AFINITOR (everolimus)

There are 9 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Efalizumab; Natalizumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system. CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV). PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000. PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7) DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)	TYSABRI
Selected Nephrotoxic Agents/Cidofovir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3) CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir. DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3)	CIDOFOVIR
Live Vaccines; Live BCG/Selected Immunosuppressive Agents SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1) CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2) PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency. PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)	ACAM2000 (NATIONAL STOCKPILE), ADENOVIRUS TYPE 4, ADENOVIRUS TYPE 4 AND TYPE 7, ADENOVIRUS TYPE 7, BCG (TICE STRAIN), BCG VACCINE (TICE STRAIN), DENGVAXIA, ERVEBO (NATIONAL STOCKPILE), FLUMIST TRIVALENT 2024-2025, IXCHIQ, M-M-R II VACCINE, PRIORIX, PROQUAD, ROTARIX, ROTATEQ, STAMARIL, VARIVAX VACCINE, VAXCHORA ACTIVE COMPONENT, VAXCHORA VACCINE, VIVOTIF, YF-VAX
Selected CYP3A4 Substrates/Mifepristone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1) CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2) PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1) DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.	KORLYM, MIFEPREX, MIFEPRISTONE
Talimogene laherparepvec/Selected Immunosuppressants SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1) CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician. DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)	IMLYGIC
Selected Nephrotoxic Agents/Bacitracin SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3) CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3) PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1) PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3) DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)	BACITRACIN, BACITRACIN MICRONIZED, BACITRACIN ZINC
Slt Immunosuppressants;Temsirolimus/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus by CYP3A4.(1-7) CLINICAL EFFECTS: Concurrent use of nirmatrelvir-ritonavir may result in increased levels of and risk of toxicity from cyclosporine, everolimus, sirolimus, tacrolimus, or temsirolimus.(1-7) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The American Society of Transplantation (AST) Statement on Oral Antiviral Therapy for COVID-19 for Organ Transplant Recipients states use of nirmatrelvir-ritonavir will be challenging in transplant patients due to significant drug interactions and difficulty with therapeutic drug monitoring in outpatients with active Covid-19 infections. Alternatives such as early use of either an appropriate monoclonal antibody or outpatient intravenous remdesivir may be preferred as first line therapy in transplant patients to prevent progression.(8) The US manufacturer of nirmatrelvir-ritonavir states concurrent use with immunosuppressants should not be used if close monitoring is not feasible.(6) Specific immunosuppressant recommendations: -Cyclosporine: For therapy with nirmatrelvir-ritonavir in patients on cyclosporine, some experts recommend lowering the cyclosporine dose by 80%. -Tacrolimus: For therapy with nirmatrelvir-ritonavir in patients on tacrolimus, experts recommend holding tacrolimus for the 5-day duration of nirmatrelvir-ritonavir therapy. Tacrolimus level is recommended on day 3 to assess the need for a one-time dose of tacrolimus during nirmatrelvir-ritonavir therapy. -As soon as possible after nirmatrelvir-ritonavir therapy, cyclosporine or tacrolimus levels should be checked, and every 2-4 days thereafter until stable, to determine when to increase cyclosporine doses or resume tacrolimus.(7) -Everolimus: For therapy with nirmatrelvir-ritonavir in patients on everolimus, AST states CYP3A4 inhibitors, such as clarithromycin, ketoconazole, voriconazole, and HIV protease inhibitors, are contraindicated with everolimus. The US manufacturer of everolimus states concurrent use should be avoided with strong CYP3A4 inhibitors. -Sirolimus: The US manufacturer of nirmatrelvir-ritonavir(6) and sirolimus protein-bound injection (Fyarro)(9) state concurrent use should be avoided. -Temsirolimus: The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as nirmatrelvir-ritonavir be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If nirmatrelvir-ritonavir is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(2) For patients concurrently taking cyclosporine, everolimus, sirolimus, tacrolimus, or temsirolimus with nirmatrelvir, therapeutic concentration monitoring of the immunosuppressant is recommended. DISCUSSION: A retrospective study evaluated the interaction between cyclosporine or tacrolimus and nirmatrelvir/ritonavir in 25 solid-organ transplant recipients. Upon nirmatrelvir/ritonavir initiation, cyclosporine doses were decreased by 80% and tacrolimus was held for the duration of nirmatrelvir/ritonavir therapy. No patients had acute rejection in the 30 days following nirmatrelvir/ritonavir. In 21 patients on tacrolimus, the median tacrolimus trough concentration before and after nirmatrelvir/ritonavir therapy was 7.4 ng/mL (IQR, 6.6-8.6) and 5.2 ng/mL (IQR, 3.6-8.7), respectively. Four patients had supratherapeutic tacrolimus troughs after restarting tacrolimus. In these patients, tacrolimus was resumed at either reduced dose or at pre-nirmatrelvir/ritonavir dose 2-5 days after completion of nirmatrelvir/ritonavir therapy.(5) Concurrent use of nirmatrelvir/ritonavir with tacrolimus resulted in elevated tacrolimus levels, treatment interruption, and acute kidney injury.(11) In a case series, 12 bilateral lung transplant recipients with COVID-19 were started on nirmatrelvir/ritonavir. All patients were on immediate-release tacrolimus and prednisone, and all except one were also on mycophenolate. Patients stopped tacrolimus 10-14 hours before starting nirmatrelvir-ritonavir and had tacrolimus levels checked between days 3-5 of therapy. One patient required a supplemental 0.5 mg dose of tacrolimus during nirmatrelvir-ritonavir therapy. Six patients had trough levels within goal, and 3 patients had troughs below goal but at adequate immunosuppression level based on the clinicians' judgement. Ten of the patients resumed tacrolimus at 25% of their baseline dose at day 8, and 9 of them resumed full dose tacrolimus by day 10. One patient was hospitalized for worsening COVID-19. No patients experienced tacrolimus side effects or acute rejection.(12) In a case series of 3 renal transplant recipients, tacrolimus was held 1 day before patients started nirmatrelvir-ritonavir therapy. Two patients resumed previous doses of tacrolimus one day after finishing nirmatrelvir/ritonavir; one had stable tacrolimus levels and the other was supratherapeutic. The 3rd patient received a supplemental dose of tacrolimus on day 4 of therapy and resumed his previous dose starting on day 5, and was supratherapeutic on day 6. No patients experienced adverse effects or graft rejection. The authors state that nirmatrelvir/ritonavir is not contraindicated and tacrolimus levels can be closely monitored for patients on tacrolimus.(13) In a case report of a 67-year old patient on chronic tacrolimus therapy, after 4 days of nirmatrelvir-ritonavir she presented to the emergency department with slowed speech, fatigue, weakness, and loss of appetite. The patient's tacrolimus level was 176.4 ng/mL (normal range is 5-20 ng/mL).(14) In a case series of 4 renal transplant recipients, tacrolimus was paused during nirmatrelvir-ritonavir therapy, which resulted in stable therapeutic levels. In one patient, tacrolimus was resumed immediately and resulted in a toxic tacrolimus level. In three patients, tacrolimus was resumed at a reduced dose 24 hours after nirmatrelvir-ritonavir was stopped and resulted in therapeutic to supratherapeutic tacrolimus levels.(15) In a case report of a 39-year-old female, the patient developed a sudden increase in tacrolimus levels after starting nirmatrelvir-ritonavir.(16) In a PKPB model, tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with tacrolimus alone.(17) The selected immunosuppressants linked to this monograph include: cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.	PAXLOVID
Lemborexant (Greater Than 5 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(1,2)	DAYVIGO
Nadofaragene Firadenovec/Selected Immunosuppressants SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1) CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1) DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)	ADSTILADRIN

