ENVARSUS XR Dosage & Rx Info | Uses, Side Effects

Envarsus Xr Generic Name & Formulations

Legal Class

General Description

Tacrolimus 0.75mg, 1mg, 4mg; ext-rel tabs.

Pharmacological Class

Immunosuppressant (calcineurin-inhibitor).

How Supplied

Ext-rel tabs—30, 100

Manufacturer

Veloxis Pharmaceuticals

Generic Availability

Mechanism of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (eg, immunosuppression).

Envarsus Xr Indications

Indications

Organ rejection prophylaxis in de novo kidney transplant patients or in stable kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants.

Envarsus Xr Dosage and Administration

Adult

Swallow whole. Take once daily in the morning, preferably on an empty stomach. De novo: initially 0.14mg/kg/day. Titrate dose based on tolerability and to achieve target whole blood trough concentration ranges. During Month 1: 6–11ng/mL; >Month 1: 4–11ng/mL. Converting from tacrolimus immediate-release: give 80% of total daily dose of the immediate-release product; monitor and titrate dose to achieve ranges 4–11ng/mL. Severe hepatic impairment (Child-Pugh ≥10): use lower initial dose. Black patients may require higher doses. See full labeling.

Children

Not established.

Envarsus Xr Contraindications

Not Applicable

Envarsus Xr Boxed Warnings

Boxed Warning

Malignancies. Serious infections.

Envarsus Xr Warnings/Precautions

Warnings/Precautions

Not interchangeable or substitutable with other tacrolimus products. Increased risk of lymphomas and other malignancies (eg, skin). Avoid sun, UV light. Epstein Barr Virus seronegative; monitor. Increased risk of infections (eg, bacterial, viral, fungal, protozoal), opportunistic infections including polyoma virus, JC virus-associated progressive multifocal leukoencephalopathy, cytomegalovirus; monitor. New-onset diabetes: monitor blood glucose levels esp. in Black and Hispanic patients. Monitor for neurotoxicity; consider dose reduction or discontinuation if occurs. Renal impairment, moderate or severe hepatic impairment: monitor and reduce dose if indicated. Obtain tacrolimus whole blood concentrations (see full labeling), serum creatinine, and serum potassium periodically. Avoid in congenital long QT syndrome. CHF, bradyarrhythmias, concomitant antiarrhythmic drugs, or electrolyte disturbances: consider obtaining ECGs and monitor electrolytes periodically. Risk for thrombotic microangiopathy (including hemolytic uremic syndrome and thrombotic thrombocytopenic purpura) esp. in those with severe infections, GVHD, HLA mismatch. Elderly. Labor & delivery. Advise females of reproductive potential and male patients to use appropriate contraception prior to initiation. Pregnancy: monitor. Nursing mothers.

Envarsus Xr Pharmacokinetics

Distribution

Plasma protein bound: ~99%; mainly bound to albumin and alpha-1-acid glycoprotein.

Metabolism

Extensively by the mixed-function oxidase system (primarily CYP3A).

Elimination

Fecal (92.6 ± 30.7%), renal (2.3 ± 1.1%). Half-life: 31.0 ± 8.1 hours. Clearance: 0.172 ± 0.088 L/hr/kg.

Envarsus Xr Interactions

Interactions

Concomitant live vaccines: not recommended. Concomitant mTOR inhibitors (eg, sirolimus, everolimus) may increase risk of thrombotic microangiopathy. Concomitant mycophenolic acid (MPA) products; monitor and reduce the dose of these as needed. Concomitant strong CYP3A4 inhibitors/inducers or substrates: must adjust dosing regimen, closely monitor tacrolimus blood concentrations and for QT prolongation. Caution with potassium-sparing diuretics, ACEIs, ARBs. Avoid grapefruit/grapefruit juice, alcohol. Additive nephrotoxicity with aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors; if concomitant use, monitor renal function and tacrolimus blood levels; adjust doses of both drugs. May be potentiated by calcium channel blockers (eg, verapamil, diltiazem, nifedipine, nicardipine), antifungals (eg, voriconazole, posaconazole, itraconazole, fluconazole, ketoconazole), macrolides (eg, troleandomycin, clarithromycin, erythromycin), lansoprazole, omeprazole, chloramphenicol, cimetidine, clotrimazole, amiodarone, danazol, ethinyl estradiol, protease inhibitors (eg, nelfinavir, telaprevir, boceprevir, ritonavir), nefazodone, Schisandra sphenanthera extracts, cobicistat, imatinib, nilotinib, letermovir, magnesium-aluminum-hydroxide, metoclopramide. Concomitant voriconazole, posaconazole: give ⅓ of original dose. May be potentiated by cannabidiol; consider tacrolimus dose reduction and monitor closely. May be antagonized by carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. Johns wort, methylprednisolone, prednisone, caspofungin. Monitor closely with direct acting antiviral therapy; may need to adjust dose.

Envarsus Xr Adverse Reactions

Adverse Reactions

Diarrhea, anemia, UTI, hypertension, tremor, constipation, diabetes mellitus, peripheral edema, hyperkalemia, headache, increased creatinine; infections, malignancies (lymphomas, skin), post-transplant lymphoproliferative disorder, nephrotoxicity or neurotoxicity (esp. in high doses), posterior reversible encephalopathy syndrome, QT prolongation, pure red cell aplasia (consider discontinuation).

Envarsus Xr Clinical Trials

See Literature

Envarsus Xr Note