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Afinitor

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Afinitor uses


WARNING : MALIGNANCIES AND SERIOUS INFECTIONS, KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND MORTALITY IN HEART TRANSP L ANTATION

Malignancies and Serious Infections


Kidney Graft Thrombosis


Nephrotoxicity


Mortality in Heart Transplantation


WARNING : MALIGNANCIES AND SERIOUS INFECTIONS, KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND MORTALITY IN HEART TRANSPLANTATION

See full prescribing information f or complete boxed warning .

1 INDICATIONS AND USAGE

- Afinitor is a 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 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 has 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-moderate immunologic risk receiving a kidney transplant [ see Clinical Studies (14.1)] . Afinitor is to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring (TDM) of Afinitor 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

Afinitor is indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Afinitor 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 , Clinical Studies (14.2) ] . Therapeutic drug monitoring (TDM) of Afinitor 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 Afinitor has not been established in the following populations:

2 DOSAGE AND ADMINISTRATION

Patients receiving Afinitor may require dose adjustments based on Afinitor blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of Afinitor 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 Afinitor should be doubled using the available tablet strengths. Dose adjustment is also required if the trough concentration is greater than 8 ng/mL on 2 consecutive measures; the dose of Afinitor® should be decreased by 0.25 mg twice daily [ s ee 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 1.0 mg twice daily starting 30 days after transplantation. (2.2)

- Monitor Afinitor concentrations: Adjust maintenance dose to achieve trough concentrations within the 3-8 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 Afinitor 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 Afinitor at least 30 days posttransplant. An initial dose of 1.0 mg orally twice daily 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 DrugMonitoring (TDM) Everolimus

Routine Afinitor whole blood therapeutic drug concentration monitoring is recommended for all patients. The recommended Afinitor therapeutic range is 3 to 8 ng/mL [ s ee Clinical Pharmacology (12. 7 ) ] . Careful attention should be made to clinical signs and symptoms, tissue biopsies, and laboratory parameters. It is important to monitor Afinitor blood concentrations, in patients with hepatic impairment, during concomitant administration of CYP3A4 inducers or inhibitors, when switching cyclosporine formulations and/or when cyclosporine dosing is reduced according to recommended target concentrations [ s ee Clinical Pharmacology (12. 7 , 12. 8 )] .

There is an interaction of cyclosporine on Afinitor, and consequently, Afinitor concentrations may decrease if cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on Afinitor, and thus, Afinitor concentrations do not decrease if the tacrolimus exposure is reduced [ s ee Drug Interactions (7 .2 )] .

The Afinitor recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in clinical practice, Afinitor whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies. Because the measured Afinitor whole blood trough concentrations depend on the assay used, individual patient sample concentration values from different assays may not be interchangeable. Consideration of assay results must be made with knowledge of the specific assay used. Therefore, communication should be maintained with the laboratory performing the assay.

2.4 Therapeutic DrugMonitoring Cyclosporine in Kidney Transplant Patients

Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with Zortress, in order to minimize the risk of nephrotoxicity [ s ee Warnings and Precautions ( 5.6 ) , Drug Interactions (7.2), Clinical Pharmacology (12. 8 )] .

The recommended cyclosporine therapeutic ranges when administered with Afinitor are 100 to 200 ng/mL through Month 1 posttransplant, 75 to 150 ng/mL at Months 2 and 3 posttransplant, 50 to 100 ng/mL at Month 4 posttransplant, and 25 to 50 ng/mL from Month 6 through Month 12 posttransplant. The median trough concentrations observed in the clinical trial ranged between 161 to 185 ng/mL through Month 1 posttransplant and between 111 to 140 ng/mL at Months 2 and 3 posttransplant. The median trough concentration was 99 ng/mL at Month 4 posttransplant and ranged between 46 to 75 ng/mL from Months 6 through Month 12 posttransplant [ s ee Clinical Pharmacology (12. 8 ) , Clinical Studies (14.1)] .

Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or intravenous administration of cyclosporine cannot be avoided. Cyclosporine, USP Modified should be initiated as soon as possible and no later than 48 hours after reperfusion of the graft and dose adjusted to target concentrations from Day 5 onwards.

If impairment of renal function is progressive the treatment regimen should be adjusted. In renal transplant patients, the cyclosporine dose should be based on cyclosporine whole blood trough concentrations [ s ee Clinical Pharmacology (12 . 8 )] .

In renal transplantation, there are limited data regarding dosing Afinitor with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 months. Afinitor has not been evaluated in clinical trials with other formulations of cyclosporine. Prior to dose reduction of cyclosporine it should be ascertained that steady-state Afinitor whole blood trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on Afinitor, and consequently, Afinitor concentrations may decrease if cyclosporine exposure is reduced [ s ee Drug Interactions (7 .2 )] .

2.5 Therapeutic Drug-Monitoring Tacrolimus in Liver Transplant Patients

Both tacrolimus doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with Afinitor, in order to minimize the potential risk of nephrotoxicity [ s ee Warnings and Precautions (5. 6 ) , Clinical Pharmacology (12. 9 )] .

The recommended tacrolimus therapeutic range when administered with Afinitor are whole blood trough (C-0h) concentrations of 3 to 5 ng/mL by three weeks after the first dose of Afinitor (approximately Month 2) and through Month 12 posttransplant.

The median tacrolimus trough concentrations observed in the clinical trial ranged between 8.6 to 9.5 ng/mL at Weeks 2 and 4 posttransplant (prior to initiation of Afinitor). The median tacrolimus trough concentrations ranged between 7 to 8.1 ng/mL at Weeks 5 and 6 posttransplant, between 5.2 to 5.6 ng/mL at Months 2 and 3 posttransplant, and between 4.3 to 4.9 ng/mL between Months 4 and 12 posttransplant [ see Clinical Pharmacology (12. 9 ) , Clinical Studies (14.2) ]

Tacrolimus is to be administered as oral capsules twice daily unless intravenous administration of tacrolimus cannot be avoided.

