everolimus

1 INDICATIONS AND USAGE Everolimus is an mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients: Kidney Transplant : at low-moderate immunologic risk. Use in combination with basiliximab, cyclosporine (reduced doses) and corticosteroids ( 1.1 ) Liver Transplant : Administer no earlier than 30 days posttransplant. Use in combination with tacrolimus (reduced doses) and corticosteroids ( 1.2 , 5.5 ) Limitations of Use : Safety and efficacy have not been established in the following: Kidney transplant patients at high immunologic risk ( 1.3 ) Recipients of transplanted organs other than kidney or liver ( 1.3 , 5.7 ) Pediatric patients (less than 18 years) ( 1.3 ) 1.1 Prophylaxis of Organ Rejection in Kidney Transplantation Everolimus tablets are indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunologic risk receiving a kidney transplant [see Clinical Studies (14.1) ] . Everolimus tablets are to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring (TDM) of everolimus and cyclosporine is recommended for all patients receiving these products [see Dosage and Administration (2.2 , 2.3) ]. 1.2 Prophylaxis of Organ Rejection in Liver Transplantation Everolimus tablets are indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Everolimus tablets are to be administered no earlier than 30 days posttransplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [see Warnings and Precautions (5.5) , Clinical Studies (14.2) ] . TDM of everolimus and tacrolimus is recommended for all patients receiving these products [see Dosage and Administration (2.3 , 2.5) ] . 1.3 Limitations of Use The safety and efficacy of everolimus tablets has not been established in the following populations: Kidney transplant patients at high immunologic risk. Recipients of transplanted organs other than kidney and liver [see Warnings and Precautions (5.7) ] . Pediatric patients (less than 18 years).

2 DOSAGE AND ADMINISTRATION Patients receiving everolimus tablets may require dose adjustments based on everolimus blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of everolimus should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. Dose adjustment is required if the trough concentration is below 3 ng/mL. The total daily dose of everolimus should be doubled using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg, or 1 mg). Dose adjustment is also required if the trough concentration is greater than 8 ng/mL on 2 consecutive measures; the dose of everolimus should be decreased by 0.25 mg twice daily [see Dosage and Administration (2.3) , Clinical Pharmacology (12.3) ] . Kidney Transplantation : starting oral dose of 0.75 mg twice daily as soon as possible after transplantation ( 2.1 ) Liver Transplantation : starting oral dose of 1 mg twice daily starting 30 days after transplantation ( 2.2 ) Monitor Everolimus Concentrations : Adjust maintenance dose to achieve trough concentrations within the 3 to 8 ng/mL target range using LC/MS/MS assay method ( 2.1 , 2.2 , 2.3 ) Administer consistently with or without food at the same time as cyclosporine or tacrolimus ( 2.6 , 12.3 ) Mild Hepatic Impairment : Reduce initial daily dose by one-third ( 2.7 ) Moderate or Severe Hepatic Impairment : Reduce initial daily dose by one- half ( 2.7 , 12.6 ) 2.1 Dosage in Adult Kidney Transplant Patients An initial everolimus dose of 0.75 mg orally twice daily (1.5 mg per day) is recommended for adult kidney transplant patients in combination with reduced-dose cyclosporine, administered as soon as possible after transplantation [see Dosage and Administration (2.3 , 2.4) , Clinical Studies (14.1) ] . Oral prednisone should be initiated once oral medication is tolerated. Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft. 2.2 Dosage in Adult Liver Transplant Patients Start everolimus at least 30 days posttransplant. An initial dose of 1 mg orally twice daily (2 mg per day) is recommended for adult liver transplant patients in combination with reduced-dose tacrolimus [see Dosage and Administration (2.3 , 2.5) , Clinical Studies (14.2) ] . Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft. 2.3 Therapeutic Drug Monitoring (TDM) - Everolimus Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients. The recommended everolimus therapeutic range is 3 to 8 ng/mL [see Clinical Pharmacology (12.7) ] . Careful attention should be made to clinical signs and symptoms, tissue biopsies, and laboratory parameters. It is important to monitor everolimus blood concentrations, in patients with hepatic impairment, during concomitant administration of CYP3A4 inducers or inhibitors or cannabidiol, when switching cyclosporine formulations and/or when cyclosporine dosing is reduced according to recommended target concentrations [see Drug Interactions (7) , Clinical Pharmacology (12.7 , 12.8) ] . There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and thus, everolimus concentrations do not decrease if the tacrolimus exposure is reduced [see Drug Interactions (7.2) ] . The everolimus recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies. Because the measured everolimus whole blood trough concentrations depend on the assay used, individual patient sample concentration values from differe…

