Zortress

Warnings and Precautions, Cannabidiol Drug Interactions ( 5.22 ) 9/2023

1 INDICATIONS AND USAGE Zortress 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 Zortress is 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)] . Zortress is 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 Zortress is indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Zortress is to be administered no earlier than 30 days posttransplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [ s ee Warnings and Precautions (5. 5 ) , Clinical Studies (14.2) ] . TDM of everolimus and tacrolimus is recommended for all patients receiving these products [ s ee Dosage and Administration (2.3 , 2.5)] . 1.3 Limitations of Use The safety and efficacy of Zortress 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 Zortress 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 Zortress 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 Zortress 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 Zortress 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 Zortress 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 [ s ee 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 Zortress 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 [ s ee 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 different assays may not be int …

3 DOSAGE FORMS AND STRENGTHS Zortress is available as 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg tablets. Table 1. Description of Zortress (everolimus) Tablets Dosage strength 0.25 mg 0.5 mg 0.75 mg 1 mg Appearance White to yellowish, marbled, round, flat tablets with beveled edge Imprint “C” on one side and “NVR” on the other “CH” on one side and “NVR” on the other “CL” on one side and “NVR” on the other “CU” on one side and “NVR” on the other Zortress is available as 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg tablets ( 3 )

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

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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 an d Precautions ( 5.4 ) ] Hepatic Artery Thrombosis [ see Warnings and Precautions (5. 5 ) ] Zortress 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 ( 5.1 2 ) ] Polyoma Virus Infections [ see Warnings and Precautions ( 5.1 3 ) ] Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS) [ see Warnings and Precautions ( 5.1 5 ) ] New Onset Diabetes After Transplant [ see Warnings and Precautions ( 5.1 6 ) ] Male Infertility [ see Warnings and Precautions ( 5.1 8 ) ] 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 Zortress in an open-label, randomized trial of de novo kidney transplant patients of concentration-controlled everolimus at an initial Zortress 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 Zortress group, 47 years control group); a majority of recipients were male (64% in the Zortress group, 69% control group); and a majority of patients were Caucasian (70% in the Zortress 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 Zortress 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 Zortress 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 Zortress at a higher dose (3 mg per day) was 95/279, 34%, including 20% due to adverse react …

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 Zortress dose adjustment ( 5.14 ) Therapeutic drug monitoring and dose reduction for Zortress should be considered when Zortress 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 Zortress with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index [ s ee Dosage and Administration ( 2. 3 ) ] . All in vivo interaction studies were conducted without concomitant cyclosporine. Pharmacokinetic interactions between Zortress 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 [ s ee Clinical Pharmaco logy (12. 5 )] . Dose adjustment of Zortress might be needed if the cyclosporine dose is altered [ s ee Dosage and Administration ( 2. 3)] . Zortress 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 Zortress [ s ee Warnings and Precautions ( 5. 1 4 ), Clinical Pharmaco logy (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 [ s ee Clinical Pharmaco logy (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 [ s ee Clinical Pharmaco logy (12. 5 ) ] . 7.6 Atorvastatin (CYP3A4 Substrate) and Pravastatin (P-gp Substrate) Single-dose administration of Zortress 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 shou …

8 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause maternal and fetal harm ( 8.1 ) Lactation : Breastfeeding not recommended ( 8.2 ) Females and Males of Reproductive Potential : May impair fertility ( 8.1 , 8.3 , 13.1 ) 8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)] , Zortress can cause fetal harm when administered to a pregnant woman. There are limited case reports of Zortress 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. 8.2 Lactation Risk Summary There is no data regarding the presence of Zortress in human milk, the effects on breastfed infants, or the effects on milk production. Everolimus and/or its metabolites are readily transferred into milk of lactating rats at a concentration 3.5 times higher than in maternal rat serum. In pre-post-natal and juvenile studies in rats, exposure to everolimus during the postnatal period caused developmental toxicity [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.2)] . Advise lactating women not to breastfeed because of the potential for serious adverse reactions in infants exposed to everolimus. 8.3 Females and Males of Reproductive Potential Contraception Females should not be pregnant or become pregnant while receiving Zortress. Advise females of reproductive potential that animal studies have been performed showing Zortress 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 Zortress and up to 8 weeks after treatment has been stopped. Infertility Females Amenorrhea occurred in female patients taking Zortress [see Adverse Reactions (6.2)] . Zortress may cause pre-implantation loss in females based on animal data [see Nonclinical Toxicology (13.1)] . Female fertility may be compromised by treatment with Zortress. Males Zortress treatment may impair fertility in males based on human [see Warnings and Precautions (5. …

12.1 Mechanism of Action Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian target of rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited. The everolimus: FKBP-12 complex has no effect on calcineurin activity. In rats and nonhuman primate models, everolimus effectively reduces kidney allograft rejection resulting in prolonged graft survival.

11 DESCRIPTION Zortress (everolimus) is a macrolide immunosuppressant. The chemical name of everolimus is (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1, 18-dihydroxy-12 -{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15, 17, 21, 23, 29, 35-hexamethyl-11, 36-dioxa-4-aza-tricyclo[30.3.1.0 4,9 ] hexatriaconta-16,24,26,28-tetraene-2, 3,10,14,20-pentaone. The molecular formula is C 53 H 83 NO 14 and the molecular weight is 958.25 g/mol. The structural formula is: Zortress is supplied as tablets for oral administration containing 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg of everolimus together with butylated hydroxytoluene, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, and magnesium stearate as inactive ingredients. Zortress structural formula of everolimus is (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1, 18-dihydroxy-12 -{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15, 17, 21, 23, 29, 35-hexamethyl-11, 36-dioxa-4-aza-tricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2, 3,10,14,20-pentaone.

10 OVERDOSAGE Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. General supportive measures should be followed in all cases of overdose. Everolimus is not considered dialyzable to any relevant degree (less than 10% of everolimus removed within 6 hours of hemodialysis). In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats.

16 HOW SUPPLIED/STORAGE AND HANDLING Zortress (everolimus) tablets are packed in child-resistant blisters. Table 11. Description of Zortress (everolimus) Tablets Dosage strength 0.25 mg 0.5 mg 0.75 mg 1 mg Appearance White to yellowish, marbled, round, flat tablets with beveled edge Imprint “C” on one side and “NVR” on the other “CH” on one side and “NVR” on the other “CL” on one side and “NVR” on the other “CU” on one side and “NVR” on the other NDC number 0078-0417-20 0078-0414-20 0078-0415-20 0078-0422-20 Each strength is available in boxes of 60 tablets (6 blister strips of 10 tablets each). Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.