In liver transplant patients, the tacrolimus dose should be based on tacrolimus whole blood trough concentrations [ s ee Clinical Pharmacology (12. 9 )] .

In liver transplantation, there are limited data regarding dosing Afinitor with reduced tacrolimus trough concentrations of 3 to 5 ng/mL after 12 months. Prior to dose reduction of tacrolimus it should be ascertained that the steady-state Afinitor whole blood trough concentration is at least 3 ng/mL. Unlike the interaction between cyclosporine and Afinitor, tacrolimus does not affect Afinitor trough concentrations, and consequently, Afinitor concentrations do not decrease if the tacrolimus exposure is reduced.

2.6 Administration

Afinitor tablets should be swallowed whole with a glass of water and not crushed before use.

Administer Afinitor consistently approximately 12 hours apart with or without food to minimize variability in absorption and at the same time as cyclosporine or tacrolimus [ s ee Clinical Pharmacology ] .

2.7 Hepatic Impairment

Whole blood trough concentrations of Afinitor should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the initial daily dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of Afinitor, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [ s ee Clinical Pharmacology (12. 6 )] .

3 DOSAGE FORMS AND STRENGTHS

Afinitor is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets.

Dosage Strength 0.25 mg 0.5 mg 0.75 mg
Appearance White to yellowish, marbled, round, flat tablets with bevelled 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

Afinitor is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets. (3)

4 CONTRAINDICATIONS

- Hypersensitivity to Afinitor, sirolimus, or to components of the drug product.

4.1 Hypersensitivity Reactions

Zortress is contraindicated in patients with known hypersensitivity to Afinitor, sirolimus, or to components of the drug product.

5 WARNINGS AND PRECAUTIONS

- Angioedema [increased risk with concomitant angiotensin converting enzyme 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/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 antilipid 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 hematological changes or symptoms. (5.15)

- New Onset Diabetes After Transplantation: Monitor serum glucose. (5.16)

- Male Infertility: Azospermia or oligospermia may occur. (5.17, 13.1)

- Immunizations: Avoid live vaccines. (5.18)

5.1 Management of Immunosuppression

Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe Afinitor. 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 CNI (calcineurin inhibition), there was an increased risk of acute rejection.

5.2 Lymphomas and Other Malignancies

Patients receiving immunosuppressants, including Afinitor, 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 Afinitor, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [ s ee Warnings and Precautions , 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 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, Afinitor should not be administered earlier than 30 days after liver transplant.

5.6 Zortress and Calcineurin Inhibitor-Induced Nephrotoxicity

In kidney transplant recipients, Afinitor 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 Afinitor in order to reduce renal dysfunction [ see Boxed Warning, Indications and Usage (1. 1 ), Clinical Pharmacology (12. 8 )] .

In liver transplant recipients, Afinitor has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus should be used in combination with Afinitor 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 Afinitor. 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, Afinitor 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 Afinitor in heart transplantation is not recommended.

5.8 Angioedema

Afinitor has been associated with the development of angioedema. The concomitant use of Afinitor with other drugs known to cause angioedema, such as angiotensin converting enzyme inhibitors may increase the risk of developing angioedema.

5.9 Wound Healing and Fluid Accumulation

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.

5.10 Interstitial Lung Disease/Non-Infectious Pneumonitis

A diagnosis of interstitial lung disease 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 Afinitor. Cases of ILD, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, have occurred in patients receiving rapamycins and their derivatives, including Afinitor. 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 antilipid therapy, have been reported to occur following initiation of Afinitor and the risk of hyperlipidemia is increased with higher Afinitor whole blood trough concentrations [ see Adverse R eactions (6.2) ] . Use of antilipid therapy may not normalize lipid levels in patients receiving Afinitor.

Any patient who is administered Afinitor 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 Afinitor therapy should be re-evaluated in patients with severe refractory hyperlipidemia. Afinitor has not been studied in patients with baseline cholesterol levels greater than 350 mg/dL.

Due to an interaction with cyclosporine, clinical trials of Afinitor and cyclosporine in kidney transplant patients strongly discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During Afinitor 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 Afinitor in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased with higher Afinitor whole blood trough concentrations. Patients receiving Afinitor should be monitored for proteinuria [ see Adverse Reactions ] .

5.13 Polyoma Virus Infections

Patients receiving immunosuppressants, including Afinitor, 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.

5.14 Interaction with Strong Inhibitors and Inducers of CYP3A4

Coadministration of Afinitor with strong CYP3A4-inhibitors and strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of Afinitor whole blood trough concentrations [ s ee Drug Interactions (7)] .

5.15 Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS)

The concomitant use of Afinitor with cyclosporine may increase the risk of thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Monitor hematologic parameters [ see Adverse Reactions (6 .2 )] .

5.16 New Onset Diabetes after Transplant

Afinitor 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.

5.17 Male Infertility

Azospermia or oligospermia may be observed [ see Adverse Reactions , Nonclinical Toxicology (13.1) ] . Zortress is an antiproliferative drug and affects rapidly dividing cells like the germ cells.

5.18 Immunizations

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

5.19 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 Afinitor and cyclosporine or tacrolimus.

5.20 Patients with Hereditary Disorders/Other

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Afinitor as this may result in diarrhea and malabsorption.

6 ADVERSE REACTIONS

Most common adverse reactions were as follows:

Kidney transplantation : peripheral edema, constipation, hypertension, nausea, anemia, 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 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:

6.2 Clinical Studies 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 Afinitor in an open-label, randomized trial of de novo kidney transplant patients of concentration-controlled Afinitor at an initial Afinitor starting dose of 1.5 mg per day [target trough concentrations 3 to 8 ng/mL with reduced exposure cyclosporine 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 Afinitor group, 47 years control group); a majority of recipients were male (64% in the Afinitor group, 69% control group); and a majority of patients were Caucasian (70% in the Afinitor 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 Afinitor 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 Afinitor 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 Afinitor at a higher dose (3 mg per day) was 95/279, 34%, including 20% due to adverse reactions, and this regimen is not recommended.

