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

    BOXED WARNING

    Fungal infection, infection

    Patients receiving everolimus are at increased risk of developing a bacterial infection, viral infection, fungal infection, or protozoal infection, including opportunistic infections; for Zortress, infection is a black box warning. Cautious use of combination immunosuppressant therapy is advised, as an overly immunosuppressed immune system can increase the susceptibility for infection. The incidence of serious infections has been reported at a higher frequency in pediatric patients younger than 6 years of age. Antimicrobial prophylaxis for pneumocystis jirovecii pneumonia (PJP) should be administered when concomitant use of corticosteroids or other immunosuppressive agents are required with Afinitor; PJP prophylaxis and cytomegalovirus (CMV) prophylaxis is also recommended in transplant recipients. Pre-existing invasive fungal infections should be resolved prior to treatment with Afinitor. Monitor patients for signs and symptoms of infection; an interruption or discontinuation of therapy may be necessary if an infection occurs during treatment.

    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 disease, renal impairment

    Use everolimus with caution in patients with a history of renal disease, as everolimus treatment has been associated with renal impairment and nephrotoxicity.  In patients receiving Afinitor, monitor renal function prior to starting therapy and annually thereafter; monitor renal function at least every 6 months in patients who have additional risk factors for renal failure. Renal function should also be monitored during the administration of Zortress. Because Zortress administered in combination with standard-dose cyclosporine increases the risk of nephrotoxicity in kidney transplant patients, reduced doses of cyclosporine are required when given with Zortress. Zortress has not been studied with standard-dose tacrolimus; however, reduced doses of tacrolimus should be used in combination with Zortress to minimize the potential risk of nephrotoxicity. Consider changing to other immunosuppressive therapies in transplant patients if renal impairment occurs and does not improve after dose adjustments or if renal dysfunction is thought to be drug-related.

    Liver transplant, renal artery thrombosis, renal graft thrombosis, renal vein thrombosis

    An increased risk of renal artery thrombosis, renal vein thrombosis, and renal graft thrombosis resulting in graft loss was reported among de novo kidney transplant patients treated with everolimus (Zortress), mostly within the first 30 days after transplantation. Mammalian target of rapamycin (mTOR) inhibitors are also associated with an increase in hepatic artery thrombosis (HAT), mostly occurring within the first 30 days after transplant and leading to graft loss or death. Do not administer Zortress earlier than 30 days after liver transplant.

    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 certain patients with breast cancer, neuroendocrine tumors of pancreatic, GI, or lung origin, renal cell carcinoma, and certain tuberous sclerosis complex (TSC)-associated conditions (e.g., subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma, and partial-onset seizures); Zortress is used for kidney or liver transplant rejection prophylaxis
    May increase the 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 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. Treatment with everolimus significantly improved the median progression-free survival compared with placebo in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially in a multicenter, randomized, double-blind clinical trial (4.9 months vs. 1.9 months); the objective response rate was 2% versus 0%, respectively.

    For the treatment of advanced renal cell cancer (RCC) in combination with lenvatinib, following one prior anti-angiogenic therapy.
    NOTE: Lenvatinib is FDA-approved in combination with everolimus for this indication.
    Oral dosage (Afinitor only)
    Adults

    5 mg PO once daily in combination with lenvatinib (18 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. Treatment with lenvatinib plus everolimus significantly improved investigator-assessed median progression-free survival compared with everolimus monotherapy in a multicenter, open-label, phase 2 clinical trial (14.6 months vs. 5.5 months); this was supported by a retrospective independent review of radiographs (HR 0.43). The median overall survival was 25.5 months with combination therapy compared with 15.4 months in patients treated with everolimus monotherapy 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 the 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 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, the use of everolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so a 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 per 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%) in patients with progressive SEGA associated with tuberous sclerosis complex (TSC) in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (EXIST-1). Patients aged 65 or younger 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%). 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 and seizure frequency 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 1/2 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 per 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%) in patients with progressive SEGA associated with tuberous sclerosis complex (TSC) in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (EXIST-1 trial). 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%). 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 and seizure frequency 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 1/2 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 (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 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 (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 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with everolimus significantly improved the confirmed response rate compared with placebo (42% vs. 0%) in a randomized, double-blind, phase 3 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    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 2 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    †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

    Breast cancer, pancreatic neuroendocrine tumors, renal cell cancer, or renal angiomyolipoma with tuberous sclerosis complex (TSC)
    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 the dose above 2.5 mg/day.
     
    Subependymal giant cell astrocytoma (SEGA) or partial seizures associated with TSC
    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 2 weeks after a change in hepatic function; 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 the 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 the 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 the 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.
    Consider the use of dexamethasone alcohol-free oral solution as a swish and spit mouthwash when starting treatment with everolimus (Afinitor) to reduce the incidence and severity of stomatitis; this has not been studied in pediatric patients.
    Do not combine everolimus tablets (Afinitor) 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.

    Oral Solid Formulations

    Swallow everolimus tablets (Afinitor and Zortress) 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 or tacrolimus.
    If an Afinitor dose is missed, it can be given 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. Do not make up the dose that was missed.

    Oral Liquid Formulations

    Give Afinitor DISPERZ as a suspension only; do not swallow everolimus tablets for oral suspension whole.
    Wear gloves when preparing suspensions for another person to avoid possible contact with everolimus.
    Prepare suspension in water only.
    Do not combine the 2 Afinitor 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 and administration using an oral syringe:
    Place the prescribed dose of Afinitor DISPERZ into a 10-mL syringe; prepare an additional syringe if the dose exceeds a maximum of 10 mg per syringe. Do not break or crush tablets.
    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.
    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 the remaining particles. Administer the entire contents of the syringe.
     
