart transplant patients in a clinical trial. Many deaths were associated with serious infections. Zortress is not indicated or recommended for use in heart transplant patients.

    Surgery, wound dehiscence

    Impaired or delayed wound healing, lymphocele, wound infection, incisional hernia, seroma, and wound dehiscence have been reported in everolimus (Zortress) recipients. Cautious use of everolimus in patients with a wound or with impending surgery may be warranted.

    Geriatric

    There was a higher incidence of death from any cause within 28 days of everolimus (Afinitor) plus exemestane therapy in geriatric patients (>= 65 years of age) with advanced hormone receptor-positive, HER2-negative breast cancer compared with younger patients (6% vs. 2%) in a randomized study. Additionally, more geriatric patients discontinued therapy due to adverse effects compared with younger patients (33% vs. 17%) in this study. No differences between elderly and younger patients have been identified in other studies. Although no initial Afinitor dosage adjustment is necessary in elderly patients, careful monitoring and appropriate dose adjustments based on toxicity are recommended.

    Lactase deficiency

    Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take Zortress, as diarrhea and malabsorption may occur.

    Pregnancy

    Based on animal studies and the mechanism of action, everolimus can cause fetal harm when administered during pregnancy. No adequate studies of everolimus exist in pregnant women, although there are a small number of case reports of pregnancy in transplant patients. Embryo-fetal toxicities occurred in rats when administered during organogenesis at maternal exposures lower than human exposures at a dose of 10 mg/day. Patients treated with everolimus should be counseled to avoid becoming pregnant during treatment and for 8 weeks after the last dose. If everolimus is used during pregnancy or if a patient becomes pregnant while receiving everolimus, the patient should be made aware of the potential harm to the fetus.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk of everolimus and discuss contraception requirements. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 8 weeks after treatment with everolimus. The manufacturer of Afinitor also recommends that male patients with female partners of reproductive potential should use effective contraception during treatment and for 4 weeks after the last dose. Everolimus may cause infertility in female and male patients. Azospermia and oligospermia have been reported with everolimus. Sperm motility, sperm count, plasma testosterone levels, and fertility were decreased at everolimus exposures approximately 10% to 81% of those achieved after a human dose of 10 mg daily; the fertility index was increased from 0% to 60% within 10 to 13 weeks after everolimus administration was stopped. Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone and follicle stimulating hormone have occurred in female patients taking Afinitor.

    Breast-feeding

    According to the manufacturer, either everolimus or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants; patients taking Afinitor should avoid breast-feeding for 2 weeks after the last dose. It is not known if everolimus is excreted in human breast milk.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 7.0-18.0
    lymphopenia / Delayed / 1.0-18.0
    hyperglycemia / Delayed / 0-17.0
    anemia / Delayed / 0-15.0
    atrial fibrillation / Early / 1.0-10.0
    hypertensive crisis / Early / 1.0-10.0
    heart failure / Delayed / 1.0-10.0
    hypophosphatemia / Delayed / 1.0-10.0
    renal tubular necrosis / Delayed / 1.0-10.0
    pulmonary embolism / Delayed / 1.0-10.0
    thromboembolism / Delayed / 1.0-10.0
    wound dehiscence / Delayed / 1.0-10.0
    osteonecrosis / Delayed / 1.0-10.0
    pleural effusion / Delayed / 1.0-10.0
    pulmonary edema / Early / 1.0-10.0
    stomatitis / Delayed / 3.0-9.0
    neutropenia / Delayed / 0-9.0
    dyspnea / Early / 2.5-7.0
    angioedema / Rapid / 0-6.8
    fever / Early / 0.2-6.0
    agitation / Early / 5.0-5.0
    anxiety / Delayed / 5.0-5.0
    fatigue / Early / 3.5-5.0
    pneumonitis / Delayed / 0-4.2
    hypokalemia / Delayed / 2.0-4.2
    hypertriglyceridemia / Delayed / 0.8-4.0
    malaise / Early / 3.5-3.5
    thrombocytopenia / Delayed / 1.0-3.2
    peripheral edema / Delayed / 0-3.0
    asthenia / Delayed / 2.2-3.0
    prolonged bleeding time / Delayed / 3.0-3.0
    diabetes mellitus / Delayed / 2.0-2.0
    leukopenia / Delayed / 0-2.0
    weight loss / Delayed / 0.5-2.0
    arthralgia / Delayed / 0.8-1.5
    edema / Delayed / 1.5-1.5
    epistaxis / Delayed / 0-1.0
    hypertension / Early / 1.0-1.0
    rash / Early / 1.0-1.0
    vasculitis / Delayed / 0-1.0
    pruritus / Rapid / 0.2-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    hyponatremia / Delayed / 1.0-1.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
    hemolytic-uremic syndrome / Delayed / 0-1.0
    thrombotic microangiopathy / Delayed / 0-1.0
    back pain / Delayed / 0.2-1.0
    dysgeusia / Early / 0.2-1.0
    headache / Early / 0.4-1.0
    hypercholesterolemia / Delayed / 0.8-1.0
    proteinuria / Delayed / 0.5-1.0
    pericardial effusion / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    cough / Delayed / 0.6-0.6
    onycholysis / Delayed / 0.5-0.5
    dizziness / Early / 0.5-0.5
    migraine / Early / 0.5-0.5
    insomnia / Early / 0.2-0.2
    dehydration / Delayed / 3.0
    pulmonary fibrosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    renal graft thrombosis / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known