The overall incidences of serious adverse reactions were 57% (159/278) in the Afinitor group and 52% (141/273) in the mycophenolic acid group. Infections and infestations reported as serious adverse reactions had the highest incidence in both groups [20% (54/274) in the Afinitor group and 25% (69/273) in the control group]. The difference was mainly due to the higher incidence of viral infections in the mycophenolic acid group, mainly CMV and BK virus infections. Injury, poisoning and procedural complications reported as serious adverse reactions had the second highest incidence in both groups [14% (39/274) in the Afinitor group and 12% (32/273) in the control group] followed by renal and urinary disorders [10% (28/274) in the Afinitor group and 13% (36/273) in the control group] and vascular disorders [10% (26/274) in the Afinitor group and 7% (20/273) in the control group].

A total of 13 patients died during the first 12 months of study; 7 (3%) in the Afinitor group and 6 (2%) in the control group. The most common causes of death across the study groups were related to cardiac conditions and infections.

There were 12 (4%) graft losses in the Afinitor group and 8 (3%) in the control group over the 12 month study period. Of the graft losses, 4 were due to renal artery and two due to renal vein thrombosis in the Afinitor group (2%) compared to two renal artery thromboses in the control group (1%) [ s ee Boxed Warning , Warnings and Precautions (5. 4 ) ] .

The most common (greater than or equal to 20%) adverse reactions observed in the Afinitor group were: peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, and hyperlipidemia.

Infections

The overall incidence of bacterial, fungal and viral infections reported as adverse reactions was higher in the control group (68%) compared to the Afinitor group (64%) and was primarily due to an increased number of viral infections (21% in the control group and 10% in the Afinitor group). The incidence of CMV infections reported as adverse reactions was 8% in the control group compared to 1% in the Afinitor group; and 3% of the serious CMV infections in the control group versus 0% in the Afinitor group were considered serious [ see Warnings and Precautions (5.3) ] .

BK Virus

BK virus infections were lower in incidence in the Afinitor group (2 patients, 1%) compared to the control group (11 patients, 4%). One of the two BK virus infections in the Afinitor group, and two of the 11 BK virus infections in the control group were also reported as serious adverse reactions. BK virus infections did not result in graft loss in any of the groups in the clinical trial.

Wound Healing and Fluid Collections

Wound healing-related reactions were identified through a retrospective search and request for additional data. The overall incidence of wound-related reactions, including lymphocele, seroma, hematoma, dehiscence, incisional hernia, and infections was 35% in the Afinitor group compared to 26% in the control group. More patients required intraoperative repair debridement or drainage of incisional wound complications and more required drainage of lymphoceles and seromas in the Afinitor group compared to control.

Adverse reactions due to major fluid collections such as edema and other types of fluid collections was 45% in the Afinitor group and 40% in the control group [ see Warnings and Precautions ( 5. 9 ) ] .

Neoplasms

Adverse reactions due to malignant and benign neoplasms were reported in 3% of patients in the Afinitor group and 6% in the control group. The most frequently reported neoplasms in the control group were basal cell carcinoma, squamous cell carcinoma, skin papilloma and seborrheic keratosis. One patient in the Afinitor group who underwent a melanoma excision prior to transplantation died due to metastatic melanoma [ see Boxed Warning , Warnings and Precautions (5.2) ] .

New O nset D iabetes M ellitus (NODM)

NODM reported based on adverse reactions and random serum glucose values, was 9% in the Afinitor group compared to 7% in the control group.

Endocrine Effects in Males

In the Afinitor group, serum testosterone levels significantly decreased while the FSH levels significantly increased without significant changes being observed in the control group. In both the Afinitor and the control groups mean testosterone and FSH levels remained within the normal range with the mean FSH level in the Afinitor group being at the upper limit of the normal range (11.1 U/L). More patients were reported with erectile dysfunction in the Afinitor treatment group compared to the control group (5% compared to 2%, respectively).

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of greater than or equal to 10% for patients receiving Afinitor with reduced dose cyclosporine or mycophenolic acid with standard dose cyclosporine. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Primary System Organ ClassPreferred Term Afinitor (e verolimus )

1.5 mg

With r educed exposure c yclosporine

N=274

n (%)

M ycophenolic acid

1.44 g

With s tandard exposure c yclosporine

N=273

n (%)

Any Adverse Reactions * 271 (99) 270 (99)
Blood lymphatic system disorders 93 (34) 111 (41)
Anemia 70 (26) 68 (25)
Leukopenia 8 (3) 33 (12)
Gastrointestinal disorders 196 (72) 207 (76)
Constipation 105 (38) 117 (43)
Nausea 79 (29) 85 (31)
Diarrhea 51 (19) 54 (20)
Vomiting 40 (15) 60 (22)
Abdominal pain 36 (13) 42 (15)
Dyspepsia 12 (4) 31 (11)
Abdominal pain upper 9 (3) 30 (11)
General disorders and administrative site conditions 181 (66) 160 (59)
Edema peripheral 123 (45) 108 (40)
Pyrexia 51 (19) 40 (15)
Fatigue 25 (9) 28 (10)
Infections and infestations 169 (62) 185 (68)
Urinary tract infection 60 (22) 63 (23)
Upper respiratory tract infection 44 (16) 49 (18)
Injury, poisoning and procedural complications 163 (60) 163 (60)
Incision site pain 45 (16) 47 (17)
Procedural pain 40 (15) 37 (14)
Investigations 137 (50) 133 (49)
Blood creatinine increased 48 (18) 59 (22)
Metabolism and nutrition disorders 222 (81) 199 (73)
Hyperlipidemia 57 (21) 43 (16)
Hyperkalemia 49 (18) 48 (18)
Hypercholesterolemia 47 (17) 34 (13)
Dyslipidemia 41 (15) 24 (9)
Hypomagnesemia 37 (14) 40 (15)
Hypophosphatemia 35 (13) 35 (13)
Hyperglycemia 34 (12) 38 (14)
Hypokalemia 32 (12) 32 (12)
Musculoskeletal and connective tissue disorders 112 (41) 105 (39)
Pain in extremity 32 (12) 29 (11)
Back pain 30 (11) 28 (10)
Nervous system disorders 92 (34) 109 (40)
Headache 49 (18) 40 (15)
Tremor 23 (8) 38 (14)
Psychiatric disorders 90 (33) 72 (26)
Insomnia 47 (17) 43 (16)
Renal and urinary disorders 112 (41) 124 (45)
Hematuria 33 (12) 33 (12)
Dysuria 29 (11) 28 (10)
Respiratory, thoracic and mediastinal disorders 86 (31) 93 (34)
Cough 20 (7) 30 (11)
Vascular disorders 122 (45) 124 (45)
Hypertension 81 (30) 82 (30)

