Buy Prograf Online

Prograf (tacrolimus)

BOXED WARNING

Immunosuppression may lead to increased risk of lymphoma and other malignancies, particularly of the skin. Increased susceptibility to infections (bacterial, viral, fungal, protozoal, opportunistic). Should only be prescribed by physicians experienced in immunosuppressive therapy and management of organ transplant patients. Manage patients in facilities equipped and staffed w/ adequate lab and supportive medical resources. Physician responsible for maintenance therapy should have complete information requisite for patient follow-up.

THERAPEUTIC CLASS

Macrolide immunosuppressant

DEA CLASS

RX

INDICATIONS

Prophylaxis of organ rejection in patients receiving allogeneic kidney, liver, or heart transplants w/ concomitant adrenal corticosteroids. In heart and kidney transplant patients, azathioprine or mycophenolate mofetil coadministration is recommended.

ADULT DOSAGE

Hepatic Transplant

Prophylaxis of organ rejection in patients receiving allogeneic liver transplant; recommended to be used concomitantly w/ adrenal corticosteroids early post-transplant

Cap:
Initial:
0.1-0.15mg/kg/day as 2 divided doses, q12h; administer no sooner than 6 hrs after liver transplant
Titrate: Based on clinical assessments of rejection and tolerability
Maint: Lower dosages than the initial dosage may be sufficient

Observed Tacrolimus Whole Blood Trough Concentrations w/ Liver Transplant:
Months 1-12: 5-20ng/mL

IV:
Initial: 0.03-0.05mg/kg/day

If receiving tacrolimus IV infusion, give 1st oral dose 8-12 hrs after discontinuing the IV infusion

Renal Transplant

Prophylaxis of organ rejection in patients receiving allogeneic kidney transplant; recommended to be used concomitantly w/ azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids (early post-transplant)

Cap:
Initial:
0.2mg/kg/day in combination w/ azathioprine or 0.1mg/kg/day in combination w/ MMF/Interleukin (IL)-2 receptor antagonist; give as 2 divided doses, q12h. May administer w/in 24 hrs of kidney transplant, but should be delayed until renal function has recovered
Titrate: Based on clinical assessments of rejection and tolerability
Maint: Lower dosages than the initial dosage may be sufficient

Observed Tacrolimus Whole Blood Trough Concentrations w/ Kidney Transplant:
W/ Azathioprine:
Months 1-3: 7-20ng/mL
Months 4-12: 5-15ng/mL
W/ MMF/IL-2 Receptor Antagonist:
Months 1-12: 4-11ng/mL

IV:
Initial: 0.03-0.05mg/kg/day

If receiving tacrolimus IV infusion, give 1st oral dose 8-12 hrs after discontinuing the IV infusion

Cardiac Transplant

Prophylaxis of organ rejection in patients receiving allogeneic heart transplant; recommended to be used concomitantly w/ azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids (early post-transplant)

Cap:
Initial: 0.075mg/kg/day as 2 divided doses, q12h; administer no sooner than 6 hrs after heart transplant
Titrate: Based on clinical assessments of rejection and tolerability
Maint: Lower dosages than the initial dosage may be sufficient

Observed Tacrolimus Whole Blood Trough Concentrations w/ Heart Transplant:
Months 1-3: 10-20ng/mL
Months ≥4: 5-15ng/mL

IV:
Initial: 0.01mg/kg/day

If receiving tacrolimus IV infusion, give 1st oral dose 8-12 hrs after discontinuing the IV infusion

PEDIATRIC DOSAGE

Hepatic Transplant

Prophylaxis of organ rejection in patients receiving allogeneic liver transplant; recommended to be used concomitantly w/ adrenal corticosteroids early post-transplant

Cap:
Initial:
0.15-0.2mg/kg/day as 2 divided doses, q12h; administer no sooner than 6 hrs after liver transplant

Observed Tacrolimus Whole Blood Trough Concentrations w/ Liver Transplant:
Months 1-12: 5-20ng/mL

IV:
Initial: 0.03-0.05mg/kg/day

DOSING CONSIDERATIONS

Concomitant Medications
Cyclosporine: Do not use simultaneously; d/c tacrolimus or cyclosporine at least 24 hrs before initiating the other