    Moderate

    hypocalcemia / Delayed / 1.0-37.0
    hyperlipidemia / Delayed / 21.0-21.0
    hypomagnesemia / Delayed / 1.0-14.0
    wheezing / Rapid / 1.0-10.0
    palpitations / Early / 1.0-10.0
    angina / Early / 1.0-10.0
    chest pain (unspecified) / Early / 1.0-10.0
    hypotension / Rapid / 1.0-10.0
    sinus tachycardia / Rapid / 1.0-10.0
    gout / Delayed / 1.0-10.0
    hyperuricemia / Delayed / 1.0-10.0
    gastritis / Delayed / 1.0-10.0
    hematoma / Early / 1.0-10.0
    impaired wound healing / Delayed / 0-10.0
    lymphocele / Delayed / 1.0-10.0
    cataracts / Delayed / 1.0-10.0
    conjunctivitis / Delayed / 1.0-10.0
    blurred vision / Early / 1.0-10.0
    osteopenia / Delayed / 1.0-10.0
    osteoporosis / Delayed / 1.0-10.0
    paresis / Delayed / 1.0-10.0
    fluid retention / Delayed / 1.0-10.0
    ascites / Delayed / 1.0-10.0
    cholangitis / Delayed / 1.0-10.0
    cholestasis / Delayed / 1.0-10.0
    lymphadenopathy / Delayed / 1.0-10.0
    thrombocytosis / Delayed / 1.0-10.0
    hallucinations / Early / 1.0-10.0
    depression / Delayed / 1.0-10.0
    vitamin B12 deficiency / Delayed / 1.0-10.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 5.0-5.0
    erythema / Early / 4.0-4.0
    bleeding / Early / 3.0-3.0
    metabolic acidosis / Delayed / Incidence not known
    BK virus-associated nephropathy / Delayed / Incidence not known