*The safety analysis population defined as all randomized kidney transplant patients who received at least one dose of treatment and had at least one postbaseline safety assessment.

Adverse reaction that occurred with at least a 5% higher frequency in the Afinitor 1.5 mg group compared to the control group were: peripheral edema (45% compared to 40%), hyperlipidemia (21% compared to 16%), dyslipidemia (15% compared to 9%), and stomatitis/mouth ulceration (8% compared to 3%).

A third treatment group of Afinitor 3.0 mg per day (1.5 mg twice daily; target trough concentrations 6 to 12 ng/mL) with reduced exposure cyclosporine was included in the study described above. Although as effective as the lower dose Afinitor group, the overall safety was worse and consequently higher doses of Afinitor cannot be recommended. Out of 279 patients, 95 (34%) discontinued the study medication with 57 (20%) doing so because of adverse reactions. The most frequent adverse reactions leading to discontinuation of Afinitor when used at this higher dose were injury, poisoning and procedural complications (Zortress 1.5 mg: 5%, Afinitor 3.0 mg: 7%, and control: 2%), infections (2%, 6%, and 3%, respectively), renal and urinary disorders (4%, 7%, and 4%, respectively) and gastrointestinal disorders (1%, 3%, and 2%).

The combination of fixed dose Afinitor and standard doses of cyclosporine in previous kidney clinical trials resulted in frequent elevations of serum creatinine with higher mean and median serum creatinine values observed than in the current study with reduced exposure cyclosporine. These results indicate that Afinitor increases the cyclosporine-induced nephrotoxicity; and therefore should only be used in a concentration-controlled regimen with reduced exposure cyclosporine [ see Boxed Warnings, Indications and Usage (1. 1 ) , Warnings and Precautions (5. 6 ) ] .

Liver transplantation

The data described below reflect exposure to Afinitor starting 30 days after transplantation in an open-label, randomized trial of liver transplant patients. Seven hundred and nineteen (719) patients who fulfilled the inclusion/exclusion criteria [ see Clinical Studies (14.2 ) ] were randomized into one of the three treatment groups of the study. During the first 30 days prior to randomization patients received tacrolimus and corticosteroids, with or without mycophenolate mofetil (about 70 to 80% received MMF). No induction antibody was administered. At randomization, MMF was discontinued and patients were randomized to Afinitor initial dose of 1.0 mg twice per day (2.0 mg daily) and adjusted to protocol specified target trough concentrations of 3 to 8 ng/mL with reduced exposure tacrolimus [protocol specified target troughs 3 to 5 ng/mL] (N=245) [ see Clinical Pharmacology (12.7, 12.9)] or to a control group of standard exposure tacrolimus [protocol specified target troughs 8 to 12 ng/mL up to Month 4 posttransplant, then 6 to 10 ng/mL Month 4 through Month 12 posttransplant] (N=241). A third randomized group was discontinued prematurely [ see Clinical Studies (14.2) ] and is not described in this section.

The population was between 18 and 70 years, more than 50% were 50 years of age (mean age was 54 years in the Afinitor group, 55 years in the tacrolimus control group); 74% were male in both Afinitor and control groups, respectively, and a majority were Caucasian (86% Afinitor group, 80% control group). Demographic characteristics were comparable between treatment groups. The most frequent diseases leading to transplantation were balanced between groups. The most frequent causes of end-stage liver disease (ESLD) were alcoholic cirrhosis, hepatitis C, and hepatocellular carcinoma and were balanced between groups.

Twenty-seven percent discontinued study drug in the Afinitor group compared with 22% for the tacrolimus control group during the first 12 months of study. The most common reason for discontinuation of study medication was due to adverse reactions (19% and 11%, respectively), including proteinuria, recurrent hepatitis C, and pancytopenia in the Afinitor group. At 24 months, the rate of discontinuation of study medication in liver transplant patients was greater for the Afinitor group (42%) compared to tacrolimus control group (33%).

The overall incidences of serious adverse reactions were 50% (122/245) in the Afinitor group and 43% (104/241) in the control group at 12 months and similar at 24 months (56% and 54% respectively). Infections and infestations were reported as serious adverse reactions with the highest incidence followed by Gastrointestinal disorders and Hepatobiliary disorders.

During the first 12 months of study, 13 deaths were reported in the Afinitor group (one patient never took Afinitor). In the same 12 month period, 7 deaths were reported in the tacrolimus control group. Deaths occurred in both groups for a variety of reasons and were mostly associated with liver-related issues, infections and sepsis. In the following 12 months of study, four additional deaths were reported in each treatment group.

The most common adverse reactions (reported for greater than or equal to 10% patients in any group) in the Afinitor group were: diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, and leukopenia (see Table 3).

Infections

The overall incidence of infections reported as adverse reactions was 50% for Afinitor and 44% in the control group and similar at 24 months (56% and 52% respectively). The types of infections were reported as follows: bacterial 16% vs 12%, viral 17% vs 13%; and fungal infections 2% vs 5% for Afinitor and control, respectively [ see Warnings and Precautions (5.3)] .