    Preparation and administration 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 a maximum of 10 mg per glass. Do not break or crush tablets.
    Allow 3 minutes for suspension to occur.
    Immediately prior to drinking, stir the contents of the glass gently with a spoon.
    After administration of the prepared suspension, add 25 mL of water to the glass and stir with the same spoon to resuspend the remaining particles. Administer the entire contents of the glass.

    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, including anaphylactic reactions, angioedema, chest pain, dyspnea, and flushing. Afinitor is contraindicated for use by patients with a hypersensitivity to everolimus or other rapamycin derivatives. Zortress is contraindicated for use by patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug product.

    Interstitial lung disease, pneumonitis

    Non-infectious pneumonitis/interstitial lung disease (ILD) and/or non-infectious pulmonary fibrosis have been observed in clinical trials of everolimus (both Afinitor and Zortress), even at reduced doses, and is a class effect of rapamycin derivatives; fatalities have occurred. Some cases of pneumonitis have been reported with pulmonary hypertension, including pulmonary arterial hypertension, as a secondary event. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms, or in patients presenting with symptoms consistent with infectious pneumonitis but not responding to antibiotic therapy and in whom infectious, neoplastic, and other non-drug causes have been ruled out. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) may be considered in the differential diagnosis. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if ILD occurs. Corticosteroids may be indicated until clinical symptoms resolve; administer PFP prophylaxis if patients are taking concomitant corticosteroids or other immunosuppressive agents. Treatment with Afinitor/Afinitor Disperz may be continued without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms; imaging appears to overestimate the incidence of clinical pneumonitis.

    Fungal infection, infection

    Patients receiving everolimus are at increased risk of developing a bacterial infection, viral infection, fungal infection, or protozoal infection, including opportunistic infections; for Zortress, infection is a black box warning. Cautious use of combination immunosuppressant therapy is advised, as an overly immunosuppressed immune system can increase the susceptibility for infection. The incidence of serious infections has been reported at a higher frequency in pediatric patients younger than 6 years of age. Antimicrobial prophylaxis for pneumocystis jirovecii pneumonia (PJP) should be administered when concomitant use of corticosteroids or other immunosuppressive agents are required with Afinitor; PJP prophylaxis and cytomegalovirus (CMV) prophylaxis is also recommended in transplant recipients. Pre-existing invasive fungal infections should be resolved prior to treatment with Afinitor. Monitor patients for signs and symptoms of infection; an interruption or discontinuation of therapy may be necessary if an infection occurs during treatment.

    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 disease, renal impairment

    Use everolimus with caution in patients with a history of renal disease, as everolimus treatment has been associated with renal impairment and nephrotoxicity.  In patients receiving Afinitor, monitor renal function prior to starting therapy and annually thereafter; monitor renal function at least every 6 months in patients who have additional risk factors for renal failure. Renal function should also be monitored during the administration of Zortress. Because Zortress administered in combination with standard-dose cyclosporine increases the risk of nephrotoxicity in kidney transplant patients, reduced doses of cyclosporine are required when given with Zortress. Zortress has not been studied with standard-dose tacrolimus; however, reduced doses of tacrolimus should be used in combination with Zortress to minimize the potential risk of nephrotoxicity. Consider changing to other immunosuppressive therapies in transplant patients if renal impairment occurs and does not improve after dose adjustments or if renal dysfunction is thought to be drug-related.

    Proteinuria

    Monitor patients receiving Zortress for proteinuria. The use of everolimus in transplant patients has been associated with increased proteinuria; this risk is higher in patients with higher everolimus whole blood trough concentrations.

    Liver transplant, renal artery thrombosis, renal graft thrombosis, renal vein thrombosis

    An increased risk of renal artery thrombosis, renal vein thrombosis, and renal graft thrombosis resulting in graft loss was reported among de novo kidney transplant patients treated with everolimus (Zortress), mostly within the first 30 days after transplantation. Mammalian target of rapamycin (mTOR) inhibitors are also associated with an increase in hepatic artery thrombosis (HAT), mostly occurring within the first 30 days after transplant and leading to graft loss or death. Do not administer Zortress earlier than 30 days after liver transplant.

    Diabetes mellitus, hyperglycemia

    Use everolimus with caution in patients with diabetes mellitus, as hyperglycemia and new-onset diabetes have been reported with treatment. When possible, achieve optimal glucose control prior to beginning therapy. In non-diabetic patients, monitor fasting serum glucose prior to starting Afinitor or Afinitor Disperz and annually thereafter; monitor fasting serum glucose more frequently as clinically indicated in patients with pre-existing diabetes. An interruption or discontinuation of therapy may be necessary if severe hyperglycemia occurs. Blood glucose concentrations should also be closely monitored in patients using Zortress after transplant.

    Vaccination

    Vaccination with live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) should be avoided during treatment with everolimus due to the potential increased risk of infection. Additionally, avoid close contact with people who have received live vaccines. Due to the potential risk of infection or reduced immune response with vaccination, consider completing recommended childhood vaccines prior to starting Afinitor therapy; use of an accelerated vaccination schedule may be necessary for these patients.

    Impaired wound healing, surgery, wound dehiscence

    As with other drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway, the use of everolimus has the potential to adversely affect wound healing. The manufacturer of Afinitor recommends withholding everolimus for at least 1 week prior to elective surgery; do not administer everolimus for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming everolimus after resolution of wound healing complications has not been established. Everolimus delays wound healing and increases the occurrence of impaired wound healing, including incisional hernia, lymphocele, seroma, wound dehiscence, and wound infection; these complications may require surgical intervention. Generalized fluid accumulation (e.g., peripheral edema and lymphedema), as well as other types of localized fluid collection (e.g., pericardial effusion, pleural effusion, and ascites), have also been reported.

    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.

    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.