    Mild

    acne vulgaris / Delayed / 10.0-22.0
    xerosis / Delayed / 13.0-13.0
    myalgia / Early / 1.0-11.0
    rhinorrhea / Early / 1.0-10.0
    nasal congestion / Early / 1.0-10.0
    hypertrichosis / Delayed / 1.0-10.0
    hirsutism / Delayed / 1.0-10.0
    night sweats / Early / 1.0-10.0
    acneiform rash / Delayed / 1.0-10.0
    hyperhidrosis / Delayed / 1.0-10.0
    alopecia / Delayed / 1.0-10.0
    nocturia / Early / 1.0-10.0
    Cushingoid features / Delayed / 1.0-10.0
    musculoskeletal pain / Early / 1.0-10.0
    weakness / Early / 1.0-10.0
    syncope / Early / 1.0-10.0
    paresthesias / Delayed / 1.0-10.0
    hypoesthesia / Delayed / 1.0-10.0
    drowsiness / Early / 1.0-10.0
    tremor / Early / 8.0-10.0
    leukocytosis / Delayed / 1.0-10.0
    chills / Rapid / 1.0-10.0
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with everolimus may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of everolimus could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If everolimus is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Everolimus is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Codeine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Acetaminophen; Hydrocodone: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of everoliumus is necessary. If everoliumus is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like everoliumus can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If everoliumus is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Tramadol: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with everolimus is necessary; the risk is greatest if everolimus is added to a stable dose of tramadol. Consider decreasing the dose of tramadol if necessary. Everolimus is a weak CYP3A4 inhibitor as well as a CYP2D6 inhibitor. Tramadol is metabolized by both CYP3A4 and CYP2D6.
    Alfentanil: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of everolimus with alfentanil is necessary; consider a reduced dose of alfentanil if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal and consider increasing the alfentanil dose if needed. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like everolimus can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If everolimus is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Aliskiren; Amlodipine: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amiodarone: (Major) A dose adjustment of everolimus is necessary when prescribed with amiodarone due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If amiodarone is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If amiodarone is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); amiodarone is a moderate CYP3A4 and P-gp inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased everolimus exposure by 3.5-fold to 4.4-fold.
    Amitriptyline: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of amitriptyline if clinically appropriate. Amitriptyline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of amitriptyline.
    Amitriptyline; Chlordiazepoxide: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of amitriptyline if clinically appropriate. Amitriptyline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of amitriptyline.
    Amlodipine: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of everolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend maximum atorvastatin doses of 10 mg/day unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. In a drug interaction study in healthy subjects, the pharmacokinetics of atorvastatin were not significantly altered by single dose administration of everolimus. (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Benazepril: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index. (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Olmesartan: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Telmisartan: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Valsartan: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Amoxapine: (Moderate) Monitor for an increase in amoxapine-related adverse reactions if coadministration with everolimus is necessary. Amoxapine is a CYP2D6 substrate and everolimus is a weak CYP2D6 inhibitor; concomitant use may increase plasma concentrations of amoxapine.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of clarithromycin with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of clarithromycin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); clarithromycin is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of clarithromycin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); clarithromycin is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Angiotensin-converting enzyme inhibitors: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Apalutamide: (Major) Depending on the indication, coadministration of apalutamide with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of apalutamide with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); apalutamide is a strong inducer of CYP3A4 and a weak P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    Aprepitant, Fosaprepitant: (Major) A dose adjustment of everolimus is necessary when prescribed with a multi-day oral regimen of aprepitant due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If aprepitant is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If aprepitant is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate. When administered as a 3-day oral regimen (125 mg/80 mg/80 mg), aprepitant is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with everolimus may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of everolimus could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If everolimus is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Everolimus is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of everoliumus is necessary. If everoliumus is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like everoliumus can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If everoliumus is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Aspirin, ASA; Pravastatin: (Moderate) Carefully weigh the benefits of combined use of everolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with everolimus. In a drug interaction study in healthy subjects, the pharmacokinetics of pravastatin were not significantly altered by single dose administration of everolimus.
    Atazanavir: (Major) Avoid coadministration of atazanavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of atazanavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of atazanavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of cobicistat with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of cobicistat with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); cobicistat is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of everolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend maximum atorvastatin doses of 10 mg/day unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. In a drug interaction study in healthy subjects, the pharmacokinetics of atorvastatin were not significantly altered by single dose administration of everolimus.
    Atorvastatin; Ezetimibe: (Moderate) Carefully weigh the benefits of combined use of everolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend maximum atorvastatin doses of 10 mg/day unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. In a drug interaction study in healthy subjects, the pharmacokinetics of atorvastatin were not significantly altered by single dose administration of everolimus.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Depending on the indication, coadministration of phenobarbital with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of phenobarbital with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); phenobarbital is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Depending on the indication, coadministration of phenobarbital with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of phenobarbital with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); phenobarbital is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%. (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with everolimus is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and everolimus is a weak CYP3A4 inhibitor.
    Benazepril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with everolimus may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of everolimus in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If everolimus is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Everolimus is a weak in vitro inhibitor of CYP3A4 and CYP2D6.
    Brigatinib: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with brigatinib. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Brigatinib is a P-gp inhibitor and may have the potential to increase concentrations of coadministered substrates of these transporters, such as everolimus. The manufacturer of Afinitor/Afinitor Disperz recommends avoiding coadministration with strong P-gp inhibitors for all indications; for patients receiving moderate P-gp inhibitors with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), the manufacturer recommends reducing the dose to 2.5 mg once daily, with a dose increase to 5 mg based on patient tolerance. For patients with subependymal giant cell astrocytoma (SEGA) with TSC receiving moderate P-gp inhibitors, the recommended starting dose of Afinitor/Afinitor Disperz is 2.5 mg/m2 once daily, rounded to the nearest tablet strength; subsequent dosing should be guided by therapeutic drug monitoring (TDM). Zortress dosing for prophylaxis of organ rejection should be guided by TDM.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Cabozantinib: (Moderate) Monitor for an increase in everolimus-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of everolimus may be necessary. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If cabozantinib is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If cabozantinib is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a substrate of P-glycoprotein (P-gp). Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Caffeine; Ergotamine: (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with everolimus is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and everolimus is a weak CYP3A4 inhibitor.
    Captopril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Carbamazepine: (Major) Depending on the indication, coadministration of carbamazepine with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of carbamazepine with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); carbamazepine is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ceritinib: (Major) Avoid coadministration of everolimus with ceritinib due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of ceritinib for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of chloramphenicol with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor.