Wound Healing and Fluid Collections

Wound healing complications were reported as adverse reactions for 11% of patients in the Afinitor group compared to 8% of patients in the control group up to 24 months. Pleural effusions were reported in 5% in both groups, and ascites in 4% of patients in the Afinitor group and 3% in the control arm.

Neoplasms

Malignant and benign neoplasms were reported as adverse reactions in 4% of patients in the Afinitor group and 7% in the control group at 12 months. In the Afinitor group 3 malignant tumors were reported compared to 9 cases in the control group. For the Afinitor group this included lymphoma, lymphoproliferative disorder and a hepatocellular carcinoma, and for the control group included Kaposi’s sarcoma (2), metastatic colorectal cancer, glioblastoma, malignant hepatic neoplasm, pancreatic neuroendocrine tumor, hemophagocytic histiocytosis, and squamous cell carcinomas. At 24 months, the rates of malignancies were similar (10% and 11% respectively) [s ee Boxed Warning , Warnings and Precautions (5.2)].

Lipid A bnormalities

Hyperlipidemia adverse reactions (including the preferred terms: hyperlipidemia, hypercholesterolemia, blood cholesterol increased, blood triglycerides increased, hypertriglyceridemia lipids increased, total cholesterol/HDL ratio increased, and dyslipidemia) were reported for 24% Afinitor patients, and 10% control patients at 12 months. Results were similar at 24 months (28% and 12%, respectively).

New Onset of Diabetes After Transplant (NODAT)

Of the patients without diabetes mellitus at randomization, NODAT was reported in 32% in the Afinitor group compared to 29% in the control group at 12 months and similar at 24 months.

Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of greater than or equal to 10% for patients receiving Afinitor with reduced exposure tacrolimus or standard dose tacrolimus from randomization to 24 months. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Preferred System Organ Class

Preferred Term

12 month 24 m onth
Afinitor

with reduced exposure tacrolimus

N= 245

n ( %)

Tacrolimus

s tandard exposure

N= 241

n ( %)

Afinitor

with reduced exposure tacrolimus

N=245

n (%)

Tacrolimus

standard exposur e

N=242

n (%)

Any Adverse Reaction/Infection 232 (95) 229 (95) 236 (96) 237 (98)
Blood & lymphatic system disorders 66 (27) 47 (20) 79 (32) 58 (24)
-Leucopenia 29 (12) 12 (5) 31 (13) 12 (5)
G as t r o i n t e s t i nal d i s ord e rs 136 (56) 121 (50) 148 (60) 138 (57)
-Diarrhea 47 (19) 50 (21) 59 (24) 61 (25)
-Nausea 33 (14) 28 (12) 36 (15) 33 (14)
-Abdominal pain 32 (13) 22 (9) 37 (15) 31(13)
G eneral d i s o rde r s and a d mi n i s t ra t i on s i t e con d i t i o ns 94 (38) 85 (35) 113 (46) 98 (41)
-Peripheral edema 43 (18) 26 (11) 49 (20) 31 (13)
-Pyrexia 32 (13) 25 (10) 43 (18) 28 (12)
-Fatigue 22 (9) 26 (11) 27 (11) 28 (12)
I n f e c t i ons and i n f es t a t i o n s 123 (50) 105 (44) 135 (56) 125 (52)
-Hepatitis C** 28 (11) 19 (8) 33 (14) 24 (10)
Inve s ti g a t i ons 81 (33) 78 (32) 92 (38) 98 (41)
-Liver function test abnormal 16 (7) 24 (10) 19 (8) 25 (10)
Metabolism and nutrition disorders 111(45) 92(38) 134(55) 106(44)
-Hypercholesterolemia 23(9) 6(3) 27(11) 9(4)
N ervous s ys t em d i s orde r s 89 (36) 85 (35) 99 (40) 101 (42)
-Headache 47 (19) 46 (19) 53 (22) 54 (22)
-Tremor 23 (9) 29 (12) 25 (10) 37(15)
-Insomnia 14 (6) 19 (8) 17 (7) 24 (10)
Renal and urinary disorder 49(20) 53(22) 67(27) 73(30)
-Renal failure 13(5) 17(7) 24(10) 37(15)
V ascu l a r d i sord e rs 56 (23) 57 (24) 72 (29) 68 (28)
-Hypertension 42 (17) 38 (16) 52 (21) 44 (18)

Primary system organ classes are presented alphabetically.

*The safety analysis population is defined as all randomized liver transplant patients who received at least one dose of treatment and had at least one postbaseline safety assessment.

**No de novo hepatitis C cases were reported

Less common adverse reactions, occurring overall in greater than or equal to 1% to less than 10% of either kidney or liver transplant patients treated with Zortress include:

Blood and Lymphatic System Disorders : anemia, leukocytosis, lymphadenopathy, neutropenia, pancytopenia, thrombocythemia, thrombocytopenia

Cardiac and Vascular Disorders: angina pectoris, atrial fibrillation, cardiac failure congestive, palpitations, tachycardia, hypertension including hypertensive crisis, hypotension, deep vein thrombosis

E ndocr i n e D i s ord e r s : Cushingoid, hyperparathyroidism, hypothyroidism

Eye Disorders: cataract, conjunctivitis, vision blurred

Gastrointestinal Disorders: abdominal distention, abdominal hernia, ascites, constipation, dyspepsia, dysphagia, epigastric discomfort, flatulence, gastritis, gastroesophageal reflux disease, gingival hypertrophy, hematemesis, hemorrhoids, ileus, mouth ulceration, peritonitis, stomatitis

General Disorders and Administrative Site Conditions: chest discomfort, chest pain, chills, fatigue, incisional hernia, inguinal hernia, malaise, edema including generalized edema, pain

Hepatobiliary Disorders: hepatic enzyme increased, bile duct stenosis, bilirubin increased, cholangitis, cholestasis, hepatitis (non-infectious)

Infections and Infestations: BK virus infection [ s ee Warnings and Precautions ( 5.1 3 ) ], bacteremia, bronchitis, candidiasis, cellulitis, CMV, folliculitis, gastroenteritis, herpes infections, influenza, lower respiratory tract, nasopharyngitis, onychomycosis, oral candidiasis, oral herpes, osteomyelitis, pneumonia, pyelonephritis, sepsis, sinusitis, tinea pedis, upper respiratory tract infection, urethritis, urinary tract infection, wound infection [ s ee Boxed Warning , Warnings and Precautions (5. 3 )] .

