Zortress

— THERAPEUTIC CATEGORIES —
  • Organ rejection prophylaxis
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Zortress Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Everolimus 0.25mg, 0.5mg, 0.75mg, 1mg; tabs.

    Pharmacological Class

    Immunosuppressant (macrolide).

    How Supplied

    Tabs—60 (10 × 6 blister strips)

    Manufacturer

    Novartis Pharmaceuticals Corp

    Generic Availability

    YES

    Mechanism of Action

    Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited.

    Zortress Indications

    Indications

    Organ rejection prophylaxis in renal transplant patients with low-moderate immunologic risk, in combination with basiliximab induction and reduced doses of cyclosporine and corticosteroids. Organ rejection prophylaxis in liver transplant patients, in combination with reduced doses of tacrolimus and corticosteroids.

    Limitations of Use

    High immunologic risk in renal transplant patients. Recipients of transplanted organs other than kidney and liver. 

    Zortress Dosage and Administration

    Adult

    Swallow whole. ≥18yrs: Renal transplant: administer as soon as possible after transplantation. Initially 0.75mg every 12 hours (1.5mg/day) in combination with reduced dose cyclosporine. Initiate oral prednisone as soon as oral medication is tolerated. Liver transplant: administer no earlier than 30 days post transplant. Initially 1mg every 12 hours (2mg/day) in combination with reduced dose tacrolimus. Both: steroid doses may be further tapered on an individualized basis. May adjust dose at 4–5 day intervals to achieve everolimus trough concentration target range 3–8ng/mL. Hepatic impairment: Mild: reduce initial daily dose by ⅓; Moderate or severe: reduce initial daily dose by ½.

    Children

    <18yrs: not established.

    Administration

    Swallow whole with water. Do not crush before use. Administer approximately 12 hours apart consistently either with or without food to minimize variability in absorption and at the same time as cyclosporine or tacrolimus.

    Nursing Considerations

    Swallow whole with water. Do not crush before use. Administer approximately 12 hours apart consistently either with or without food to minimize variability in absorption and at the same time as cyclosporine or tacrolimus. Inform patients to avoid grapefruit and grapefruit juice. Advise women of childbearing age to avoid becoming pregnant throughout treatment and for 8 weeks after therapy has stopped.

    Zortress Contraindications

    Contraindications

    Sirolimus allergy.

    Zortress Boxed Warnings

    Boxed Warning

    Malignancies. Serious infections. Kidney graft thrombosis. Nephrotoxicity. Mortality in heart transplantation.

    Zortress Warnings/Precautions

    Warnings/Precautions

    Increased risk of infections and possible malignancies (eg, lymphoma, skin); kidney graft thrombosis; hepatic artery thrombosis; nephrotoxicity; and mortality in heart transplantation. Use in heart transplantation: not recommended. Avoid sun, UV light. Hereditary disorders (eg, galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption): not recommended. Interstitial lung disease (ILD)/non-infectious pneumonitis. Monitor for hyperlipidemia. Consider risk/benefit in patients with established hyperlipidemia prior to initiation; reevaluate continued therapy in those with severe refractory hyperlipidemia. Baseline cholesterol >350mg/dL: not studied. New onset diabetes after transplant. Obtain everolimus, cyclosporine and tacrolimus whole blood concentrations periodically (see full labeling); and trough concentrations during dose adjustments. Monitor CBCs, renal function, urine protein, lipids, blood glucose; and for pneumonitis and serious (eg, bacterial, viral, fungal, protozoal) including opportunistic infections; polyoma virus infections (eg, BK virus-associated nephropathy, and JC virus-associated progressive multiple leukoencephalopathy). Antimicrobial prophylaxis for PCP and CMV recommended. Hepatic impairment: see Adult dose. Embryo-fetal toxicity. Advise females of reproductive potential to use highly effective contraception during and up to 8 weeks after the last dose. Pregnancy: avoid. Nursing mothers: not recommended.

    Zortress Pharmacokinetics

    Absorption

    Peak everolimus concentrations occur 1–2 hours post dose.

    Food effect: high-fat breakfast (44.5g fat) reduced everolimus Cmax by 60%, delayed Tmax by a median 1.3 hours, and reduced AUC by 16% compared with a fasting administration.

    Distribution

    Apparent volume of distribution in maintenance kidney transplant patients: 342–107 L (range 128–589 L). Plasma protein bound: ~74%.

    Metabolism

    Hepatic (CYP3A4 and P-gp).

    Elimination

    Fecal (80%), renal (5%).

    Zortress Interactions

    Interactions

    Avoid live vaccines, standard doses of cyclosporine. Increased risk of angioedema with ACE-inhibitors. Potentiated by CYP3A4 and/or P-glycoprotein inhibitors; avoid strong inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir, grapefruit juice, digoxin); monitor and adjust dose with moderate inhibitors (eg, erythromycin, fluconazole, nicardipine, diltiazem, nelfinavir, indinavir, amprenavir), or CYP3A4 and P-glycoprotein substrate (eg, verapamil). May be potentiated by cannabidiol; consider everolimus dose reduction and monitor closely. Potentiates octreotide, midazolam. Antagonized by CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, St. John's Wort); avoid strong inducers (eg, rifampin, rifabutin). Avoid simvastatin, lovastatin; monitor if used with atorvastatin or pravastatin. Caution with other nephrotoxic drugs, CYP3A4 or CYP2D6 substrates with a narrow therapeutic index. 

    Zortress Adverse Reactions

    Adverse Reactions

    Peripheral edema, nausea, diarrhea, constipation, hypertension, headache, pyrexia, abdominal pain, leukopenia, anemia, infections (eg, UTI), hyperlipidemia, hypercholesterolemia; angioedema, malignancies (eg, lymphomas, skin), proteinuria, delayed wound healing/dehiscence, polyoma virus infections, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, male infertility.

    Zortress Clinical Trials

    See Literature

    Zortress Note

    Not Applicable

    Zortress Patient Counseling

    See Literature

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