    Chlorpheniramine; Codeine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with everolimus may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of everolimus could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If everolimus is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Everolimus is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with everolimus may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of everolimus could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If everolimus is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Everolimus is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ciprofloxacin: (Major) A dose adjustment of everolimus is necessary when prescribed with ciprofloxacin due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If ciprofloxacin is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If ciprofloxacin is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of clarithromycin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); clarithromycin is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Clofazimine: (Moderate) Monitor for increased toxicity of everolimus if used concomitantly with clofazimine. Concomitant use may increase the concentration of everolimus, increasing the risk of adverse effects. Everolimus is a CYP3A4 substrate that has a narrow therapeutic range; in vitro data suggest clofazimine inhibits CYP3A4.
    Clomipramine: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if coadministration with everolimus is necessary. Clomipramine is a CYP2D6 substrate and everolimus is a weak CYP2D6 inhibitor; concomitant use may increase plasma concentrations of clomipramine.
    Clozapine: (Moderate) Monitor for an increase in clozapine-related adverse reactions, including a risk of seizures, orthostasis, QT prolongation, if coadministration with everolimus is necessary; the effect of clozapine on neutropenia is not concentration-dependent. Clozapine is a CYP2D6 and CYP3A4 substrate, everolimus is a weak CYP3A4 and a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of clozapine.
    Cobicistat: (Major) Avoid coadministration of cobicistat with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of cobicistat with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); cobicistat is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Codeine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Codeine; Guaifenesin: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Codeine; Promethazine: (Moderate) Monitor for signs and symptoms of respiratory depression or sedation and analgesic response if coadministration of codeine and everolimus is necessary, particularly if everolimus is added after a stable dose of codeine is achieved. If concurrent use is necessary, use the lowest effective dose of codeine and carefully titrate to desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Codeine is a substrate of CYP3A4 and CYP2D6; everolimus is a weak CYP3A4 inhibitor and CYP2D6 inhibitor. Concurrent use of a CYP3A4 inhibitor may shift codeine metabolism away from the CYP3A4 pathway such that more codeine is metabolized by CYP2D6, resulting in a higher rate of conversion to morphine and subsequent adverse events including respiratory depression, hypotension, profound sedation, and death. Discontinuation of a CYP3A4 inhibitor in a patient stabilized on codeine may decrease opioid efficacy and lead to withdrawal symptoms. Alternatively, CYP2D6 inhibitors can increase the plasma concentration of codeine, but decrease exposure to morphine resulting in decreased analgesia or opioid withdrawal. Discontinuation of a CYP2D6 inhibitor results in decreased codeine concentrations as the effect of the inhibitor declines but increased morphine plasma concentrations which may result in increased or prolonged opioid-related adverse reactions and potentially fatal respiratory depression.
    Colchicine: (Moderate) Monitor for an increase in colchicine-related adverse reactions including neuromuscular toxicity and other serious toxicities if coadministration with everolimus is necessary, especially in patients with renal or hepatic impairment. Everolimus is a weak inhibitor of CYP3A while colchicine is a CYP3A4 substrate with a narrow therapeutic index.
    Colchicine; Probenecid: (Moderate) Monitor for an increase in colchicine-related adverse reactions including neuromuscular toxicity and other serious toxicities if coadministration with everolimus is necessary, especially in patients with renal or hepatic impairment. Everolimus is a weak inhibitor of CYP3A while colchicine is a CYP3A4 substrate with a narrow therapeutic index.
    Conivaptan: (Major) Avoid coadministration of conivaptan with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus; subsequent treatment with everolimus should be initiated no sooner than 1 week after the conivaptan infusion is completed. Coadministration of conivaptan with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); conivaptan is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Crizotinib: (Major) A dose adjustment of everolimus is necessary when prescribed with crizotinib due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If crizotinib is discontinued, increase the everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If crizotinib is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Cyclosporine: (Major) A dose adjustment of everolimus is necessary when prescribed with cyclosporine due to increased plasma concentrations of everolimus; increased exposure to cyclosporine may also occur. However, for some indications, everolimus is indicated to be administered in combination with cyclosporine. An increased incidence of nephrotoxicity may occur with concomitant use. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If cyclosporine is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If cyclosporine is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Monitor cyclosporine concentrations and adjust the dose as appropriate. The recommended cyclosporine therapeutic ranges when administered with everolimus (Zortress) are 100 to 200 ng/mL through Month 1 post-transplant, 75 to 150 ng/mL at Months 2 and 3 post-transplant, 50 to 100 ng/mL at Month 4 post-transplant, and 25 to 50 ng/mL from Month 6 through Month 12 post-transplant. Everolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate, as well as a weak CYP3A4 inhibitor. Cyclosporine is a CYP3A4 and P-gp inhibitor, as well as a CYP3A4 substrate with a narrow therapeutic index. Coadministration with other moderate CYP3A4/P-gp inhibitors increased everolimus exposure by 3.5-fold to 4.4-fold. Everolimus (Zortress) had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine. Steady-state exposure to everolimus was significantly increased by coadministration of a single dose of cyclosporine.
    Daclatasvir: (Major) Monitor for clinical response in patients taking everolimus concurrently with daclatasvir. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Daclatasvir is a P-gp inhibitor.
    Danazol: (Major) Everolimus is a substrate of CYP3A4. Coadministration with strong or moderate inhibitors of CYP3A4, such as danazol, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered.
    Darunavir: (Major) Avoid coadministration of everolimus with darunavir due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of darunavir for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of cobicistat with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); cobicistat is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold. (Major) Avoid coadministration of everolimus with darunavir due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of darunavir for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of cobicistat with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); cobicistat is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold. (Major) Avoid coadministration of everolimus with darunavir due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of darunavir for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of ritonavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); ritonavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Delavirdine: (Major) Avoid coadministration of delavirdine with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of delavirdine with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor.
    Desipramine: (Moderate) Monitor for an increase in desipramine-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of desipramine if clinically appropriate. Desipramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of desipramine.
    Dextromethorphan; Quinidine: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with quinidine. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Quinidine is a P-gp inhibitor, and may interact with P-gp substrates.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with everolimus may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of everolimus could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If everolimus is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Everolimus is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Dihydroergotamine: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with everolimus is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and everolimus is a weak CYP3A4 inhibitor.
    Diltiazem: (Major) A dose adjustment of everolimus is necessary when prescribed with diltiazem due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If diltiazem is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If diltiazem is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with everolimus is necessary. Disopyramide is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of disopyramide. Specific drug interaction studies have not been done for disopyramide; however, cases of life-threatening interactions have been reported when coadministered with moderate and strong CYP3A4 inhibitors. Coadministration of disopyramide with CYP3A4 inhibitors could result in a potentially fatal interaction.
    Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with everolimus is necessary. Everolimus is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Doxepin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of doxepin if clinically appropriate. Doxepin is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of doxepin.
    Dutasteride; Tamsulosin: (Moderate) Monitor for an increase in tamsulosin-related adverse reactions if coadministration with everolimus is necessary. Tamsulosin is a CYP3A4 and CYP2D6 substrate. Everolimus is a weak CYP3A4 inhibitor and a CYP2D6 inhibitor. The effects of coadministration of both a CYP3A4 and CYP2D6 inhibitor with tamsulosin have not been evaluated; however, there is a potential for significantly increased plasma concentrations of tamsulosin.
    Duvelisib: (Major) A dose adjustment of everolimus is necessary if coadministered with duvelisib due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If duvelisib is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If duvelisib is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased everolimus exposure by 4.4-fold.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like everolimus. Although documentation is lacking, use of echinacea with immunosuppressants is not recommended by some resources. Furthermore, everolimus is metabolized by CYP3A4 in the liver and there are some data suggesting Echinacea affects CYP3A4 and this may lead to altered everolimus exposure. In vitro data suggest that echinacea can inhibit the CYP3A4 isoenzyme; the clinical significance is not yet known. Other limited in vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. While the overall effect on CYP3A4 substrates is not known, it may be prudent to monitor everolimus blood concentrations if combined use is necessary.