5 WARNINGS AND PRECAUTIONS Angioedema [increased risk with concomitant angiotensin converting enzyme (ACE inhibitors)] : Monitor for symptoms and treat promptly ( 5.8 ) Delayed Wound Healing/Fluid Accumulation : Monitor symptoms; treat promptly to minimize complications ( 5.9 ) Interstitial Lung Disease (ILD)/Non-Infectious Pneumonitis : Monitor for symptoms or radiologic changes; manage by dose reduction or discontinuation until symptoms resolve; consider use of corticosteroids ( 5.10 ) Hyperlipidemia (elevations of serum cholesterol and triglycerides) : Monitor and consider anti-lipid therapy ( 5.11 ) Proteinuria (increased risk with higher trough concentrations) : Monitor urine protein ( 5.12 ) Polyoma Virus Infections (activation of latent viral infections; BK virus associated nephropathy) : Consider reducing immunosuppression ( 5.13 ) TMA/TTP/HUS (concomitant use with cyclosporine may increase risk) : Monitor for hematologic changes or symptoms ( 5.15 ) New Onset Diabetes After Transplantation : Monitor serum glucose ( 5.16 ) Male Infertility: Azoospermia or oligospermia may occur ( 5.18 , 13.1 ) Immunizations : Avoid live vaccines ( 5.19 ) Embryo-Fetal Toxicity : Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with everolimus and for 8 weeks after final dose ( 5.17 , 8.1 , 8.3 ) 5.1 Management of Immunosuppression Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe everolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient. In limited data with the complete elimination of calcineurin inhibition (CNI), there was an increased risk of acute rejection. 5.2 Lymphomas and Other Malignancies Patients receiving immunosuppressants, including everolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. 5.3 Serious Infections Patients receiving immunosuppressants, including everolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions (5.13) , Adverse Reactions (6.1 , 6.2) ] . These infections may lead to serious, including fatal, outcomes. Because of the danger of over-immunosuppression, which can cause increased susceptibility to infection, combination immunosuppressant therapy should be used with caution. Antimicrobial prophylaxis for Pneumocystis jiroveci ( carinii ) pneumonia and prophylaxis for cytomegalovirus (CMV) is recommended in transplant recipients. 5.4 Kidney Graft Thrombosis An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, usually within the first 30 days posttransplantation [see Boxed Warning ] . 5.5 Hepatic Artery Thrombosis Mammalian target of rapamycin (mTOR) inhibitors are associated with an increase in hepatic artery thrombosis (HAT). Reported cases mostly have occurred within the first 30 days posttransplant and most also lead to graft loss or death. Therefore, everolimus should not be administered earlier than 30 days after liver transplant. 5.6 Everolimus and Calcineurin Inhibitor-Induced Nephrotoxicity In kidney transplant recipients, everolimus with standard dose cyclosporine increases the risk of nephrotoxicity resulting in a lower glomerular filtration rate. Reduced doses of cyclosporine are required for use in combinat…

4 CONTRAINDICATIONS Hypersensitivity to everolimus, sirolimus, or to components of the drug product ( 4 ) 4.1 Hypersensitivity Reactions Everolimus is contraindicated in patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug product.

7 DRUG INTERACTIONS Strong-moderate CYP3A4 inhibitors (e.g., cyclosporine, ketoconazole, erythromycin, verapamil) and CYP3A4 inducers (e.g., rifampin) may affect everolimus concentrations ( 7.1 ). Consider everolimus dose adjustment ( 5.14 ) Therapeutic drug monitoring and dose reduction for everolimus should be considered when everolimus is coadministered with cannabidiol ( 5.22 , 7.13 ) 7.1 Interactions With Strong Inhibitors or Inducers of CYP3A4 and P-glycoprotein Everolimus is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the multidrug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-gp. Concurrent treatment with strong inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and inducers (e.g., rifampin, rifabutin) of CYP3A4 is not recommended. Inhibitors of P-gp (e.g., digoxin, cyclosporine) may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro , everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of medicinal products eliminated by these enzymes. Thus, caution should be exercised when coadministering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index [see Dosage and Administration (2.3) ] . All in vivo interaction studies were conducted without concomitant cyclosporine. Pharmacokinetic interactions between everolimus and concomitantly administered drugs are discussed below. Drug interaction studies have not been conducted with drugs other than those described below. 7.2 Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate) The steady-state C max and area under the curve (AUC) estimates of everolimus were significantly increased by coadministration of single dose cyclosporine [see Clinical Pharmacology (12.5) ] . Dose adjustment of everolimus might be needed if the cyclosporine dose is altered [see Dosage and Administration (2.3) ] . Everolimus had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine (Neoral). 7.3 Ketoconazole and Other Strong CYP3A4 Inhibitors Multiple-dose ketoconazole administration to healthy volunteers significantly increased single dose estimates of everolimus C max , AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be coadministered with everolimus [see Warnings and Precautions (5.14) , Clinical Pharmacology (12.5) ] . 7.4 Erythromycin (Moderate CYP3A4 Inhibitor) Multiple-dose erythromycin administration to healthy volunteers significantly increased single dose estimates of everolimus C max , AUC, and half-life. If erythromycin is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see Clinical Pharmacology (12.5) ] . 7.5 Verapamil (CYP3A4 and P-gp Substrate) Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of everolimus C max and AUC. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see Clinical Pharmacology (12.5) ] . 7.6 Atorvastatin (CYP3A4 Substrate) and Pravastatin (P-gp Substrate) Single-dose administration of everolimus with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors. Patients should be moni…

