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Zortress

"Analysis of three biomarkers in the urine of kidney transplant recipients can diagnose — and even predict — transplant rejection, according to results from a clinical trial sponsored by the National Institute of Allergy and Infect"...

Zortress

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Management of Immunosuppression

Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe Zortress. 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.

Lymphomas and Other Malignancies

Patients receiving immunosuppressants, including Zortress, 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.

Serious Infections

Patients receiving immunosuppressants, including Zortress, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. [See ADVERSE REACTIONS] 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.

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 post-transplantation. [See BOXED WARNING]

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 post-transplant and most also lead to graft loss or death. Therefore, Zortress should not be administered earlier than 30 days after liver transplant.

Zortress and Calcineurin Inhibitor-Induced Nephrotoxicity

In kidney transplant recipients, Zortress 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 Zortress in order to reduce renal dysfunction. [See BOXED WARNING, INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY]

In liver transplant recipients, Zortress has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus should be used in combination with Zortress in order to minimize the potential risk of nephrotoxicity. [See INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY]

Renal function should be monitored during the administration of Zortress. 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.

Heart Transplantation

In a clinical trial of de novo heart transplant patients, Zortress in an immunosuppressive regimen with or without induction therapy, resulted in an increased mortality often associated with serious infections within the first three months post-transplantation compared to the control regimen. Use of Zortress in heart transplantation is not recommended.

Angioedema

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

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.

Interstitial Lung Disease/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 have been reported with Zortress, which generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred.

Hyperlipidemia

Increased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, have been reported to occur following initiation of Zortress and the risk of hyperlipidemia is increased with higher everolimus whole blood trough concentrations. [See ADVERSE REACTIONS] Use of anti-lipid therapy may not normalize lipid levels in patients receiving Zortress.

Any patient who is administered Zortress should be monitored for hyperlipidemia. If detected, interventions, such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen containing Zortress. Similarly, the risk/benefit of continued Zortress therapy should be reevaluated in patients with severe refractory hyperlipidemia. Zortress has not been studied in patients with baseline cholesterol levels > 350 mg/dL.

Due to an interaction with cyclosporine, clinical trials of Zortress and cyclosporine in kidney transplant patients strongly discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During Zortress therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents. [See DRUG INTERACTIONS]

Proteinuria

The use of Zortress in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased with higher everolimus whole blood trough concentrations. Patients receiving Zortress should be monitored for proteinuria. [See ADVERSE REACTIONS]

Polyoma Virus Infections

Patients receiving immunosuppressants, including Zortress, are at increased risk for opportunistic infections; including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus associated progressive multiple leukoencephalopathy (PML). PVAN has been observed in patients receiving immunosuppressants, including Zortress. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss. [See ADVERSE REACTIONS] 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.

Interaction with Strong Inhibitors and Inducers of CYP3A4

Co-administration of Zortress with strong CYP3A4-inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of everolimus whole blood trough concentrations. [See DRUG INTERACTIONS]

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

The concomitant use of Zortress with cyclosporine may increase the risk of thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Monitor hematologic parameters. [See ADVERSE REACTIONS]

New Onset Diabetes After Transplant

Zortress has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients using Zortress.

Male Infertility

Azospermia or oligospermia may be observed. [See ADVERSE REACTIONS and Carcinogenesis, Mutagenesis, Impairment of Fertility] Zortress is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

Immunizations

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

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 Zortress and cyclosporine or tacrolimus.

Patients with Hereditary Disorders/Other

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

Patient Counseling Information

Administration

Inform patients that Zortress 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. [See WARNINGS AND PRECAUTIONS]

Advise patients that Zortress 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 Zortress.