    Efavirenz: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with everolimus is necessary. Efavirenz is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with everolimus is necessary. Efavirenz is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with everolimus is necessary. Efavirenz is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Administration of tezacaftor; ivacaftor may increase the systemic exposure of everolimus. Appropriate monitoring should be used; adjust everolimus dosage as necessary. Everolimus is a P-gp substrate; ivacaftor is a weak inhibitor of P-gp. (Moderate) Monitor for increased everolimus adverse reactions if coadministered with ivacaftor as concurrent use may increase everolimus exposure. Everolimus is a substrate of CYP3A4 and P-gp with a narrow therapeutic index; ivacaftor is an inhibitor of CYP3A4 and P-gp.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of everolimus and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Everolimus is a weak CYP3A (and CYP2D6) inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of cobicistat with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); cobicistat is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of cobicistat with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); cobicistat is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Emapalumab: (Moderate) Monitor for decreased efficacy of everolimus and adjust the dose as needed during coadministration with emapalumab. Everolimus is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
    Enalapril, Enalaprilat: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Enalapril; Felodipine: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Encorafenib: (Moderate) Coadministration of encorafenib with everolimus may result in increased toxicity or decreased efficacy of everolimus. Everolimus is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enzalutamide: (Major) Depending on the indication, coadministration of enzalutamide with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of enzalutamide with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib with everolimus due to the potential for altered plasma concentrations of everolimus which may lead to loss of activity or increased toxicity of everolimus. Everolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range. Erdafitinib is a time dependent inhibitor and inducer of CYP3A4; the effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Everolimus is also a P-glycoprotein (P-gp) substrate and erdafitinib is a P-gp inhibitor.
    Ergotamine: (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with everolimus is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and everolimus is a weak CYP3A4 inhibitor.
    Erythromycin: (Major) A dose adjustment of everolimus is necessary when prescribed with erythromycin due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If erythromycin is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If erythromycin is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); erythromycin is a moderate CYP3A4 and P-gp inhibitor. Coadministration with erythromycin increased everolimus exposure by 4.4-fold.
    Erythromycin; Sulfisoxazole: (Major) A dose adjustment of everolimus is necessary when prescribed with erythromycin due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If erythromycin is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If erythromycin is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); erythromycin is a moderate CYP3A4 and P-gp inhibitor. Coadministration with erythromycin increased everolimus exposure by 4.4-fold.
    Ethosuximide: (Moderate) Monitor for ethosuximide-related adverse reactions if coadministration with everolimus is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic range and everolimus is a weak CYP3A4 inhibitor.
    Ezetimibe; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of simvastatin was strongly discouraged due to reported interactions between cyclosporine and simvastatin. However, the FDA-approved labeling for Afinitor states no clinically significant pharmacokinetic interaction was observed in drug interaction studies between simvastatin and Afinitor.
    Fedratinib: (Major) A dose adjustment of everolimus is necessary if coadministered with fedratinib due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If fedratinib is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If fedratinib is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased everolimus exposure by 4.4-fold.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. If everolimus is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like everolimus can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If everolimus is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Flecainide: (Moderate) Monitor for an increase in flecainide-related adverse reactions, including QT prolongation, if coadministration with everolimus is necessary. Flecainide is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; plasma concentrations of flecainide may increase, especially in extensive CYP2D6 metabolizers.
    Flibanserin: (Major) Monitor for clinical response in patients taking everolimus concurrently with flibanserin. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Patients may also experience an increased risk of hypotension and syncope due to elevated flibanserin exposure, especially if taking multiple weak CYP3A4 inhibitors. Everolimus is a substrate of P-glycoprotein (P-gp) as well as a weak CYP3A4 inhibitor. Flibanserin is a P-gp inhibitor and a CYP3A4 substrate.
    Fluconazole: (Major) A dose adjustment of everolimus is necessary when prescribed with fluconazole due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If fluconazole is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If fluconazole is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor.
    Fluoxetine: (Major) Everolimus is a substrate of CYP3A4. Coadministration with weak inhibitors of CYP3A4, such as fluoxetine, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, everolimus is a mixed inhibitor of CYP2D6. The effect of everolimus on a CYP2D6 substrate, such as fluoxetine, has not been established.
    Fluoxetine; Olanzapine: (Major) Everolimus is a substrate of CYP3A4. Coadministration with weak inhibitors of CYP3A4, such as fluoxetine, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, everolimus is a mixed inhibitor of CYP2D6. The effect of everolimus on a CYP2D6 substrate, such as fluoxetine, has not been established.
    Fluvastatin: (Moderate) Carefully weigh the benefits of combined use of everolimus and fluvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of fluvastatin to 40 mg/day if combined with everolimus.
    Fluvoxamine: (Major) A dose adjustment of everolimus is necessary when prescribed with fluvoxamine due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If fluvoxamine is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If fluvoxamine is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor.
    Fosamprenavir: (Major) Avoid coadministration of fosamprenavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of fosamprenavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor.
    Fosinopril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Fosphenytoin: (Major) Depending on the indication, coadministration of fosphenytoin with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of fosphenytoin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer.
    Fostamatinib: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with fostamatinib. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of CYP3A4 and P-glycoprotein (P-gp). Fostamatinib is a weak CYP3A4 inhibitor and P-gp inhibitor.
    Grapefruit juice: (Major) Avoid coadministration of grapefruit juice with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of grapefruit juice with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); grapefruit juice is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration of everolimus with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Guaifenesin; Hydrocodone: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Haloperidol: (Moderate) Monitor for an increase in haloperidol-related adverse reactions if coadministration with everolimus is necessary. Haloperidol is a CYP3A4 and CYP2D6 substrate. Everolimus is a weak CYP3A4 inhibitor as well as a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of haloperidol.
    Homatropine; Hydrocodone: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Hydrocodone: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of everoliumus is necessary. If everoliumus is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like everoliumus can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If everoliumus is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Idelalisib: (Major) Avoid coadministration of idelalisib with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of idelalisib with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor.
    Imatinib: (Major) A dose adjustment of everolimus is necessary when prescribed with imatinib due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If imatinib is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If imatinib is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Imipramine: (Moderate) Monitor for an increase in imipramine-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of imipramine if clinically appropriate. Imipramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of imipramine.
    Indinavir: (Major) Avoid coadministration of indinavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of indinavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Depending on the indication, coadministration of rifampin with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of rifampin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); rifampin is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with rifampin decreased everolimus exposure by 63%.
    Isoniazid, INH; Rifampin: (Major) Depending on the indication, coadministration of rifampin with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of rifampin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); rifampin is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with rifampin decreased everolimus exposure by 63%.
    Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions, including hypotension, if coadministration with everolimus is necessary. Isradipine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of isradipine.
    Istradefylline: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with istradefylline 40 mg daily. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Everolimus is a substrate of CYP3A4 with a narrow therapeutic index; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
    Itraconazole: (Major) Avoid coadministration of itraconazole with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of itraconazole with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); itraconazole is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Ivacaftor: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with ivacaftor as concurrent use may increase everolimus exposure. Everolimus is a substrate of CYP3A4 and P-gp with a narrow therapeutic index; ivacaftor is an inhibitor of CYP3A4 and P-gp.