Renal Impairment
Liver/Heart Transplant:
Preexisting Renal Impairment: Start at lower end of dosing range

Kidney Transplant:
Postoperative Oliguria: Initial dose should be administered no sooner than 6 hrs and w/in 24 hrs of transplantation, but may be delayed until renal function shows evidence of recovery

Hepatic Impairment
Severe (Child-Pugh ≥10): May require lower doses

Elderly
Start at lower end of dosing range

Other Important Considerations
Black patients may require higher doses
Do not eat grapefruit or drink grapefruit juice

ADMINISTRATION

Oral/IV route

Inj should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of cap

Cap
Take consistently, either w/ or w/o food

IV
Dilute product w/ 0.9% NaCl inj or D5 inj to concentration between 0.004mg/mL and 0.02mg/mL prior to use
Diluted infusion sol should be stored in glass or polyethylene containers and should be discarded after 24 hrs; do not store in PVC container due to decreased stability and potential for extraction of phthalates; in situations where more dilute sol are utilized (eg, pediatric dosing), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto tubing
Should not be mixed or co-infused w/ sol of pH ≥9 (eg, ganciclovir, acyclovir)

HOW SUPPLIED

Cap: 0.5mg, 1mg, 5mg; Inj: 5mg/mL [1mL]

CONTRAINDICATIONS

(Inj) Hypersensitivity to polyoxyl 60 hydrogenated castor oil (HCO-60).

WARNINGS/PRECAUTIONS

Limit exposure to sunlight and UV light in patients at increased risk for skin cancer. Increased risk for polyoma virus infections, CMV viremia, and CMV disease. Polyoma virus-associated nephropathy (PVAN) reported; may lead to renal function deterioration and kidney graft loss. Progressive multifocal leukoencephalopathy (PML) reported; consider PML in differential diagnosis in patients reporting neurological symptoms and consider consultation w/ a neurologist. Consider reductions in immunosuppression if CMV viremia, CMV disease, or if evidence of PVAN or PML develops. May cause new onset diabetes mellitus; closely monitor blood glucose concentrations. May cause acute/chronic nephrotoxicity; closely monitor patients w/ renal dysfunction. Consider changing to another immunosuppressive therapy in patients w/ persistent SrCr elevations unresponsive to dose adjustments. May cause neurotoxicity (eg, posterior reversible encephalopathy syndrome [PRES], delirium, coma); if PRES is suspected or diagnosed, maintain BP control and immediately reduce immunosuppression. Hyperkalemia and HTN reported. May prolong the QT/QTc interval and may cause torsades de pointes; avoid in patients w/ congenital long QT syndrome and consider obtaining ECGs and monitoring electrolytes (Mg2+, K+, Ca2+) periodically in patients w/ CHF, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those w/ electrolyte disturbances. Myocardial hypertrophy reported; consider dose reduction or discontinuation if diagnosed and consider echocardiographic evaluation in patients who develop renal failure or clinical manifestations of ventricular dysfunction. Pure red cell aplasia (PRCA) reported; consider discontinuation if diagnosed. GI perforation reported; institute appropriate medical/surgical management promptly. (Inj) Anaphylactic reactions may occur; should be reserved for patients unable to take cap orally. Patients should be under continuous observation for at least the first 30 min following the start of infusion and at frequent intervals thereafter; d/c infusion if signs/symptoms of anaphylaxis occur.

ADVERSE REACTIONS

Lymphoma, malignancies, infections, tremor, HTN, abnormal renal function, headache, insomnia, hyperglycemia, hyperkalemia, hypomagnesemia, diarrhea, N/V, paresthesia.