Injury Poisoning and Procedural Complications: incision site complications including infections, perinephric collection, seroma, wound dehiscence, incisional hernia, perinephric hematoma, localized intraabdominal fluid collection, impaired healing, lymophocele, lymphorrhea

Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood glucose increased, hemoglobin decreased, white blood cell count decreased, transaminases increased

Metabolism and Nutrition Disorders: blood urea increased, acidosis, anorexia, dehydration, diabetes mellitus [ s ee Warnings and Precautions ( 5.1 6 ) ], decreased appetite, fluid retention, gout, hypercalcemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hypokalemia, hypoglycemia, hypomagnesemia, hyponatremia, iron deficiency, new onset diabetes mellitus, vitamin B12 deficiency

Musculoskeletal and Connective Tissues Disorders: arthralgia, joint swelling, muscle spasms, muscular weakness, musculoskeletal pain, myalgia, osteoarthritis, osteonecrosis, osteopenia, osteoporosis, spondylitis

Nervous System Disorders: dizziness, hemiparesis, hypoesthesia, lethargy, migraine, neuralgia, paresthesia, somnolence, syncope, tremor

Psychiatric Disorders: agitation, anxiety, depression, hallucination

Renal and Urinary Disorders: bladder spasm, hydronephrosis, micturation urgency, nephritis interstitial, nocturia, pollakiuria, polyuria, proteinuria [s ee Warnings and Precautions ( 5.1 2 )], pyuria, renal artery thrombosis [ s ee Boxed Warning , Warnings and Precautions ( 5.4 ) ], acute renal failure, renal impairment [ s ee Warnings and Precautions ( 5. 6 ) ], renal tubular necrosis, urinary retention

Reproductive System and Breast Disorders: amenorrhea, benign prostatic hyperplasia, erectile dysfunction, ovarian cyst, scrotal edema

Respiratory, Thoracic, Mediastinal Disorders: atelectasis, bronchitis, dyspnea, cough, epistaxis, lower respiratory tract infection, nasal congestion, oropharyngeal pain, pleural effusions, pulmonary edema, rhinorrhea, sinus congestion, wheezing

Skin and Subcutaneous Tissue Disorders: acne, alopecia, dermatitis acneiform, ecchymosis, hirsutism, hyperhydrosis, hypertrichosis, night sweats, pruritus, rash

Vascular D isorders: venous thromboembolism (including deep vein thrombosis), phlebitis, pulmonary embolism

Less common, serious adverse reactions occurring overall in less than 1% of either kidney or liver transplant patients treated with Afinitor include:

6.3 Postmarketing Experience

Adverse reactions identified from the postmarketing use of the combination regimen of Afinitor and cyclosporine that are not specific to any one transplant indication include angioedema [ s ee Warnings and Precautions (5. 8 ) ], erythroderma, leukocytoclastic vasculitis, pancreatitis, pulmonary alveolar proteinosis, and pulmonary embolism. There have also been reports of male infertility with mTOR inhibitors including Zortress [ s ee Warnings and Precautions ( 5.1 7 ) ] .

7 DRUG INTERACTIONS

Strong-moderate CYP3A4 inhibitors and CYP3A4 inducers (e.g., rifampin) may affect Afinitor concentrations. (7.1). Consider Afinitor dose adjustment. (5.14)

7.1 Interactions with Strong Inhibitors or Inducers of CYP3A4 and P-glycoprotein

Afinitor 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 Afinitor 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 Afinitor from intestinal cells and increase Afinitor blood concentrations. In vitro, Afinitor 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 co-administering Afinitor 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 Afinitor and concomitantly administered drugs are discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

7.2 Cyclosporine

The steady-state Cmax and area under curve (AUC) estimates of Afinitor were significantly increased by coadministration of single dose cyclosporine [ s ee Clinical Pharmaco logy (12. 5 )] . Dose adjustment of Afinitor 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 Afinitor Cmax, AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 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 Afinitor Cmax, AUC, and half-life. If erythromycin is co-administered, Afinitor blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Clinical Pharmaco logy (12. 5 )] .

7.5 Verapamil

Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of Afinitor Cmax and AUC. Everolimus half-life was not changed. If verapamil is coadministered, Afinitor blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Clinical Pharmaco logy (12. 5 ) ] .

7.6 Atorvastatin and Pravastatin (P-gp substrate)

Single-dose administration of Afinitor with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and Afinitor, 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 Afinitor 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 ] .

7.8 Rifampin (Strong CYP3A4/P-gp Inducers)

Pretreatment of healthy subjects with multiple-dose rifampin followed by a single dose of Afinitor increased Afinitor clearance and decreased the Afinitor Cmax and AUC estimates. Combination with rifampin is not recommended [ s ee Warnings and Precautions ( 5.1 4 ) , Clinical Pharmacology (12. 5 )] .

7.9 Midazolam

Single-dose administration of midazolam to healthy volunteers following administration of multiple-dose Afinitor indicated that Afinitor is a weak inhibitor of CYP3A4/5. Dose adjustment of midazolam or other CYP3A4/5 substrates is not necessary when Afinitor 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 Afinitor blood concentrations. Inducers of CYP3A4 may increase the metabolism of Afinitor and decrease Afinitor blood concentrations (e.g., St. John’s Wort [Hypericum perforatum]; anticonvulsants: carbamazepine, phenobarbital, phenytoin; efavirenz, nevirapine).

7.11 Octreotide

Coadministration of Afinitor and depot octreotide increased octreotide Cmin by approximately 50%.

