In a clinical trial of de novo heart transplant patients, Zortress in an immunosuppressive regimen with or without induction therapy, resulted in an increased mortality often associated with serious infections within the first three months posttransplantation compared to the control regimen. Use of Zortress in heart transplantation is not recommended.
Zortress has been associated with the development of angioedema. The concomitant use of Zortress with other drugs known to cause angioedema, such as angiotensin converting enzyme (ACE) inhibitors may increase the risk of developing angioedema.
Zortress increases the risk of delayed wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele and seroma. These wound-related complications may require more surgical intervention. Generalized fluid accumulation, including peripheral edema (e.g., lymphoedema) and other types of localized fluid collection, such as pericardial and pleural effusions and ascites have also been reported.
A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled out through appropriate investigations. Cases of ILD, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some reported with pulmonary hypertension [including pulmonary arterial hypertension (PAH)] as a secondary event, have occurred in patients receiving rapamycins and their derivatives, including Zortress. Most cases generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred.
Increased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, have been reported to occur following initiation of Zortress and the risk of hyperlipidemia is increased with higher everolimus whole blood trough concentrations [ see Adverse R eactions (6.2) ] . Use of anti-lipid therapy may not normalize lipid levels in patients receiving Zortress.
Any patient who is administered Zortress should be monitored for hyperlipidemia. If detected, interventions, such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen containing Zortress. Similarly, the risk/benefit of continued Zortress therapy should be reevaluated in patients with severe refractory hyperlipidemia. Zortress has not been studied in patients with baseline cholesterol levels greater than 350 mg/dL.
Due to an interaction with cyclosporine, clinical trials of Zortress and cyclosporine in kidney transplant patients strongly discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During Zortress therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents [ see Drug Interactions (7 . 7 )] .
The use of Zortress in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased with higher everolimus whole blood trough concentrations. Patients receiving Zortress should be monitored for proteinuria [ see Adverse Reactions (6.2) ] .
Patients receiving immunosuppressants, including Zortress, are at increased risk for opportunistic infections; including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus associated progressive multiple leukoencephalopathy (PML). PVAN has been observed in patients receiving immunosuppressants, including Zortress. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss [ see Adverse Reactions (6.2) ] . Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.
Coadministration of Zortress with strong CYP3A4-inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of everolimus whole blood trough concentrations [ s ee Drug Interactions (7)] .
The concomitant use of Zortress with cyclosporine may increase the risk of thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Monitor hematologic parameters [see Adverse Reactions (6.2)].
Zortress has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients using Zortress.
Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)] , Zortress may cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception while using Zortress and for 8 weeks after ending treatment [see Use in Specific Populations (8.1, 8.3)].
Azospermia or oligospermia may be observed [ see Adverse Reactions (6. 2 ) , Nonclinical Toxicology (13.1) ] . Zortress is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.
The use of live vaccines should be avoided during treatment with Zortress; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
Grapefruit and grapefruit juice inhibit cytochrome P450 3A4 and P-gp activity and should therefore be avoided with concomitant use of Zortress and cyclosporine or tacrolimus.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Zortress as this may result in diarrhea and malabsorption.
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 ) ]
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