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. [See WARNINGS AND PRECAUTIONS]

Increased 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. [See WARNINGS AND PRECAUTIONS]

Kidney Graft Thrombosis

Inform patients that Zortress has been associated with an increased risk of kidney arterial and venous thrombosis, resulting in graft loss, usually within the first 30 days post-transplantation. [See WARNINGS AND PRECAUTIONS]

Zortress and Calcineurin Inhibitor-Induced Nephrotoxicity

Advise patients of the risks of impaired kidney function with the combination of Zortress and cyclosporine as well as the need for routine blood concentration monitoring for both drugs. Advise patients of the importance of serum creatinine monitoring. [See WARNINGS AND PRECAUTIONS]

Angioedema

Inform patients of the risk of angioedema and that concomitant use of angiotensin converting enzyme (ACE) inhibitors may increase this risk. Advise patients to seek prompt medical attention if symptoms occur. [See WARNINGS AND PRECAUTIONS]

Wound Healing Complications and Fluid Accumulation

Inform patients the use of Zortress has been associated with impaired or delayed wound healing, fluid accumulation and the need for careful observation of their incision site. [See WARNINGS AND PRECAUTIONS]

Interstitial lung disease/Non-Infectious Pneumonitis

Inform patients the use of Zortress may increase the risk of non-infectious pneumonitis. Advise patients to seek medical attention if they develop clinical symptoms consistent with pneumonia. [See WARNINGS AND PRECAUTIONS]

Hyperlipidemia

Inform patients the use of Zortress has been associated with increased serum cholesterol and triglycerides that may require treatment and the need for monitoring of blood lipid concentrations. [See WARNINGS AND PRECAUTIONS]

Proteinuria

Inform patients the use of Zortress has been associated with an increased risk of proteinuria. [See WARNINGS AND PRECAUTIONS]

Pregnancy

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

Medications that Interfere with Zortress

Some medications can increase or decrease blood concentrations of Zortress. 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. [See WARNINGS AND PRECAUTIONS]

New Onset Diabetes

Inform patients the use of Zortress may increase the risk of diabetes mellitus and to contact their physician if they develop symptoms. [See WARNINGS AND PRECAUTIONS]

Immunizations

Inform patients that vaccinations may be less effective while they are being treated with Zortress. Advise patients live vaccines should be avoided. [See WARNINGS AND PRECAUTIONS]

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 Zortress. [See WARNINGS AND PRECAUTIONS]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Everolimus was not carcinogenic in mice or rats when administered daily by oral gavage for 2 years at doses of 0.9 mg/kg. In these studies, AUCs in mice were much higher (at least 20 times) than those in humans receiving 0.75 mg twice daily, and AUCs in rats were in the same range as those in humans receiving 0.75 mg twice daily.

Everolimus was not mutagenic in the bacterial reverse mutation, the mouse lymphoma thymidine kinase assay, or the chromosome aberration assay using V79 Chinese hamster cells, or in vivo following two daily doses of 500 mg/kg in the mouse micronucleus assay.

In a 13-week male fertility oral gavage study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone concentrations were diminished at 5 mg/kg which caused a decrease in male fertility. There was evidence of reversibility of these findings in animals examined after 13 weeks post-dosing. The 0.5 mg/kg dose in male rats resulted in AUCs in the range of clinical exposures, and the 5 mg/kg dose resulted in AUCs approximately 5 times the AUCs in humans receiving 0.75 mg twice daily. Everolimus did not affect female fertility in nonclinical studies, but everolimus crossed the placenta and was toxic to the conceptus. [See Pregnancy]

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Zortress in pregnant women. In rats and rabbits, everolimus crossed the placenta and was toxic to the conceptus. The potential risk for humans is unknown. Zortress 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 effective contraception methods while they are receiving Zortress and up to 8 weeks after treatment has been stopped.

Everolimus 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). Everolimus 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.

Nursing Mothers

It is not known whether everolimus is excreted in human milk. Everolimus 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 everolimus, women should avoid breast-feeding during treatment with Zortress.

Pediatric Use

The safe and effective use of Zortress in kidney or liver transplant patients younger than 18 years of age has not been established. [See CLINICAL PHARMACOLOGY]

Geriatric Use

There is limited clinical experience on the use of Zortress in patients of age 65 or older. There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients. [See CLINICAL PHARMACOLOGY]

Hepatic Impairment

Everolimus 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 everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL. [See CLINICAL PHARMACOLOGY]

Renal Impairment

No dose adjustment is needed in patients with renal impairment. [See CLINICAL PHARMACOLOGY]

Last reviewed on RxList: 3/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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