EVEROLIMUS Drug Interactions: What You Need to Know

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 tablets dose adjustment ( 5.14 ) Therapeutic drug monitoring and dose reduction for everolimus tablets should be considered when everolimus tablets are 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 [ s ee 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 [ s ee Clinical Pharmaco logy (12. 5 )] . Dose adjustment of everolimus might be needed if the cyclosporine dose is altered [ s ee 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 [ 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 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 monitored for the development of rhabdomyolysis and other adverse reactions as described in the respective labeling for these products.

7.7 Simvastatin and Lovastatin Due to an interaction with cyclosporine, clinical studies of everolimus with cyclosporine conducted in kidney transplant patients strongly discouraged patients with receiving HMG-CoA reductase inhibitors such as simvastatin and lovastatin [ s ee Warnings and Precautions ( 5.1 1 )] .

7.8 Rifampin (Strong CYP3A4/P-gp Inducers) Pretreatment of healthy subjects with multiple-dose rifampin followed by a single dose of everolimus increased everolimus clearance and decreased the everolimus C max and AUC estimates. Combination with rifampin is not recommended [ s ee Warnings and Precautions ( 5.1 4 ) , Clinical Pharmacology (12. 5 )] .

7.9 Midazolam (CYP3A4/5 Substrate) Single-dose administration of midazolam to healthy volunteers following administration of multiple-dose everolimus indicated that everolimus is a weak inhibitor of CYP3A4/5. Dose adjustment of midazolam or other CYP3A4/5 substrates is not necessary when everolimus is coadministered with midazolam or other CYP3A4/5 substrates [ s ee Clinical Pharmacology (12. 5 )] .

7.10 Other Possible Interactions Moderate inhibitors of CYP3A4 and P-gp may increase everolimus blood concentrations (e.g., fluconazole; macrolide antibiotics; nicardipine, diltiazem; nelfinavir, indinavir, amprenavir). Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood concentrations (e.g., St. John’s Wort [ Hypericum perforatum ]; anticonvulsants: carbamazepine, phenobarbital, phenytoin; efavirenz, nevirapine).

7.11 Octreotide Coadministration of everolimus and depot octreotide increased octreotide C min by approximately 50%.

7.12 Tacrolimus There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and consequently, dose adjustment of everolimus is not necessary when everolimus is coadministered with tacrolimus.

7.13 Cannabidiol The blood levels of everolimus may increase upon concomitant use with cannabidiol. When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol <span class="opacity-50 text-xs">[see Dosage and Administration (2.3), Warnings and Precautions (5.22)]</span>.

7.13 Cannabidiol The blood levels of everolimus may increase upon concomitant use with cannabidiol. When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol <span class="opacity-50 text-xs">[see Dosage and Administration (2.3), Warnings and Precautions (5.22)]</span>.

Hypersensitivity to everolimus, sirolimus, or to components of the drug product ( 4 ) 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.

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 tablets 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 tablets. 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 [ s ee Warnings and Precautions ( 5.1 3 ) , 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 [ s ee 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 tablets 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 combination with everolimus in order to reduce renal dysfunction [ see Boxed Warning, Indications and Usage (1. 1 ), Clinical Pharmacology (12. 8 )] . In liver transplant recipients, everolimus has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus should be used in combination with everolimus in order to minimize the potential risk of nephrotoxicity [ s ee Indications and Usage (1.2), Clinical Pharmacology (12. 9 )] . Renal function should be monitored during the administration of everolimus. Consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to be drug related. Caution should be exercised when using other drugs which are known to impair renal function.

5.7 Heart Transplantation In a clinical trial of de novo heart transplant patients, everolimus 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 everolimus in heart transplantation is not recommended.

5.8 Angioedema Everolimus has been associated with the development of angioedema. The concomitant use of everolimus with other drugs known to cause angioedema, such as angiotensin converting enzyme (ACE) inhibitors may increase the risk of developing angioedema.

5.9 Wound Healing and Fluid Accumulation Everolimus 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.

5.10 Interstitial Lung Disease (ILD)/Non-Infectious Pneumonitis 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 everolimus. Most cases generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred.

5.11 Hyperlipidemia Increased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, have been reported to occur following initiation of everolimus 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 everolimus tablets. Any patient who is administered everolimus tablets 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 everolimus. Similarly, the risk/benefit of continued everolimus tablets therapy should be reevaluated in patients with severe refractory hyperlipidemia. Everolimus has not been studied in patients with baseline cholesterol levels greater than 350 mg/dL. Due to an interaction with cyclosporine, clinical trials of everolimus and cyclosporine in kidney transplant patients strongly discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During everolimus 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 )] .

5.12 Proteinuria The use of everolimus in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased with higher everolimus whole blood trough concentrations. Patients receiving everolimus tablets should be monitored for proteinuria [ see Adverse Reactions (6.2) ] .

5.13 Polyoma Virus Infections Patients receiving immunosuppressants, including everolimus, 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 everolimus. 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.

5.14 Interaction With Strong Inhibitors and Inducers of CYP3A4 Coadministration of everolimus with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) or strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of everolimus whole blood trough concentrations [ s ee Drug Interactions (7)] .

5.15 Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome The concomitant use of everolimus with cyclosporine may increase the risk of thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Monitor hematologic parameters <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> .

5.16 New Onset Diabetes After Transplant Everolimus has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients using everolimus.

5.17 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.1)]</span> , everolimus 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 everolimus tablets and for 8 weeks after ending treatment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1, 8.3)]</span> .

5.18 Male Infertility Azoospermia or oligospermia may be observed [ see Adverse Reactions (6. 2 ) , Nonclinical Toxicology (13.1) ] . Everolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

5.19 Immunizations The use of live vaccines should be avoided during treatment with everolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

5.20 Interaction With Grapefruit Juice Grapefruit and grapefruit juice inhibit cytochrome P450 3A4 and P-gp activity and should therefore be avoided with concomitant use of everolimus and cyclosporine or tacrolimus.

5.21 Patients With Hereditary Disorders/Other Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take everolimus as this may result in diarrhea and malabsorption.

5.22 Cannabidiol Drug Interactions When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol <span class="opacity-50 text-xs">[see Dosage and Administration (2.3), Drug Interactions (7.13)]</span>.

5.22 Cannabidiol Drug Interactions When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol <span class="opacity-50 text-xs">[see Dosage and Administration (2.3), Drug Interactions (7.13)]</span>.