    Ivosidenib: (Moderate) Monitor for loss of efficacy of everolimus during coadministration of ivosidenib; an everolimus dose adjustment may be necessary. Everolimus is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased everolimus concentrations.
    Ixabepilone: (Moderate) Monitor for an increase in acute ixabepilone-related adverse reactions if coadministration with everolimus is necessary (e.g., frequently monitor peripheral blood counts between cycles). Ixabepilone is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor. The effect of weak CYP3A4 inhibitors on ixabepilone exposure has not been studied; however, concomitant use may increase plasma concentrations of ixabepilone.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of ketoconazole with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); ketoconazole is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with ketoconazole increased everolimus exposure by 15-fold.
    Lanreotide: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with lanreotide. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of CYP3A4. Somatostatin analogs, such as lanreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4.
    Lapatinib: (Major) Monitor for clinical response in patients taking everolimus concurrently with lapatinib. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Lapatinib is a P-gp inhibitor.
    Lefamulin: (Major) A dose adjustment of everolimus is necessary if coadministered with oral lefamulin due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If oral lefamulin is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If oral lefamulin is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor increased everolimus exposure by 4.4-fold.
    Letermovir: (Major) A dose adjustment of everolimus is necessary when prescribed with letermovir due to increased plasma concentrations of everolimus. In patients also receiving cyclosporine, avoid coadministration of letermovir with everolimus (Afinitor; Afinitor Disperz), because the magnitude of the interaction may be increased. Coadministration of everolimus (Zortress) is not recommended in these patients without close monitoring of everolimus whole blood trough concentrations. Dosage adjustment recommendations for use of letermovir without cyclosporine are as follows: for patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If letermovir is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If letermovir is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In the presence of a moderate inhibitor, the AUC of everolimus was increased by 4.4-fold and by 15-fold with a strong inhibitor.
    Lisinopril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Live Vaccines: (Severe) Do not administer live vaccines to everolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving everolimus. Before initiation of everolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Everolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Lomitapide: (Major) Concomitant use of lomitapide and everolimus may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Everolimus is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of lopinavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); lopinavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold. (Major) Avoid coadministration of ritonavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of ritonavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); ritonavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Lovastatin: (Major) Guidelines recommend avoiding coadministration of lovastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of lovastatin was strongly discouraged due to reported interactions between cyclosporine and lovastatin.
    Lovastatin; Niacin: (Major) Guidelines recommend avoiding coadministration of lovastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of lovastatin was strongly discouraged due to reported interactions between cyclosporine and lovastatin.
    Lumacaftor; Ivacaftor: (Major) Depending on the indication, coadministration of lumacaftor; ivacaftor with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of lumacaftor; ivacaftor with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Lumacaftor; Ivacaftor: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with ivacaftor as concurrent use may increase everolimus exposure. Everolimus is a substrate of CYP3A4 and P-gp with a narrow therapeutic index; ivacaftor is an inhibitor of CYP3A4 and P-gp.
    Maprotiline: (Moderate) Monitor for an increase in maprotiline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of maprotiline if clinically appropriate. Maprotiline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of maprotiline.
    Mefloquine: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with mefloquine. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Mefloquine is a P-gp inhibitor in vitro, and may interact with P-gp substrates although the clinical relevance is unknown.
    Mephobarbital: (Major) Depending on the indication, coadministration of mephobarbital with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of mephobarbital with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); mephobarbital is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    Methadone: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of everolimus is necessary; consider reducing the dose of methadone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 and CYP2D6 substrate; coadministration with weak CYP3A4/2D6 inhibitors like everolimus can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If everolimus is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary. Midazolam is a sensitive CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor. Coadministration with everolimus increased midazolam exposure by 30%.
    Mifepristone: (Major) Avoid coadministration of mifepristone with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of mifepristone with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); mifepristone is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Mitotane: (Major) Depending on the indication, coadministration of mitotane with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of mitotane with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Moexipril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with everolimus.
    Nefazodone: (Major) Avoid coadministration of nefazodone with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of nefazodone with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Nelfinavir: (Major) Avoid coadministration of nelfinavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of nelfinavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); nelfinavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Niacin; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of simvastatin was strongly discouraged due to reported interactions between cyclosporine and simvastatin. However, the FDA-approved labeling for Afinitor states no clinically significant pharmacokinetic interaction was observed in drug interaction studies between simvastatin and Afinitor.
    Nimodipine: (Moderate) Monitor blood pressure and watch for an increase in nimodipine-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of nimodipine if needed. Nimodipine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of nimodipine.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with everolimus due to increased plasma concentrations of nisoldipine. Nisoldipine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    Nortriptyline: (Moderate) Monitor for an increase in nortriptyline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of nortriptyline if clinically appropriate. Nortriptyline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of nortriptyline.
    Octreotide: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with octreotide. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of CYP3A4. Somatostatin analogs, such as octreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of ritonavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); ritonavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of everoliumus is necessary. If everoliumus is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like everoliumus can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If everoliumus is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Perindopril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Perindopril; Amlodipine: (Moderate) Monitor for increased everolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase everolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; everolimus is a substrate of CYP3A4 with a narrow therapeutic index. (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of amitriptyline if clinically appropriate. Amitriptyline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of amitriptyline.
    Phenobarbital: (Major) Depending on the indication, coadministration of phenobarbital with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of phenobarbital with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); phenobarbital is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    Phenytoin: (Major) Depending on the indication, coadministration of phenytoin with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of phenytoin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
    Pimozide: (Major) Avoid coadministration of pimozide with everolimus due to the risk of increased plasma concentrations of pimozide, which may result in ventricular arrhythmias. Pimozide is a CYP3A4 and CYP2D6 substrate. Everolimus is a weak CYP3A4 inhibitor and a CYP2D6 inhibitor.
    Pitavastatin: (Major) Guidelines recommend avoiding coadministration of pitavastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and everolimus, a P-gp substrate, may increase the exposure of everolimus. Use caution when everolimus is used in combination with P-gp inhibitors. If these agents are used together, reduce the everolimus (Afinitor) dose.
    Posaconazole: (Major) Avoid coadministration of posaconazole with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of posaconazole with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); posaconazole is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Pravastatin: (Moderate) Carefully weigh the benefits of combined use of everolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with everolimus. In a drug interaction study in healthy subjects, the pharmacokinetics of pravastatin were not significantly altered by single dose administration of everolimus.
    Primidone: (Major) Depending on the indication, coadministration of primidone with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of primidone with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); primidone is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    Propafenone: (Major) Avoid coadministration of propafenone with everolimus due to the risk of increased exposure to both drugs. Everolimus is a weak CYP3A4 inhibitor and a CYP2D6 inhibitor, as well as a P-glycoprotein (P-gp) substrate. Propafenone is a CYP3A4 and CYP2D6 substrate, in addition to being a P-gp inhibitor. The combination of CYP3A4 and CYP2D6 inhibition may significantly increase propafenone concentrations, increasing the risk of proarrhythmia and other adverse events, while P-gp inhibition increases everolimus exposure.