Drug contraindication overview.

*Known hypersensitivity to everolimus, other rapamycin derivatives (e.g., sirolimus, temsirolimus), or any ingredient in the everolimus formulations.

Adverse reaction overview.

Adverse effects reported in 30% or more of patients receiving everolimus for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer, progressive neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, or advanced renal cell carcinoma, and more frequently with the drug than with placebo include stomatitis (including mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration), infections (including urinary tract infections, upper and lower respiratory tract infections, skin, and gastrointestinal tract infections), rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite. Adverse effects reported in 30% or more of patients receiving everolimus for the treatment of renal angiomyolipoma with tuberous sclerosis complex (TSC) and more frequently with the drug than with placebo include stomatitis (including mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and stomatitis). Adverse effects reported in 30% or more of patients receiving everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) with TSC include stomatitis (including mouth and lip ulceration, and stomatitis) and respiratory tract infections (including respiratory tract infection, upper respiratory tract infection, and viral respiratory tract infection).

Adverse effects reported in 30% or more of patients receiving everolimus for the adjunctive treatment of partial-onset seizures with TSC include stomatitis (including stomatitis, mouth ulceration, apththous ulcer, lip and tongue ulceration, mucosal inflammation, and gingival pain). Adverse effects reported in 20% or more of patients receiving everolimus in combination with reduced-exposure cyclosporine for prevention of organ rejection after renal transplantation include peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, and hyperlipidemia. Adverse effects reported in more than 10% of patients receiving everolimus in combination with reduced-exposure tacrolimus for prevention of organ rejection after hepatic transplantation include diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, leukopenia, and hypercholesterolemia.

Safety and efficacy of everolimus for the treatment of SEGA associated with TSC have been evaluated in pediatric patients 1 year of age and older. Safety and efficacy have not been established in pediatric patients younger than 1 year of age with SEGA. Although a determination remains inconclusive based on available data, the use of everolimus did not appear to adversely affect growth and pubertal development in 115 pediatric patients with TSC-associated SEGA treated with everolimus over a median duration of 4.1

years. Safety and efficacy of everolimus for the adjunctive treatment of partial-onset seizures associated with TSC have been evaluated in pediatric patients 2 years of age and older. Safety and efficacy as an adjunctive treatment have not been established in pediatric patients younger than 2 years of age with TSC-associated partial-onset seizures.

The incidence of infections, including serious infections, in pediatric patients under 6 years of age receiving everolimus treatment have been reported at a higher frequency in comparison to patients 6 years of age and older. Safety and efficacy of everolimus for the treatment of renal angiomyolipoma with TSC in the absence of SEGA, hormone-receptor positive, HER2-negative breast cancer, NET, and renal cell carcinoma (RCC) have not been established in pediatric patients. Clearance of everolimus normalized to body surface area was higher in pediatric patients with SEGA and TSC-associated partial-onset seizures compared with adults. Safety and efficacy of everolimus for the prevention of renal or hepatic allograft rejection have not been established in pediatric patients younger than 18 years of age.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None