    Stomatitis

    Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with everolimus in clinical trials. It most often occurs within the first 8 weeks of treatment. When starting treatment with Afinitor, consider initiating dexamethasone alcohol-free oral solution (0.5 mg/5 mL four times daily) as a swish and spit mouthwash to reduce the incidence and severity of stomatitis; this has not been studied in pediatric patients. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products, as they exacerbate the condition. Do not administer antifungal agents unless a fungal infection has been diagnosed.

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Use everolimus with caution in patients with established hypercholesterolemia and hypertriglyceridemia or in patients with severe refractory hyperlipidemia as these effects have been commonly reported with treatment; the risk of hyperlipidemia is increased with higher everolimus whole blood trough concentrations. When possible, achieve optimal lipid control prior to beginning therapy; the use of anti-lipid therapy may not normalize lipid levels in patients receiving everolimus. Monitor lipid profile prior to starting therapy with Afinitor or Afinitor Disperz and annually thereafter; patients treated with Zortress should also be monitored for hyperlipidemia. If detected, implement treatments as described by the National Cholesterol Education Program guidelines (e.g., diet, exercise, and lipid-lowering agents). An interruption of therapy or discontinuation of therapy may be necessary if hyperlipidemia occurs. Zortress has not been studied in patients with baseline cholesterol levels greater than 350 mg/dL.

    Bone marrow suppression

    Bone marrow suppression including anemia, lymphopenia, neutropenia, and thrombocytopenia has been reported in patients treated with Afinitor or Afinitor Disperz in clinical trials. Monitor complete blood counts prior to starting therapy with Afinitor, every 6 months for the first year of treatment, and annually thereafter. An interruption or discontinuation of therapy may be necessary if myelosuppression occurs.

    Angioedema

    Hypersensitivity reactions have occurred with everolimus including anaphylaxis, dyspnea, flushing, chest pain, and angioedema. Use everolimus with caution in patients taking other drugs known to cause angioedema (e.g., ACE inhibitors), as the incidence of angioedema may be higher in these patients. Permanently discontinue Afinitor for the development of clinically significant hypersensitivity or angioedema.

    Radiation therapy

    Closely monitor patients receiving everolimus concomitantly or sequentially with radiation therapy. Radiation recall reaction and radiation sensitization including cutaneous and visceral organ reactions (e.g., radiation esophagitis and pneumonitis) have been reported in patients who received radiation therapy prior to, during, or after everolimus therapy in postmarketing experience; some cases were severe.

    Geriatric

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

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during everolimus treatment and for at least 8 weeks after the last dose. Although there are no adequately controlled studies in pregnant humans, everolimus can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies.  No adequate studies of everolimus exist in pregnant women, although there are a small number of case reports of pregnancy in transplant patients; these reports are not sufficient to inform about the risks of birth defects or miscarriage. Women who are pregnant or who become pregnant while receiving everolimus should be apprised of the potential hazard to the fetus. Administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities in the absence of maternal toxicities, including increased resorption, pre- and postimplantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development; these toxicities occurred at exposures of approximately 4% of the human exposure at an everolimus dose of 10 mg once daily. Increased preimplantation loss and embryonic resorptions also occurred in rats given everolimus prior to mating and through organogenesis at exposures of approximately 10% of the human dose of 0.75 mg twice daily. When everolimus was administered to pregnant rats from implantation through lactation at exposures of approximately 4% of the human exposure at an everolimus dose of 10 mg once daily, there were no adverse effects on delivery or drug-related effects on morphological development, motor activity, learning, or fertility assessment in the offspring; however, there were reductions in body weight (up to 9%) and in survival of offspring (approximately 5% died or were missing). In rabbits, administration during organogenesis resulted in abortions, maternal toxicity, and increased fetal resorptions at exposures of approximately 10%, 50%, and 50% the exposures in humans at a dose of 0.75 mg twice daily, respectively.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk of everolimus and discuss contraception requirements. Females of reproductive potential should avoid pregnancy and use highly effective contraception during and for 8 weeks after treatment with everolimus. Females of reproductive potential should undergo pregnancy testing prior to initiation of 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. Women who become pregnant while receiving everolimus should be apprised of the potential hazard to the fetus. Everolimus may cause infertility in female and male patients. Cases of reversible azoospermia have been reported in male patients taking everolimus; oligospermia may also occur. Sperm motility, sperm count, plasma testosterone levels, and fertility were decreased in male rats at everolimus exposures similar to those of the clinical dose of everolimus 10 mg PO once daily, although effects on male fertility also occurred at exposures 10% to 81% lower than human exposure at this dose; the fertility index increased from 0% to 60% within 10 to 13 weeks after everolimus administration was stopped. Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) have occurred in female patients taking Afinitor. Everolimus may cause preimplantation loss in females based on animal data.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from everolimus, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether everolimus is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 7.0-18.0
    lymphopenia / Delayed / 0-18.0
    hyperglycemia / Delayed / 0-17.0
    anemia / Delayed / 0-15.0
    hypertensive crisis / Early / 0-10.0
    heart failure / Delayed / 0-10.0
    atrial fibrillation / Early / 0-10.0
    pleural effusion / Delayed / 0-10.0
    pulmonary edema / Early / 0-10.0
    hypophosphatemia / Delayed / 0-10.0
    renal failure (unspecified) / Delayed / 2.0-10.0
    pulmonary embolism / Delayed / 0-10.0
    thromboembolism / Delayed / 0-10.0
    wound dehiscence / Delayed / 1.0-10.0
    pancytopenia / Delayed / 0-10.0
    osteonecrosis / Delayed / 0-10.0
    prostatic hypertrophy / Delayed / 0-10.0
    stomatitis / Delayed / 0-9.0
    angioedema / Rapid / 0-6.8
    fever / Early / 0-6.0
    hypokalemia / Delayed / 0-6.0
    fatigue / Early / 0-6.0
    agitation / Early / 0-5.0
    anxiety / Delayed / 0-5.0
    vomiting / Early / 0-4.0
    hypercholesterolemia / Delayed / 0-4.0
    neutropenia / Delayed / 0-4.0
    asthenia / Delayed / 0-4.0
    peripheral edema / Delayed / 0-3.0
    nausea / Early / 0.4-3.0
    hypertriglyceridemia / Delayed / 0-3.0
    thrombocytopenia / Delayed / 0-3.0
    prolonged bleeding time / Delayed / 0-3.0
    diabetes mellitus / Delayed / 0-2.0
    leukopenia / Delayed / 0-2.0
    anorexia / Delayed / 0-2.0
    weight loss / Delayed / 0-2.0
    proteinuria / Delayed / 0-1.5
    hypertension / Early / 0-1.0
    pericardial effusion / Delayed / 0-1.0
    rash / Early / 0-1.0
    xerosis / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    hyponatremia / Delayed / 0-1.0
    dysgeusia / Early / 0-1.0
    epistaxis / Delayed / 0-1.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
    thrombotic microangiopathy / Delayed / 0-1.0
    hemolytic-uremic syndrome / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    hypoalbuminemia / Delayed / 0-1.0
    headache / Early / 0-1.0
    hypocalcemia / Delayed / 0-0.5
    dizziness / Early / 0-0.5
    insomnia / Early / 0-0.2
    myocarditis / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    renal graft thrombosis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known