7.12 Tacrolimus

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

8 USE IN SPECIFIC POPULATIONS

- Pregnancy: Based on animal data may cause fetal harm.

- Nursing Mothers: Discontinue drug or nursing. (8.3)



8.1 Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies of Afinitor in pregnant women. In rats and rabbits, Afinitor crossed the placenta and was toxic to the conceptus. The potential risk for humans is unknown. Afinitor should be given to pregnant women only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should be advised to use highly effective contraception methods while they are receiving Afinitor and up to 8 weeks after treatment has been stopped.

Afinitor administered daily to pregnant rats by oral gavage at 0.1 mg/kg from before mating through organogenesis resulted in increased preimplantation loss and early resorptions of fetal implants. AUCs in rats at this dose were approximately one-third those in humans administered the starting dose (0.75 mg twice daily). Afinitor administered daily by oral gavage at 0.8 mg/kg to pregnant rabbits during organogenesis resulted in increased late resorptions of fetal implants. At this dose, AUCs in rabbits were slightly less than the AUCs in humans administered the starting clinical dose.

8.3 Nursing Mothers

It is not known whether Afinitor is excreted in human milk. Afinitor and/or its metabolites readily transferred into milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Afinitor, women should avoid breast-feeding during treatment with Afinitor.

8.4 Pediatric Use

The safe and effective use of Afinitor in kidney or liver transplant patients younger than 18 years of age has not been established.

8.5 Geriatric Use

There is limited clinical experience on the use of Afinitor in patients of age 65 years or older. There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients [ s ee C linical Pharmacology ] .

8.6 Hepatic Impairment

Afinitor whole blood trough concentrations should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of Afinitor, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [ s ee Clinical Pharmacology (12. 6 )] .

8.7 Renal Impairment

No dose adjustment is needed in patients with renal impairment [ s ee Clinical Pharmacology (12. 6 ) ] .

10 OVERDOSAGE

Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg Afinitor 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. Afinitor is not considered dialyzable to any relevant degree (less than 10% of Afinitor removed within 6 hours of hemodialysis). In animal studies, Afinitor 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.

11 DESCRIPTION

Afinitor (everolimus) is a macrolide immunosuppressant.

The chemical name of Afinitor 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.

The molecular formula is C53H83NO14 and the molecular weight is 958.25. The structural formula is:

*Zortress dosing was initiated 30 days after transplantation

Although the initial protocol was designed for 24 months, the study was subsequently extended to 36 months. One hundred six patients (43%) in the Afinitor group and 125 patients (51%) in the control group participated in the extension study from Month 24 to Month 36 after transplantation. The results for the Afinitor group at 36 months were consistent with the results at 24 months in terms of tBPAR, graft loss, death and eGFR.

16 HOW SUPPLIED/STORAGE AND HANDLING

Afinitor (everolimus) Tablets are packed in child-resistant blisters.

Dosage Strength 0.25 mg 0.5 mg 0.75 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
NDC Number 0078-0417-20 0078-0414-20 0078-0415-20

Each strength is available in boxes of 60 tablets (6 blister strips of 10 tablets each).

Storage

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).

Protect from light and moisture.

17 PATIENT COUNSELING INFORMATION

Administration

Inform patients that Afinitor should be taken orally twice a day approximately 12 hours apart consistently either with or without food.

Inform patients to avoid grapefruit and grapefruit juice which increase blood drug concentrations of Zortress [s ee Warnings and Precautions ( 5.1 9 )].

Advise patients that Afinitor should be used concurrently with reduced doses of cyclosporine and that any change in doses of these medications should be made under physician supervision. A change in the cyclosporine dose may also require a change in the dosage of Afinitor.

Inform patients of the necessity of repeated laboratory tests according to physician recommendations while they are taking Zortress.

Development of Lymphomas and Other Malignancies

Inform patients they are at risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a sunscreen with a high protection factor [ s ee Warnings and Precautions (5.2) ] .

Increa s ed Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression. Advise patients to contact their physician if they develop any symptoms of infection [ s ee Warnings and Precautions (5.3, 5.1 3 ) ] .

Kidney Graft Thrombosis

Inform patients that Afinitor has been associated with an increased risk of kidney arterial and venous thrombosis, resulting in graft loss, usually within the first 30 days posttransplantation [ s ee Warnings and Precautions ( 5.4 ) ] .

Afinitor and Calcineurin Inhibitor-Induced Nephrotoxicity

Advise patients of the risks of impaired kidney function with the combination of Afinitor and cyclosporine as well as the need for routine blood concentration monitoring for both drugs. Advise patients of the importance of serum creatinine monitoring [ s ee Warning s and Precautions ( 5. 6 ) ] .

Angioedema

Inform patients of the risk of angioedema and that concomitant use of ACE inhibitors may increase this risk. Advise patients to seek prompt medical attention if symptoms occur [ s ee Warnings and Precautions ( 5. 8 ) ] .

Wound Healing Complications and Fluid Accumulation

Inform patients the use of Afinitor has been associated with impaired or delayed wound healing, fluid accumulation and the need for careful observation of their incision site [ s ee Warnings and Precautions ( 5. 9 ) ] .

Interstitial L ung D isease/Non-Infectious Pneumonitis

Inform patients the use of Afinitor may increase the risk of noninfectious pneumonitis. Advise patients to seek medical attention if they develop clinical symptoms consistent with pneumonia [ s ee Warnings and Precautions (5. 10 )] .

Hyperlipidemia

Inform patients the use of Afinitor has been associated with increased serum cholesterol and triglycerides that may require treatment and the need for monitoring of blood lipid concentrations [ s ee Warnings and Precautions ( 5. 11 ) ] .

Proteinuria

Inform patients the use of Afinitor has been associated with an increased risk of proteinuria [ s ee Warnings and Precautions ( 5.1 2 ) ] .

Pregnancy

Advise women of childbearing age to avoid becoming pregnant throughout treatment and for 8 weeks after Afinitor therapy has stopped.