DRUG INTERACTIONS

See Dose Modification. Not recommended w/ sirolimus in liver or heart transplants; safety and efficacy not established in kidney transplant. Due to potential for additive/synergistic renal impairment, caution w/ drugs that may be associated w/ renal dysfunction (eg, aminoglycosides, ganciclovir, amphotericin B). Increased whole blood concentrations w/ CYP3A inhibitors (eg, antifungals, calcium channel blockers [CCBs], macrolide antibiotics), and magnesium and aluminum hydroxide antacids. Decreased whole blood concentrations w/ CYP3A inducers. May increase mycophenolic acid (MPA) exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving MPA-containing products. Avoid w/ nelfinavir unless the benefits outweigh the risks. Monitor whole blood concentrations and adjust tacrolimus dose if used concomitantly w/ protease inhibitors (eg, ritonavir, telaprevir, boceprevir), CCBs (eg, verapamil, diltiazem, nifedipine), erythromycin, clarithromycin, troleandomycin, chloramphenicol, rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, St. John's wort, magnesium and aluminum hydroxide antacids, bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone, methylprednisolone, herbal products containing Schisandra sphenanthera extracts, or CYP3A inhibitors/inducers. Monitor whole blood concentrations and adjust tacrolimus dose when concomitant use of antifungal drugs (eg, azoles, caspofungin) w/ tacrolimus is initiated or discontinued; initially reduce tacrolimus dose to 1/3 of the original dose when initiating therapy w/ voriconazole or posaconazole. May increase levels of phenytoin; monitor phenytoin levels and adjust phenytoin dose as needed. Caution w/ antihypertensive agents (eg, K+-sparing diuretics, ACE inhibitors, ARBs) or other agents associated w/ hyperkalemia. Reduce tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitor for QT prolongation when coadministered w/ CYP3A4 substrates and/or inhibitors that also have the potential to prolong the QT interval. Amiodarone may increase whole blood concentrations w/ or w/o concurrent QT prolongation. Avoid live vaccines during therapy. Caution w/ concomitant immunosuppressants.

PREGNANCY AND LACTATION

Category C, not for use in nursing.

MECHANISM OF ACTION

Macrolide immunosuppressant; not established. Inhibits T-lymphocyte activation. Binds to an intracellular protein, FKBP-12, forming a complex of tacrolimus-FKBP-12, Ca2+, calmodulin, and calcineurin, and inhibiting phosphatase activity of calcineurin. This effect may prevent dephosphorylation and translocation of nuclear factor of activated T-cells, a nuclear component thought to initiate gene transcription for the formation of lymphokines.

PHARMACOKINETICS

Absorption: (Oral) Incomplete and variable. Administration of variable doses in different populations resulted in different pharmacokinetic parameters. Distribution: Plasma protein binding (approx 99%); crosses placenta; found in breast milk. Metabolism: Liver, via CYP3A (demethylation and hydroxylation); 13-demethyl tacrolimus (major metabolite); 31-demethyl (active metabolite). Elimination: (Oral) Feces (92.6%), urine (2.3%). (IV) Feces (92.4%); urine (<1% unchanged). Refer to PI for T1/2 values in different populations.

ASSESSMENT

Assess for drug hypersensitivity, congenital long QT syndrome, CHF, bradyarrhythmias, electrolyte disturbances, renal/hepatic impairment, pregnancy/nursing status, and possible drug interactions. (Inj) Assess for hypersensitivity to HCO-60.

MONITORING

Monitor tacrolimus blood concentrations in conjunction w/ other laboratory and clinical parameters. Monitor for lymphomas and other malignancies, infections, neurotoxicity, HTN, QT prolongation, PRCA, GI perforation, and other adverse reactions. Monitor serum K+ and glucose concentrations. (Inj) Monitor for anaphylactic reactions.

PATIENT COUNSELING

Inform of the risks and benefits of therapy. Advise to take medicine at the same 12-hr interval every day and not to eat grapefruit or drink grapefruit juice in combination w/ the drug. Advise to limit exposure to sunlight and UV light by wearing protective clothing and to use a sunscreen w/ a high protection factor. Instruct to contact physician if frequent urination, increased thirst or hunger, vision changes, deliriums, tremors, or any symptoms of infection develop. Advise to attend all visits and complete all blood tests ordered by medical team. Inform that therapy may cause high BP, which may require treatment w/ antihypertensive therapy. Instruct to inform physician if planning to become pregnant or breastfeed or when starting or stopping any medication (prescription and nonprescription medicines, natural/herbal remedies, nutritional supplements, vitamins). Inform that therapy may interfere w/ the usual response to immunizations and that live vaccines should be avoided.

STORAGE

(Cap) 25°C (77°F); excursions permitted to 15-30°C (59-86°F). (Inj) 5-25°C (41-77°F).

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