    Moderate

    hyperlipidemia / Delayed / 0-21.0
    hypomagnesemia / Delayed / 0-14.0
    impaired wound healing / Delayed / 0-11.0
    osteomyelitis / Delayed / 1.0-10.0
    hypotension / Rapid / 0-10.0
    wheezing / Rapid / 0-10.0
    chest pain (unspecified) / Early / 0-10.0
    angina / Early / 0-10.0
    sinus tachycardia / Rapid / 0-10.0
    palpitations / Early / 0-10.0
    fluid retention / Delayed / 0-10.0
    ascites / Delayed / 0-10.0
    hypercalcemia / Delayed / 0-10.0
    metabolic acidosis / Delayed / 0-10.0
    dysphagia / Delayed / 0-10.0
    gastritis / Delayed / 0-10.0
    phlebitis / Rapid / 0-10.0
    hematoma / Early / 1.0-10.0
    lymphocele / Delayed / 1.0-10.0
    conjunctivitis / Delayed / 0-10.0
    blurred vision / Early / 0-10.0
    cataracts / Delayed / 0-10.0
    paresis / Delayed / 0-10.0
    hypoglycemia / Early / 0-10.0
    cholestasis / Delayed / 0-10.0
    cholangitis / Delayed / 0-10.0
    lymphadenopathy / Delayed / 0-10.0
    thrombocytosis / Delayed / 0-10.0
    depression / Delayed / 0-10.0
    hallucinations / Early / 0-10.0
    iron deficiency / Delayed / 0-10.0
    vitamin B12 deficiency / Delayed / 0-10.0
    dehydration / Delayed / 0-10.0
    hyperuricemia / Delayed / 0-10.0
    gout / Delayed / 0-10.0
    gingival hyperplasia / Delayed / 0-10.0
    osteopenia / Delayed / 0-10.0
    osteoporosis / Delayed / 0-10.0
    migraine / Early / 0-10.0
    hypothyroidism / Delayed / 0-10.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-5.0
    erythema / Early / 0-4.0
    bleeding / Early / 0-3.0
    glossitis / Early / Incidence not known
    colitis / Delayed / Incidence not known
    BK virus-associated nephropathy / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known

    Mild

    acne vulgaris / Delayed / 1.0-22.0
    xerostomia / Early / 0-11.0
    myalgia / Early / 0-11.0
    chills / Rapid / 0-10.0
    rhinorrhea / Early / 0-10.0
    nasal congestion / Early / 0-10.0
    gastroesophageal reflux / Delayed / 0-10.0
    dyspepsia / Early / 0-10.0
    nocturia / Early / 0-10.0
    Cushingoid features / Delayed / 0-10.0
    musculoskeletal pain / Early / 0-10.0
    hypoesthesia / Delayed / 0-10.0
    paresthesias / Delayed / 0-10.0
    leukocytosis / Delayed / 0-10.0
    weakness / Early / 0-10.0
    lethargy / Early / 0-10.0
    hirsutism / Delayed / 0-10.0
    alopecia / Delayed / 0-10.0
    hypertrichosis / Delayed / 0-10.0
    syncope / Early / 0-10.0
    acneiform rash / Delayed / 0-3.0
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    steatorrhea / Delayed / Incidence not known