Medications that Interfere with Afinitor

Some medications can increase or decrease blood concentrations of Afinitor. Advise patients to inform their physician if they are taking any of the following: antifungals, antibiotics, antivirals, anti-epileptic medicines including carbamazepine, phenytoin and barbiturates, herbal/dietary supplements (St. John’s Wort), and/or rifampin [ s ee Warnings an d Precautions ( 5.1 4 )] .

New Onset Diabetes

Inform patients the use of Afinitor may increase the risk of diabetes mellitus and to contact their physician if they develop symptoms [ s ee Warnings and Precautions ( 5.1 6 ) ] .

Immunizations

Inform patients that vaccinations may be less effective while they are being treated with Afinitor. Advise patients live vaccines should be avoided [ s ee Warnings an d Precautions ( 5.1 8 )] .

Patient with Hereditary Disorders

Advise patients to inform their physicians that if they have hereditary disorders of galactose intolerance (Lapp-lactase deficiency or glucose-galactose malabsorption) not to take Afinitor [ s ee Warnings and Precautions ( 5. 20 ) ] .

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

© Novartis

T2016-87

October 2016


MEDICATION GUIDE

Afinitor (ZOR-tres)

(everolimus)

Tablets

Read this Medication Guide before you start using Afinitor and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

What is the most important information I should know about Afinitor?

Afinitor can cause serious side effects, including:

  • Increased risk of getting certain cancers. People who take Afinitor have a higher chance of getting lymphoma and other cancers, especially skin cancer. Talk to your doctor about your risk for cancer.

  • Increased risk of serious infections. Afinitor weakens the body’s immune system and affects your ability to fight infections. Serious infections can happen with Afinitor that may lead to death. People taking Afinitor have a higher chance of getting infections caused by viruses, bacteria, and fungi (yeast).
    • Call your doctor if you have symptoms of infection including fever or chills.
  • Blood clot in the blood vessels of your transplanted kidney. If this happens, it usually occurs within the first 30 days after your kidney transplant. Tell your doctor right away if you:
    • have pain in your groin, lower back, side or stomach (abdomen)

    • make less urine or you do not pass any urine

    • have blood in your urine or dark colored urine (tea-colored)

    • have fever, nausea, or vomiting

  • Serious problems with your transplanted kidney (nephrotoxicity). You will need to start with a lower dose of cyclosporine when you take it with Afinitor. Your Doctor should do regular blood tests to check your levels of both Afinitor and cyclosporine.

  • Increased risk of death that can be related to infection, in people who have had a heart transplant. You should not take Afinitor if you have had a heart transplant without talking to your doctor.
See the section “What are the possible side effects of Afinitor?” for information about other serious side effects.

What is Afinitor?

Afinitor is a prescription medicine used to prevent transplant rejection (antirejection medicine) in people who have received a kidney transplant or liver transplant. Transplant rejection happens when the body’s immune system perceives the new transplanted kidney as “foreign” and attacks it.

Afinitor is used with other medicines called cyclosporine, corticosteroids and certain other transplant medicines to prevent rejection of your transplanted kidney. Zortress is used with other medicines called tacrolimus and corticosteroids to prevent rejection of your transplanted liver.

It is not known if Afinitor is safe and effective in transplanted organs other than the kidney and liver.

It is not known if Afinitor is safe and effective in children under 18 years of age.

Who should not take Afinitor?

Do not take Afinitor if you are allergic to:


What should I tell my doctor before taking Afinitor?

Before taking Afinitor, tell your doctor if you:


Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Afinitor may affect the way other medicines work, and other medicines may affect how Afinitor works.

Especially tell your doctor if you take:


Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. Do not take any new medicine without talking with your doctor first.

How should I take Afinitor?


What should I avoid while taking Afinitor?


What are possible side effects of Afinitor?

Afinitor can cause serious side effects, including:


Your doctor should do blood and urine tests to monitor your cholesterol, triglycerides and kidney function.


The most common side effects of Afinitor in people who have had a kidney or liver transplant include:

These common side effects have been reported in both kidney and liver transplant patients:


The most common side effects of Afinitor in people who have had a kidney transplant include:


The most common side effects of Afinitor in people who have had a liver transplant include:


These are not all of the possible side effects of Afinitor. Tell your doctor about any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How do I store Afinitor?


Keep Afinitor and all medicines out of the reach of children.

General information about the safe and effective use of Afinitor.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Afinitor for a condition for which it was not prescribed. Do not give Afinitor to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Afinitor. For more information, talk with your doctor. You can ask your doctor or pharmacist for information about Afinitor that is written for healthcare professionals. For more information, call 1-888-669-6682 or visit www.zortress.com.

What are the ingredients in Afinitor?

Active ingredient: Afinitor

Inactive ingredients: butylated hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone and lactose anhydrous.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Any other trademarks in this document are the property of their respective owners.

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

© Novartis

Rapamune® is a registered trademark of Pfizer Inc

Gengraf® is a registered trademark of Abbott Laboratories

T2016-85

October 2016

Afinitor pharmaceutical active ingredients containing related brand and generic drugs:


Afinitor available forms, composition, doses:


Afinitor destination | category:


Afinitor Anatomical Therapeutic Chemical codes:


Afinitor pharmaceutical companies:


References

  1. Dailymed."ZORTRESS (EVEROLIMUS) TABLET [NOVARTIS PHARMACEUTICALS CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Cancer.Net."Angiogenesis and Angiogenesis Inhibitors to Treat Cancer". http://www.cancer.net/navigating-ca... (accessed August 28, 2018).
  3. Dailymed."EVEROLIMUS: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Afinitor?

Depending on the reaction of the Afinitor after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Afinitor not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Afinitor addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Afinitor, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Afinitor consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

One visitor reported frequency of use

How often in a day do you take the medicine?
Are you taking the Afinitor drug as prescribed by the doctor?
Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Afinitor is mentioned below.
Visitors%
Once in a day1
100.0%

One visitor reported doses

What is the dose of Afinitor drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 6-10mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
6-10mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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