8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ], everolimus can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus use in pregnant women; however, these reports are insufficient to inform a drug-associated risk of adverse developmental outcomes. Reproductive studies in animals have demonstrated that everolimus was maternally toxic in rabbits and caused embryo-fetal toxicities in rats and rabbits, at exposures near or below those achieved in human transplant patients. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data Everolimus crossed the placenta and was toxic to the conceptus. Everolimus administered daily to pregnant rats by oral gavage at 0.1 mg/kg (approximately one tenth the exposure in humans administered the lowest starting dose of 0.75 mg twice daily), from before mating through organogenesis, resulted in increased preimplantation loss and embryonic resorptions. These effects occurred in the absence of maternal toxicities. Everolimus administered daily by oral gavage to pregnant rabbits during organogenesis resulted in abortions, maternal toxicity and lethality, and increased fetal resorptions. At these doses, exposure to everolimus (AUC) was approximately one-tenth-, one-half-, and one- and one-half- fold the exposures in humans administered the starting clinical dose, respectively. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At a dose of 0.1 mg/kg (0.6 mg/m 2 ), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction) and in survival of offspring (~5%). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

8.3 Females and Males of Reproductive Potential Contraception Females should not be pregnant or become pregnant while receiving everolimus. Advise females of reproductive potential that animal studies have been performed showing everolimus to be harmful to the mother and developing fetus [see Use in Specific Populations (8.1) ] . Females of reproductive potential are recommended to use highly effective contraception methods while receiving everolimus and up to 8 weeks after treatment has been stopped. Infertility Females Amenorrhea occurred in female patients taking everolimus [see Adverse Reactions (6.2) ] . Everolimus may cause pre- implantation loss in females based on animal data [see Nonclinical Toxicology (13.1) ] . Female fertility may be compromised by treatment with everolimus. Males Everolimus treatment may impair fertility in males based on human [see Warnings and Precautions (5.18) , Adverse Reactions (6.2 , 6.3) ] and animal findings [see Nonclinical Toxicology (13.1) ] .

6 ADVERSE REACTIONS Most common adverse reactions were as follows: Kidney Transplantation (incidence greater than or equal to 20%) : peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection (UTI), and hyperlipidemia ( 6.1 ) Liver Transplantation (incidence greater than 10%) : diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, leukopenia, and hypercholesterolemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc., at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Serious and Otherwise Important Adverse Reactions The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity Reactions [see Contraindications (4.1) ] Lymphomas and Other Malignancies [see Boxed Warning, Warnings and Precautions (5.2) ] Serious Infections [see Warnings and Precautions (5.3) ] Kidney Graft Thrombosis [see Warnings and Precautions (5.4) ] Hepatic Artery Thrombosis [see Warnings and Precautions (5.5) ] Everolimus and Calcineurin Inhibitor-Induced Nephrotoxicity [see Warnings and Precautions (5.6) ] Heart Transplantation [see Warnings and Precautions (5.7) ] Angioedema [see Warnings and Precautions (5.8) ] Wound Healing and Fluid Accumulation [see Warnings and Precautions (5.9) ] Interstitial Lung Disease/Non-Infectious Pneumonitis [see Warnings and Precautions (5.10) ] Hyperlipidemia [see Warnings and Precautions (5.11) ] Proteinuria [see Warnings and Precautions (5.12) ] Polyoma Virus Infections [see Warnings and Precautions (5.13) ] Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS) [see Warnings and Precautions (5.15) ] New Onset Diabetes After Transplant [see Warnings and Precautions (5.16) ] Male Infertility [see Warnings and Precautions (5.18) ] 6.2 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Kidney Transplantation The data described below reflect exposure to everolimus in an open-label, randomized trial of de novo kidney transplant patients of concentration-controlled everolimus at an initial everolimus starting dose of 1.5 mg per day [target trough concentrations 3 to 8 ng/mL with reduced exposure cyclosporine (N = 274) compared to mycophenolic acid (N = 273) with standard exposure cyclosporine]. All patients received basiliximab induction therapy and corticosteroids. The population was between 18 and 70 years, more than 43% were 50 years of age or older (mean age was 46 years in the everolimus group, 47 years control group); a majority of recipients were male (64% in the everolimus group, 69% control group); and a majority of patients were Caucasian (70% in the everolimus group, 69% control group). Demographic characteristics were comparable between treatment groups. The most frequent diseases leading to transplantation were balanced between groups and included hypertension/nephrosclerosis, glomerulonephritis/glomerular disease and diabetes mellitus. Significantly more patients discontinued everolimus 1.5 mg per day treatment (83/277, 30%) than discontinued the control regimen (60/277, 22%). Of those patients who prematurely discontinued treatment, most discontinuations were due to adverse reactions: 18% in the everolimus group compared to 9% in the control group (p-value = 0.004). This difference was more prominent between treatment groups among female patients. In those patients discontinuing study medication, adverse reactions were collected up to 7 days after study medication discontinuation and serious adverse reactions up to 30 days after study medication discontinuation. Discontinuation of everolimus at a higher dose (3 mg per day) was 95/279, 34%, including 20% due to adverse reactions, and this regimen is not recommende…