    DRUG INTERACTIONS

    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; Chlorpheniramine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. If everolimus is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. 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.
    Alprazolam: (Major) Avoid coadministration of alprazolam and everolimus due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with everolimus, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
    Amiodarone: (Major) Coadministration of everolimus with amiodarone requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of amiodarone and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Amiodarone is a moderate CYP3A4 and P-gp inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 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.
    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.
    Amlodipine; Benazepril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Amobarbital: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with amobarbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and amobarbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    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; Omeprazole: (Major) Avoid coadministration of everolimus with clarithromycin due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Angiotensin-converting enzyme inhibitors: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Apalutamide: (Major) Avoid coadministration of everolimus with apalutamide due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of apalutamide and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Aprepitant, Fosaprepitant: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with a multi-day oral regimen of aprepitant is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Aprepitant is a moderate CYP3A4 inhibitor when administered as part of a multi-day regimen; it is a weak CYP3A4 inhibitor when given as a single dose. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold. An interaction is not expected with single oral or IV doses of aprepitant/fosaprepitant.
    Aripiprazole: (Major) Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response if coadministration with everolimus is necessary; monitor for aripiprazole-related adverse reactions. Adults receiving everolimus for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Aripiprazole is a substrate for CYP2D6 and CYP3A4; everolimus is a weak CYP3A4 inhibitor as well as a competitive inhibitor of CYP2D6.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with butalbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with butalbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations. (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 everolimus with atazanavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Atazanavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of everolimus with atazanavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Atazanavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold. (Major) Avoid coadministration of everolimus with cobicistat due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus 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.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of everolimus with phenobarbital due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of phenobarbital and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Benazepril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate, and coadministration with strong/moderate/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 benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
    Berotralstat: (Major) Coadministration of everolimus with berotralstat requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of berotralstat and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 and P-gp substrate; berotralstat is a P-gp and moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Bexarotene: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with bexarotene is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Bosentan: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with bosentan is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Brexpiprazole: (Moderate) Use caution if coadministration of everolimus with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and everolimus are coadministered with a moderate to strong inhibitor of CYP3A4. If everolimus is discontinued, adjust the brexpiprazole dosage to its original level. Everolimus is a moderate CYP2D6 inhibitor. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of moderate CYP2D6 inhibitors with a strong or moderate CYP3A4 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brigatinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions or changes in efficacy if coadministration with brigatinib is necessary. The dose of everolimus may need to be adjusted. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Brigatinib is a moderate CYP3A4 inducer and a P-gp inhibitor. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with everolimus is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine and everolimus can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when everolimus is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping everolimus, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If everolimus is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Everolimus is a weak CYP3A4 inhibitor.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and everolimus can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when everolimus is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping everolimus, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If everolimus is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Everolimus is a weak CYP3A4 inhibitor.
    Butabarbital: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with butabarbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and butabarbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Butalbital; Acetaminophen: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with butalbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with butalbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with butalbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations. (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.
    Cabozantinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with cabozantinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and cabozantinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Canakinumab: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if treatment with canakinumab is initiated for a patient on chronic everolimus therapy. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate. During chronic inflammation, increased levels of certain cytokines can decrease the formation of CYP450 enzymes. Thus, the formation of CYP3A4 could be normalized during canakinumab administration. The addition of canakinumab to everolimus therapy may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Cannabidiol: (Major) Initiate everolimus at a lower starting dose in patients taking a stable dose of cannabidiol. Monitor everolimus concentrations during cannabidiol and everolimus coadministration and adjust the everolimus dose accordingly. Coadministration of cannabidiol and everolimus results in an approximately 2.5-fold increase in everolimus exposure. Everolimus is a P-gp substrate; in vivo data demonstrate cannabidiol can affect P-gp efflux activity in the intestine.
    Capmatinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with capmatinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Captopril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Carbamazepine: (Major) Avoid coadministration of everolimus with carbamazepine due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of carbamazepine and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Carbetapentane; Chlorpheniramine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carvedilol: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with carvedilol is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and carvedilol is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Cenobamate: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with cenobamate is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Ceritinib: (Major) Avoid coadministration of everolimus with ceritinib due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Ceritinib is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Chloramphenicol: (Major) Avoid coadministration of everolimus with chloramphenicol due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Chlordiazepoxide; 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.
    Chlorpheniramine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Codeine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor. (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; Dextromethorphan: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    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. (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    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. (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Phenylephrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Chlorpromazine: (Moderate) Monitor for an increase in chlorpromazine-related adverse reactions if coadministration with everolimus is necessary. Chlorpromazine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciprofloxacin: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ciprofloxacin is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Cisapride: (Moderate) Monitor for an increase in cisapride-related adverse reactions if coadministration with everolimus is necessary. Everolimus is a weak inhibitor of CYP3A while cisapride is a CYP3A4 substrate with narrow therapeutic range.
    Clarithromycin: (Major) Avoid coadministration of everolimus with clarithromycin due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    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 CYP2D6 inhibitor; concomitant use may increase plasma concentrations of clomipramine.
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with everolimus and monitor for adverse reactions. If everolimus is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is metabolized by CYP3A4 and CYP2D6. Everolimus is a weak CYP3A4 inhibitor and a CYP2D6 inhibitor.
    Cobicistat: (Major) Avoid coadministration of everolimus with cobicistat due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus 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; Guaifenesin; Pseudoephedrine: (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.
    Conivaptan: (Major) Coadministration of everolimus with conivaptan requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of conivaptan and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A substrate and a P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor. Coadministration with other moderate CYP3A/P-gp inhibitors increased the overall exposure of everolimus by 3.5 to 4.4-fold.
    Crizotinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with crizotinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Crizotinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Cyclosporine: (Major) Coadministration of everolimus with cyclosporine requires an everolimus dose reduction for some indications and close monitoring for others; also, closely monitor cyclosporine whole blood trough concentrations as appropriate and adjust the dose as necessary to remain in the recommended therapeutic range. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of cyclosporine and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, as well as a weak CYP3A4 inhibitor. Cyclosporine is a moderate CYP3A4 and P-gp inhibitor, as well as a CYP3A4 substrate. In a single-dose study, coadministration cyclosporine increased the AUC of everolimus by 168% (range, 46% to 365%) and the Cmax by 82% (range, 25% to 158%). Concurrent use may also increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events.
