Everolimus 1 mg Tablet, 60-count

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 )

5.1Management 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.

5.2Lymphomas 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.

5.3Serious 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.

5.4Kidney 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].

5.5Hepatic 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.

5.6Everolimus 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…

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 than10%): diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, leukopenia, and hypercholesterolemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 ( www.fda.gov/medwatch ).

6.1Serious 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 ) ]

6.2Clinical 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%, incl…

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 )

7.1Interactions 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.

7.2Cyclosporine (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).

7.3Ketoconazole 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 ) ].

7.4Erythromycin (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 ) ].

7.5Verapamil (CYP3A4 and P-gp Substrate) Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax 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 ) ].

7.6Atorvastatin (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…