tacrolimus; FK506; fujimycin (Prograf, Advagraf, Envarsus XR)
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Introduction
Also tacrolimus. Tradename Prograf.
Origin
Produced by Streptomyces tsukubaensis
Indications
- prophylaxis of organ transplantation rejection in patients receiving allogeneic liver transplantation
- used concomitantly with glucocorticoids
- immunosuppressive agent used for maintenance of immunosuppression after cardiac transplantation & for treatment of refractory transplantation rejection
- lichen sclerosus, atopic dermatitis (topical)[4]
Contraindications
- concurrent use of cyclosporine; separate use by at least 24 hours
Dosage
- IV continuous infusion: 0.05-1 mg/kg/day until oral dose is tolerated starting no sooner than 6 hours after transplantation
- oral: 0.15-0.3 mg/kg/day divided every 12 hours
Tabs: 1 mg, 5 mg.
Topical: 0.1%
Pharmacokinetics
- absorption is highly variable; food decreases absorption
- volume of distribution (Vd) = 17 L/kg[6]
- extensively metabolized in the liver by predominantly by CYP3A5 & to a lesser extent CYP3A5
- eliminated primarily via the bile
- protein binding 75-99%
elimination via liver
protein binding = 75-99 %
elimination by hemodialysis = -
1/2life = 4-40 hours
Monitor
- tacrolimus in serum/plasma
- CYP3A5 gene mutation may expedite achieving therapeutic levels [NGC]
Adverse effects
not common (1-10%)
- nephrotoxicity with hyperkalemia, elevated serum creatinine & hypertension
- neurotoxicity including insomnia, mild tremors, headache, photophobia, hyperesthesia, confusion, seizures, dysarthria, persistent coma
- infections & malignant complications including post-transplant lymphoproliferative disorder, bacterial infections, viral infection, & fungal infections
- hyperglycemia including new onset diabetes mellitus
- dyslipidemia[2]
- gastrointestinal symptoms including nausea/vomiting, abdominal pain
- peripheral edema at high to toxic levels
- BK virus-associated nephropathy in renal transplant patients[5]
Drug interactions
- separate antacids from tacrolimus by at least 2 hours
- agents which may increase plasma tacrolimus
- cyclosporine is associated with synergistic immunosuppression & increased nephrotoxicity
- nephrotoxic antibiotics & amphotericin B increase nephrotoxicity
- agents which may decrease plasma tacrolimus
- any drug that inhibits CYP3A4 or CYP3A5 may increase levels of tacrolimus
- any drug that induces CYP3A4 or CYP3A5 may diminish levels of tacrolimus
Mechanism of action
- inhibits calcineurin[4]
- inhibits formation of interleukin-2
More general terms
- heterocyclic compound, 3 rings
- lactone
- immunosuppressive agent
- prokaryote-specific molecule
- calcineurin inhibitor
More specific terms
Additional terms
- cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
- FK506-binding protein 1A (12 kD FK506-binding protein, immunophilin FKBP12, FKBP1A)
- FK506-binding protein 2 (13 kD FK506-binding protein, FKBP2)
- FK506-binding protein 3, 25 kD FK506-binding protein or rapamycin-selective 25 kD immunophilin
- sirolimus; rapamycin (Rapamune)
- tacrolimus in blood
- tacrolimus toxicity
Component of
References
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Jump up to: 2.0 2.1 Medical Knowledge Self Assessment Program (MKSAP) 11, 17. American College of Physicians, Philadelphia 1998, 2015
- ↑ Department of Veterans Affairs, VA National Formulary
- ↑ Jump up to: 4.0 4.1 4.2 Hengge UR et al, Multicentre, phase II trial on the safety and efficacy of topical tacrolimus ointment for the treatment of lichen sclerosus. Br J Dermatol 2006, 155:1021 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17034535
- ↑ Jump up to: 5.0 5.1 FDA Medwatch http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171828.htm
- ↑ Jump up to: 6.0 6.1 The Drug Monitor Tacrolimus http://www.thedrugmonitor.com/tacro.html
- ↑ Jump up to: 7.0 7.1 Deprecated Reference
- ↑ Wikipedia: Tacrolimus https://en.wikipedia.org/wiki/Tacrolimus