    Dabrafenib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with dabrafenib is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Daclatasvir: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with daclatasvir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and daclatasvir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Danazol: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with danazol is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. danazol is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Darunavir: (Major) Avoid coadministration of everolimus with darunavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Darunavir; Cobicistat: (Major) Avoid coadministration of everolimus with cobicistat due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold. (Major) Avoid coadministration of everolimus with darunavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of everolimus with cobicistat due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold. (Major) Avoid coadministration of everolimus with darunavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of everolimus with ritonavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Delavirdine: (Major) Avoid coadministration of everolimus with delavirdine due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Delavirdine is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    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.
    Dexamethasone: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with dexamethasone is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and dexamethasone is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Dextromethorphan; Quinidine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with quinidine is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and everolimus is a CYP3A4 inhibitor.
    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.
    Diltiazem: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with diltiazem is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Diltiazem is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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.
    Dronedarone: (Major) Coadministration of everolimus with dronedarone requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of dronedarone and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Dronedarone is a moderate CYP3A4 and a P-gp inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    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: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with duvelisib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Duvelisib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 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 everolimus whole blood trough concentrations as appropriate if coadministration with efavirenz is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with efavirenz is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with efavirenz is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Elagolix: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with elagolix is necessary. The dose of everolimus may need to be adjusted. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. elagolix is a weak to moderate CYP3A4 inducer; it may also increase plasma concentrations of P-gp substrates. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with elagolix is necessary. The dose of everolimus may need to be adjusted. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. elagolix is a weak to moderate CYP3A4 inducer; it may also increase plasma concentrations of P-gp substrates. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ivacaftor is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    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 everolimus with cobicistat due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of everolimus with cobicistat due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Emapalumab: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if treatment with emapalumab is initiated for a patient on chronic everolimus therapy. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate. During chronic inflammation, increased levels of certain cytokines can decrease the formation of CYP450 enzymes. Thus, the formation of CYP3A4 could be normalized during emapalumab administration. The addition of emapalumab to everolimus therapy may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Enalapril, Enalaprilat: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Enalapril; Felodipine: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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. (Moderate) Concurrent use of felodipine and everolimus should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Enasidenib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with enasidenib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Enzalutamide: (Major) Avoid coadministration of everolimus with enzalutamide due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of enzalutamide and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Erdafitinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with erdafitinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and erdafitinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Erythromycin: (Major) Coadministration of everolimus with erythromycin requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of erythromycin and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Erythromycin is a moderate CYP3A4 and P-gp inhibitor. Coadministration with erythromycin increased the Cmax, AUC, and half-life of everolimus by 2-fold, 4.4-fold, and 39%, respectively.
    Erythromycin; Sulfisoxazole: (Major) Coadministration of everolimus with erythromycin requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of erythromycin and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Erythromycin is a moderate CYP3A4 and P-gp inhibitor. Coadministration with erythromycin increased the Cmax, AUC, and half-life of everolimus by 2-fold, 4.4-fold, and 39%, respectively.
    Eslicarbazepine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with eslicarbazepine is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Etravirine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with etravirine is necessary. The dose of everolimus may need to be adjusted. Everolimus is a sensitive CYP3A4 substrate as well as a P-glycoprotein (P-gp) substrate. Etravirine is a moderate CYP3A4 inducer as well as a P-gp inhibitor. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    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: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fedratinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Fedratinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Felodipine: (Moderate) Concurrent use of felodipine and everolimus should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    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.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or everolimus; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and everolimus is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
    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: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with flibanserin is necessary; the dose of everolimus may need to be reduced. Also, monitor for potentially increased flibanserin-induced adverse reactions such as hypotension, syncope, somnolence, or other adverse reactions. Everolimus is a weak CYP3A4 inhibitor as well as a P-glycoprotein (P-gp) substrate. Flibanserin is a CYP3A4 substrate as well as a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors may increase flibanserin concentrations.
    Fluconazole: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fluconazole is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Fluconazole is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Fluoxetine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fluoxetine is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    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: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fluvoxamine is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Fosamprenavir: (Major) Avoid coadministration of everolimus with fosamprenavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Fosinopril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Fosphenytoin: (Major) Avoid coadministration of everolimus with fosphenytoin due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of fosphenytoin and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Fostamatinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fostamatinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Fostamatinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Glecaprevir; Pibrentasvir: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with glecaprevir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and glecaprevir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with pibrentasvir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and pibrentasvir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Grapefruit juice: (Major) Instruct patients to avoid grapefruit or grapefruit juice with everolimus due to the potential for increased everolimus exposure and subsequent toxicity. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Grapefruit juice is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ibrutinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ibrutinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate. Ibrutinib may inhibit P-gp. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    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 everolimus with idelalisib due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Idelalisib is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Imatinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with imatinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Imatinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    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 everolimus with indinavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Indinavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Isavuconazonium: (Major) Coadministration of everolimus with isavuconazonium requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of isavuconazonium and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Isavuconazonium is a moderate CYP3A4 and P-gp inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of everolimus with rifampin due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of rifampin and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the Cmax and AUC of everolimus by 58% and 63%, respectively. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of everolimus with rifampin due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of rifampin and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the Cmax and AUC of everolimus by 58% and 63%, respectively. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    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 everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with istradefylline is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and Istradefylline is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Itraconazole: (Major) Avoid coadministration of everolimus with itraconazole due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Itraconazole is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Ivacaftor: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ivacaftor is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood 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 everolimus with ketoconazole due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ketoconazole is a strong CYP3A4 and P-gp inhibitor. Coadministration with ketoconazole increased the Cmax, AUC, and half-life of everolimus by 3.9-fold, 15-fold, and 89%, respectively.