    Protriptyline: (Moderate) Monitor for an increase in protriptyline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of protriptyline if clinically appropriate. Protriptyline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of protriptyline.
    Quinapril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Quinidine: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with quinidine. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Quinidine is a P-gp inhibitor, and may interact with P-gp substrates.
    Ramipril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Ranolazine: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with ranolazine. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Ranolazine is a P-gp inhibitor.
    Ribociclib: (Major) Avoid coadministration of everolimus with ribociclib due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of ribociclib for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of everolimus with ribociclib due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of ribociclib for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Rifampin: (Major) Depending on the indication, coadministration of rifampin with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of rifampin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); rifampin is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with rifampin decreased everolimus exposure by 63%.
    Ritonavir: (Major) Avoid coadministration of ritonavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of ritonavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); ritonavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Sapropterin: (Major) Monitor for clinical response in patients taking everolimus concurrently with sapropterin. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Sapropterin is a P-gp inhibitor.
    Saquinavir: (Major) Avoid coadministration of saquinavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of saquinavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); saquinavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of simvastatin was strongly discouraged due to reported interactions between cyclosporine and simvastatin. However, the FDA-approved labeling for Afinitor states no clinically significant pharmacokinetic interaction was observed in drug interaction studies between simvastatin and Afinitor.
    Simvastatin; Sitagliptin: (Major) Guidelines recommend avoiding coadministration of simvastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of simvastatin was strongly discouraged due to reported interactions between cyclosporine and simvastatin. However, the FDA-approved labeling for Afinitor states no clinically significant pharmacokinetic interaction was observed in drug interaction studies between simvastatin and Afinitor.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with voxilaprevir. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Voxilaprevir is a P-gp inhibitor, and may interact with P-gp substrates.
    St. John's Wort, Hypericum perforatum: (Major) Depending on the indication, coadministration of St. John's Wort with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of St. John's Wort with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); St. Johns Wort is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if everolimus must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. If everolimus is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like everolimus can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If everolimus is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Tamsulosin: (Moderate) Monitor for an increase in tamsulosin-related adverse reactions if coadministration with everolimus is necessary. Tamsulosin is a CYP3A4 and CYP2D6 substrate. Everolimus is a weak CYP3A4 inhibitor and a CYP2D6 inhibitor. The effects of coadministration of both a CYP3A4 and CYP2D6 inhibitor with tamsulosin have not been evaluated; however, there is a potential for significantly increased plasma concentrations of tamsulosin.
    Telithromycin: (Major) Avoid coadministration of telithromycin with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of telithromycin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate. Telithromycin is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Testosterone: (Major) Everolimus is an inhibitor and substrate of CYP3A4 and Pgp. Coadministration with inhibitors of Pgp, such as testosterone, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, testosterone is a substrate of CYP3A4. The effect of everolimus on testosterone pharmacokinetics has not been established; however, pharmacokinetic studies showed no significant impact of the coadministration of everolimus with the CYP3A4 and Pgp substrate atorvastatin.
    Tezacaftor; Ivacaftor: (Moderate) Administration of tezacaftor; ivacaftor may increase the systemic exposure of everolimus. Appropriate monitoring should be used; adjust everolimus dosage as necessary. Everolimus is a P-gp substrate; ivacaftor is a weak inhibitor of P-gp. (Moderate) Monitor for increased everolimus adverse reactions if coadministered with ivacaftor as concurrent use may increase everolimus exposure. Everolimus is a substrate of CYP3A4 and P-gp with a narrow therapeutic index; ivacaftor is an inhibitor of CYP3A4 and P-gp.
    Thioridazine: (Moderate) Monitor for thioridazine-related adverse events if coadministered with everolimus. Thioridazine exposure may be increased which may increase the risk of QT prolongation and serious, potentially fatal, cardiac arrhythmias, such as torsades de pointes. Thioridazine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Tipranavir: (Major) Avoid coadministration of tipranavir with everolimus (Afinitor; Afinitor Disperz) due to an unpredictable effect on plasma concentrations of everolimus. Coadministration of tipranavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Additionally, everolimus is a P-glycoprotein (P-gp) substrate. Tipranavir in combination with ritonavir inhibits P-gp after the first dose, followed by induction of P-gp over time; thus, it is difficult to predict the net effect of tipranavir plus ritonavir on plasma concentrations of drugs that are dual substrates of CYP3A4 and P-gp, such as everolimus.
    Tocilizumab: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with tocilizumab. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Tocilizumab is a P-gp inhibitor, and may interact with P-gp substrates.
    Tofacitinib: (Major) Avoid use tofacitinib in combination with potent immunosuppressants such as everolimus. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Tramadol: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with everolimus is necessary; the risk is greatest if everolimus is added to a stable dose of tramadol. Consider decreasing the dose of tramadol if necessary. Everolimus is a weak CYP3A4 inhibitor as well as a CYP2D6 inhibitor. Tramadol is metabolized by both CYP3A4 and CYP2D6.
    Trandolapril: (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Trandolapril; Verapamil: (Major) A dose adjustment of everolimus is necessary when prescribed with verapamil due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If verapamil is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If verapamil is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); verapamil is a moderate CYP3A4 and P-gp inhibitor. Coadministration with verapamil increased everolimus exposure by 3.5-fold. (Moderate) The risk of angioedema, with or without respiratory impairment, may be increased if everolimus is given with other drugs known to cause angioedema such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). In a pooled analysis of randomized, double-blind oncology clinical trials, angioedema was reported in 6.8% of patients receiving concomitant everolimus and ACE inhibitor therapy, compared to 1.3% of patients with an ACE inhibitor alone. If coadministration is necessary, educate patients regarding signs and symptoms of angioedema and monitor therapy closely.
    Trimipramine: (Moderate) Monitor for an increase in trimipramine-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of trimipramine if clinically appropriate. Trimipramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of trimipramine.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Upadacitinib: (Major) Avoid use upadacitinib in combination with potent immunosuppressants such as everolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Venetoclax: (Major) If concomitant use is necessary, take everolimus at least 6 hours before venetoclax; monitor for clinical response and everolimus-related toxicities. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Venetoclax is an inhibitor of P-glycoprotein (P-gp) and everolimus is a P-gp substrate with a narrow therapeutic index (NTI). Coadministration of a single dose of venetoclax with another P-gp substrate with a NTI led to an increase in the Cmax and AUC values of the P-gp substrate by 35% and 9%, respectively. The manufacturer of Afinitor/Afinitor Disperz recommends avoiding coadministration with strong P-gp inhibitors for all indications; for patients receiving moderate P-gp inhibitors with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), the manufacturer recommends reducing the dose to 2.5 mg once daily, with a dose increase to 5 mg based on patient tolerance. For patients with subependymal giant cell astrocytoma (SEGA) with TSC receiving moderate P-gp inhibitors, the recommended starting dose of Afinitor/Afinitor Disperz is 2.5 mg/m2 once daily, rounded to the nearest tablet strength; subsequent dosing should be guided by therapeutic drug monitoring (TDM). Zortress dosing for prophylaxis of organ rejection should be guided by TDM.
    Venlafaxine: (Moderate) Monitor for an increase in venlafaxine-related adverse reactions if coadministration with everolimus is necessary. Venlafaxine is a sensitive CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of venlafaxine.
    Verapamil: (Major) A dose adjustment of everolimus is necessary when prescribed with verapamil due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If verapamil is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If verapamil is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); verapamil is a moderate CYP3A4 and P-gp inhibitor. Coadministration with verapamil increased everolimus exposure by 3.5-fold.
    Vinblastine: (Moderate) Monitor for increased severity or earlier onset of vinblastine-related adverse reactions if coadministration with everolimus is necessary. Vinblastine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of vinblastine.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with everolimus is necessary. Vinorelbine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    Voriconazole: (Major) Avoid coadministration of everolimus with voriconazole due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of voriconazole for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.