    Lanreotide: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with lanreotide is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Somatostatin analogs, such as lanreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of everolimus with clarithromycin due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Lapatinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with lapatinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Lasmiditan: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with lasmiditan is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and lasmiditan is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Ledipasvir; Sofosbuvir: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ledipasvir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ledipasvir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Lefamulin: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with lefamulin is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Lefamulin is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with everolimus as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; everolimus is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    Letermovir: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with letermovir is necessary. The dose of everolimus may need to be reduced. In patients also receiving cyclosporine, avoid coadministration of everolimus with letermovir. If concomitant use of both letermovir and cyclosporine is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with everolimus is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with everolimus is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    Lisinopril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Live Vaccines: (Contraindicated) 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.
    Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and everolimus. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; everolimus is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with everolimus is necessary; concomitant use may significantly increase the serum concentration of lomitapide. Also, monitor everolimus whole blood trough concentrations and watch for everolimus-related adverse reactions. Everolimus is a weak CYP3A4 inhibitor and a P-glycoprotein (P-gp) substrate; lomitapide is a sensitive CYP3A4 substrate and a P-gp inhibitor. The exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Lonafarnib: (Major) Avoid coadministration of lonafarnib and everolimus; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If concomitant use is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor everolimus levels and for adverse effects from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing everolimus. Lonafarnib is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp inhibitor; everolimus is a sensitive CYP3A4 substrate, P-gp substrate, and weak CYP3A4 inhibitor. Coadministration with a dual strong CYP3A4 and P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of everolimus with ritonavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Lorlatinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with lorlatinib is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of everolimus with lumacaftor; ivacaftor due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of lumacaftor; ivacaftor and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Lumacaftor; Ivacaftor: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ivacaftor is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    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.
    Maribavir: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with maribavir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and maribavir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Meclizine: (Moderate) Monitor for meclizine-related adverse effects, such as drowsiness and anticholinergic effects, when coadministered with everolimus. Concomitant use may increase the exposure to meclizine. Meclizine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Mefloquine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with mefloquine is necessary; also, monitor for mefloquine-related adverse events. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and a weak CYP3A4 inhibitor. Mefloquine is a P-gp inhibitor and a CYP3A4 substrate. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. Concurrent use with CYP3A4 inhibitors may increase mefloquine exposure.
    Mephobarbital: (Major) Avoid coadministration of everolimus with mephobarbital due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of mephobarbital and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    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.
    Methohexital: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with methohexital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and methohexital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions, including bradycardia and hypotension, during coadministration with everolimus. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased metoprolol adverse reactions, including bradycardia and hypotension, during coadministration with everolimus. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Mexiletine: (Moderate) Use caution when midazolam is coadministered with everolimus. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    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 everolimus with mifepristone due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Mifepristone is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid coadministration of everolimus with mitotane due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of mitotane and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Moexipril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Nafcillin: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with nafcillin is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    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 everolimus with nefazodone due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Nefazodone is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Nelfinavir: (Major) Avoid coadministration of everolimus with nelfinavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Nelfinavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Neratinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with neratinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with netupitant is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Netupitant is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Nevirapine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with nevirapine is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and nevirapine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    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.
    Nilotinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with nilotinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Nilotinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    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.
    Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of everolimus with ritonavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    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 everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with octreotide is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Somatostatin analogs, such as octreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Olanzapine; Fluoxetine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fluoxetine is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of everolimus with ritonavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with rifabutin is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Osimertinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with osimertinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    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.
    Pentobarbital: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with pentobarbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Perindopril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Perindopril; Amlodipine: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    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.
    Pexidartinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with pexidartinib is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Phenobarbital: (Major) Avoid coadministration of everolimus with phenobarbital due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of phenobarbital and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of everolimus with phenobarbital due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of phenobarbital and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Phenytoin: (Major) Avoid coadministration of everolimus with phenytoin due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of phenytoin and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Pimozide: (Major) Concurrent use of pimozide and everolimus should be avoided. Coadministration may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Everolimus is a competitive CYP2D6 inhibitor and a weak CYP3A4 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.
    Posaconazole: (Major) Coadministration of everolimus with everolimus requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of everolimus and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Everolimus is a moderate CYP3A4 and P-gp inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-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) Avoid coadministration of everolimus with primidone due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of primidone and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Propafenone: (Major) Avoid concurrent use of propafenone and everolimus; concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity; everolimus exposure may also increase. Propafenone is a CYP3A4 and CYP2D6 substrate and a P-glycoprotein (P-gp) substrate; everolimus is a P-gp substrate, a competitive CYP2D6 inhibitor, and a weak CYP3A4 inhibitor.
    Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of everolimus as concurrent use may increase propranolol exposure. Propranolol is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of everolimus as concurrent use may increase propranolol exposure. Propranolol is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
    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: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Quinapril; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Quinidine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with quinidine is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Quinine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with quinine is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and quinine is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Ramipril: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Ranolazine: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ranolazine is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ranolazine is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Ribociclib: (Major) Avoid coadministration of everolimus with ribociclib due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of everolimus with ribociclib due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Rifabutin: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with rifabutin is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Rifampin: (Major) Avoid coadministration of everolimus with rifampin due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of rifampin and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the Cmax and AUC of everolimus by 58% and 63%, respectively. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Rifapentine: (Major) Avoid coadministration of everolimus with rifapentine due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of rifapentine and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Ritonavir: (Major) Avoid coadministration of everolimus with ritonavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Rolapitant: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with rolapitant is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and rolapitant is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Saquinavir: (Major) Avoid coadministration of everolimus with saquinavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Saquinavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Sarecycline: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with sarecycline is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and sarecycline is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Sarilumab: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with sarilumab. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as everolimus, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Everolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Secobarbital: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with secobarbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and secobarbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Secukinumab: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if treatment with secukinumab is initiated for a patient on chronic everolimus therapy. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate. During chronic inflammation, increased levels of certain cytokines can decrease the formation of CYP450 enzymes. Thus, the formation of CYP3A4 could be normalized during secukinumab administration. The addition of secukinumab to everolimus therapy may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Siltuximab: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with siltuximab. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as everolimus, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Everolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    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: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with velpatasvir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with velpatasvir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with voxilaprevir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and voxilaprevir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Sorafenib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with sorafenib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Sotorasib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with sotorasib is necessary. Concurrent use may alter the exposure of everolimus, which may result in decreased efficacy or increased toxicity. The dose of everolimus may need to be adjusted. Everolimus is a sensitive CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of everolimus with St. Johns Wort due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of St. Johns Wort and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    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.
    Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with everolimus is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; everolimus is a weak CYP3A4 inhibitor.
    Tamoxifen: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with everolimus is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Everolimus is a CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    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 everolimus with telithromycin due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Telithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Temsirolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with temsirolimus is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Tepotinib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with tepotinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and tepotinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Tezacaftor; Ivacaftor: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ivacaftor is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Thiopental: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with thiopental is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and thiopental is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Thioridazine: (Contraindicated) Everolimus is a mild inhibitor of CYP2D6 in vitro and the use of thioridazine concomitantly with CYP2D6 inhibitors is contraindicated due to the possible risk of QT prolongation and subsequent arrhythmias, or other serious side effects, occurring from elevated serum concentrations of thioridazine.
    Ticagrelor: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ticagrelor is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ticagrelor is a weak P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Tipranavir: (Major) Avoid coadministration of everolimus with tipranavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Tipranavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Tocilizumab: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if treatment with tocilizumab is initiated for a patient on chronic everolimus therapy. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate. During chronic inflammation, increased levels of certain cytokines can decrease the formation of CYP450 enzymes. Thus, the formation of CYP3A4 could be normalized during tocilizumab administration. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. The addition of tocilizumab to everolimus therapy may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Tofacitinib: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as everolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Tolvaptan: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with tolvaptan is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and tolvaptan is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    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.
    Tramadol; Acetaminophen: (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: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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.
    Trandolapril; Verapamil: (Major) Avoid coadministration of everolimus with angiotensin-converting enzyme inhibitors (ACE inhibitors) as the risk of angioedema, with or without respiratory impairment, may be increased. 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. (Major) Coadministration of everolimus with verapamil requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of verapamil and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Verapamil is a moderate CYP3A4 and P-gp inhibitor. Coadministration with verapamil increased the Cmax and AUC of everolimus by 2.3-fold and 3.5-fold, respectively.
    Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with everolimus and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    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.
    Tucatinib: (Major) Avoid coadministration of everolimus with tucatinib due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Tucatinib is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with everolimus. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; everolimus is a weak CYP3A4 inhibitor.
    Ulipristal: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with once daily ulipristal is necessary; this interaction can be mitigated by separating administration by 1.5 hours. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ulipristal is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. Single-dose ulipristal has no effect on P-gp substrates.
    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.
    Vemurafenib: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with vemurafenib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and vemurafenib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Venetoclax: (Moderate) If concomitant use is necessary, take everolimus at least 6 hours before venetoclax. Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and venetoclax is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    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) Coadministration of everolimus with verapamil requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of verapamil and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Verapamil is a moderate CYP3A4 and P-gp inhibitor. Coadministration with verapamil increased the Cmax and AUC of everolimus by 2.3-fold and 3.5-fold, respectively.
    Viloxazine: (Moderate) Monitor for an increase in everolimus-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase everolimus exposure; viloxazine is a weak CYP3A inhibitor and everolimus is a CYP3A substrate.
    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.
    Voclosporin: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with voclosporin is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and voclosporin is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Voriconazole: (Major) Avoid coadministration of everolimus with voriconazole due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Voriconazole is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with everolimus is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Everolimus is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zonisamide: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with zonisamide is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during everolimus treatment and for at least 8 weeks after the last dose. Although there are no adequately controlled studies in pregnant humans, everolimus can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies.  No adequate studies of everolimus exist in pregnant women, although there are a small number of case reports of pregnancy in transplant patients; these reports are not sufficient to inform about the risks of birth defects or miscarriage. Women who are pregnant or who become pregnant while receiving everolimus should be apprised of the potential hazard to the fetus. Administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities in the absence of maternal toxicities, including increased resorption, pre- and postimplantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development; these toxicities occurred at exposures of approximately 4% of the human exposure at an everolimus dose of 10 mg once daily. Increased preimplantation loss and embryonic resorptions also occurred in rats given everolimus prior to mating and through organogenesis at exposures of approximately 10% of the human dose of 0.75 mg twice daily. When everolimus was administered to pregnant rats from implantation through lactation at exposures of approximately 4% of the human exposure at an everolimus dose of 10 mg once daily, there were no adverse effects on delivery or drug-related effects on morphological development, motor activity, learning, or fertility assessment in the offspring; however, there were reductions in body weight (up to 9%) and in survival of offspring (approximately 5% died or were missing). In rabbits, administration during organogenesis resulted in abortions, maternal toxicity, and increased fetal resorptions at exposures of approximately 10%, 50%, and 50% the exposures in humans at a dose of 0.75 mg twice daily, respectively.

    Counsel patients about the reproductive risk of everolimus and discuss contraception requirements. Females of reproductive potential should avoid pregnancy and use highly effective contraception during and for 8 weeks after treatment with everolimus. Females of reproductive potential should undergo pregnancy testing prior to initiation of 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. Women who become pregnant while receiving everolimus should be apprised of the potential hazard to the fetus. Everolimus may cause infertility in female and male patients. Cases of reversible azoospermia have been reported in male patients taking everolimus; oligospermia may also occur. Sperm motility, sperm count, plasma testosterone levels, and fertility were decreased in male rats at everolimus exposures similar to those of the clinical dose of everolimus 10 mg PO once daily, although effects on male fertility also occurred at exposures 10% to 81% lower than human exposure at this dose; the fertility index increased from 0% to 60% within 10 to 13 weeks after everolimus administration was stopped. Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) have occurred in female patients taking Afinitor. Everolimus may cause preimplantation loss in females based on animal data.

    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.