    PREGNANCY AND LACTATION

    Pregnancy

    Based on animal studies and the mechanism of action, everolimus can cause fetal harm when administered during pregnancy. No adequate studies of everolimus exist in pregnant women, although there are a small number of case reports of pregnancy in transplant patients. Embryo-fetal toxicities occurred in rats when administered during organogenesis at maternal exposures lower than human exposures at a dose of 10 mg/day. Patients treated with everolimus should be counseled to avoid becoming pregnant during treatment and for 8 weeks after the last dose. If everolimus is used during pregnancy or if a patient becomes pregnant while receiving everolimus, the patient should be made aware of the potential harm to the fetus.

    According to the manufacturer, either everolimus or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants; patients taking Afinitor should avoid breast-feeding for 2 weeks after the last dose. It is not known if everolimus is excreted in human breast milk.

    MECHANISM OF ACTION

    Everolimus inhibits the mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/Akt pathway. The mTOR pathway has been shown to be dysregulated in several cancers, resulting in tumor cell growth and proliferation. In normal cellular function, PI3K and Akt are activated in response to growth factor and/or mitogenic stimuli; this activity is modulated by the tumor suppressor gene, PTEN. Excess stimulation of the PI3K/Akt pathway results in an increase in mTOR activity, resulting in increased mRNA translation. Everolimus inhibits mTOR by forming a complex (mTOR complex 1, mTORC1) with the intracellular protein FK506 binding protein-12 (FKBP-12), downstream of PI3K/Akt stimulation. Inhibition of mTOR is complete after a 10 mg daily dose. This reduces the activity of S6 ribosomal protein kinase (S6K1), a substrate of mTORC1, and eukaryotic initiation factor 4E-binding protein (4E-BP1), both downstream effectors of mTOR which are involved in protein synthesis. S6K1 also phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. Reduced activity of S6K1 and 4E-BP1 can cause cell cycle arrest in the G1 phase. In addition, in clear-cell renal cell carcinoma, loss of the von-Hippel Landau tumor suppressor gene leads to an accumulation of the hypoxia-inducible factor 1 (HIF-1) and over expression of HIF-1 target gene products. HIF-1 target gene products include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and glucose transporter 1 (GLUT 1). These products cause an increase in angiogenesis, cell proliferation, and glucose metabolism. Everolimus has been shown to inhibit the expression of HIF-1 and subsequently reduce the expression of the HIF-1 target gene products.
     
    In kidney transplant rejection prophylaxis, everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. In vivo, everolimus binds to the FK506 binding protein, and the complex binds to and inhibits mTOR. In the presence of everolimus phosphorylation of p70S6 ribosomal protein kinase (p70S6K), a substrate of mTOR is inhibited. As a result, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited.

    PHARMACOKINETICS

    Everolimus is administered orally. It is about 74% bound to plasma proteins in heathy subjects and patients with moderate hepatic impairment. The blood-to-plasma ratio of everolimus is 17% to 73%, and is concentration dependent at levels from 5 to 5000 ng/mL. Following administration of everolimus 10 mg/day, about 20% of the dose was found in the plasma of cancer patients. In a single-dose pharmacokinetic study in kidney transplant patients, the apparent volume of distribution (Vd) ranged from 128 to 589 L. At steady state, the Vd was 110 L, the clearance was 8.8 L/hour, and the elimination half-life was 30 +/- 11 hours (range, 19 to 53 hours) in kidney transplant patients who received everolimus (Zortress) 0.75 mg PO twice daily. After the oral administration of a single 3-mg dose of radiolabeled everolimus in organ transplant patients also receiving cyclosporine, 80% of the radioactivity was recovered from the feces and 5% was excreted in the urine; the parent drug was not detected in urine or feces. Elimination studies have not been performed in cancer patients.
     
    Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A4, CYP2D6, P-glycoprotein (P-gp)
    Everolimus is a substrate of CYP3A4 and P-gp. Six main metabolites (3 monohydroxylated metabolites, 2 hydrolytic ring-opened products, and a phosphatidylcholine conjugate) have been identified; these metabolites have about 100 times less activity than everolimus. It is also a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6 in vitro. Strong CYP3A4 and/or P-gp inhibitors and strong CYP3A4 and/or P-gp inducers have been shown to significantly alter everolimus concentrations in drug interaction studies; the concomitant use of these agents and everolimus should be avoided if possible; dosage adjustments may be necessary.

    Oral Route

    Steady state was reached after 4 days of twice daily dosing in kidney transplant patients (0.75 mg) and within 2 weeks following once-daily dosing in patients with advanced solid tumors. After twice-daily dosing in kidney transplant patients, Cmax levels of 11.1 +/- 4.6 ng/mL were achieved at a Tmax of 1 to 2 hours; the mean AUC value was 75 +/- 31 ng/mL x hour. A Tmax of 1 to 2 hours was also observed in patients with advanced solid tumors (dose range, 5 mg to 70 mg). Everolimus dose proportionality has been demonstrated over the dose range of 0.5 mg to 2 mg twice daily in kidney transplant patients, 5 mg to 10 mg daily in patients with advanced solid tumors, and 1.35 mg/m2 to 14.4 mg/m2 in patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). The Cmax was less than dose proportional in patients with advanced solid tumors receiving single doses of 20 mg and higher, but the AUC values were proportional over the dose range of 5 mg to 70 mg. The relative bioavailability of everolimus tablets for oral suspension (Afinitor Disperz) is equivalent to everolimus (Afinitor) tablets. The Cmax is 20% to 36% lower with Afinitor Disperz compared with Afinitor tablets; however, the predicted steady-state trough concentrations are similar following daily administration.
     
    Effects of Food: Administration of everolimus with a high-fat meal has been shown to reduce the Cmax and AUC values; administer everolimus consistently either with or without food. In healthy subjects who received Afinitor 10 mg with a high-fat meal, the Cmax and AUC decreased by 54% and 22%, respectively; administration with a low-fat meal reduced the Cmax by 42% and AUC by 32%. In healthy patients who received Afinitor Disperz 9 mg, high-fat meals containing approximately 1000 calories and 55 grams of fat reduced the everolimus Cmax by 60% and AUC by 12%; low-fat meals containing approximately 500 calories and 20 grams of fat reduced the everolimus Cmax and AUC by 50% and 30%, respectively. In 24 healthy subjects who took Zortress with a high-fat breakfast (44.5 grams of fat), the everolimus Cmax and AUC were reduced by 60% and 16%, respectively, compared with fasting administration; additionally, the Tmax was delayed by 1.3 hours.