药品详细

Tacrolimus(他克莫司)

基本信息
剂型规格
适应症
药理
临床
理化性质
相互作用
文档
专利
Pathway
文献
序列

化学结构式图

中文名

他克莫司

英文名

Tacrolimus

分子式

C₄₄H₆₉NO₁₂

化学名

(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0^{4,9}]octacos-18-ene-2,3,10,16-tetrone

分子量

Average: 804.0182
Monoisotopic: 803.481976677

CAS号

104987-11-3

ATC分类

L04A 未知;D11A 未知

药物类型

small molecule

阶段

approved

商品名

Fujimycin;LCP-Tacro;Prograf;Protopic;

同义名

FK-506;FK5;K506;Tacarolimus;tacrolimus;tacrolimus hydrate;

基本介绍

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient’s immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.

生产厂家

Astellas Pharma US
Astellas pharma us inc
Dr reddys laboratories ltd
Sandoz inc
Watson laboratories inc

封装厂家

Astellas Pharma Inc.
B&B Pharmaceuticals
Cardinal Health
Caremark LLC
Doctor Reddys Laboratories Ltd.
Kaiser Foundation Hospital
Mckesson Corp.
Murfreesboro Pharmaceutical Nursing Supply
Neuman Distributors Inc.
Physicians Total Care Inc.
Rebel Distributors Corp.
Sandoz
Watson Pharmaceuticals

参考

Synthesis Reference

Not Available

General Reference

Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987 Sep;40(9):1249-55. Pubmed
Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. Pubmed
Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. Pubmed
Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K: Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient. Drug Metab Pharmacokinet. 2006 Apr;21(2):122-5. Pubmed
Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. Pubmed

剂型

规格

化合物类型

Type	small molecule

Classes

Not Available

Substructures

Not Available

适应症

IMMUNOSUPPRESSIVE 免疫抑制;

药理

Indication

For use after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.

Pharmacodynamics

Tacrolimus is a macrolide antibiotic. It acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporine studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporine. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.

Mechanism of action

The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells.

Absorption

20% bioavailability; less after eating food rich in fat

Volume of distribution

2.6±2.1 L/kg [pediatric patients]

Protein binding

75-99%

Metabolism

Hepatic, extensive, primarily by CYP3A4. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate	Enzymes	Product
Tacrolimus	Cytochrome P450 3A4	31-O-Demethyltacrolimus	Details
Tacrolimus		13-demethyl tacrolimus	Details

Route of elimination

In man, less than 1% of the dose administered is excreted unchanged in urine. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Half life

11.3 hours (range from 3.5 to 40.6 hours)

Clearance

0.029 +/- 0.009 L/hr/kg [healthy subjects IV administered]
0.172 +/- 0.088 L/hr/kg [Healthy subjects administered PO]
0.138 +/- 0.071 L/hr/kg [liver transplantation pediatric patients]
0.038 +/-0.014 L/hr/kg [patients with renal impairment 0.02 mg/kg/4 hr, IV]
0.042 +/- 0.02 L/hr/kg [Mild Hepatic Impairment 0.02 mg/kg/4 hr, IV]
0.034 +/- 0.019 L/hr/kg [Mild Hepatic Impairment 7.7 mg PO]
0.017 +/- 0.013 L/hr/kg [Severe hepatic impairement 0.02 mg/kg/4 hr, IV]

Toxicity

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD₅₀=134-194 mg/kg (rat).

Affected organisms

Humans and other mammals

Pathways

Not Available

理化性质

Properties

State

solid

Experimental Properties

Property	Value	Source
melting point	126 °C	Not Available
water solubility	Insoluble	Not Available
logP	3.3	Not Available

Predicted Properties

Property	Value	Source
water solubility	4.02e-03 g/l	ALOGPS
logP	3.19	ALOGPS
logP	5.59	ChemAxon
logS	-5.3	ALOGPS
pKa (strongest acidic)	9.96	ChemAxon
pKa (strongest basic)	-2.9	ChemAxon
physiological charge	0	ChemAxon
hydrogen acceptor count	11	ChemAxon
hydrogen donor count	3	ChemAxon
polar surface area	178.36	ChemAxon
rotatable bond count	7	ChemAxon
refractivity	215.62	ChemAxon
polarizability	87.41	ChemAxon

药物相互作用

Drug	Interaction
Abarelix	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ado-trastuzumab emtansine	Avoid combination due to the increase in immunosuppressant side effects.
Amikacin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Amikacin. Use caution during concomitant therapy.
Amiodarone	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amitriptyline	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amoxapine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amphotericin B	Additive renal impairment may occur during concomitant therapy with Amphotericin B. Use caution during concomitant therapy.
Amprenavir	The protease inhibitor, Amprenavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Amprenavir therapy is initiated, discontinued or altered.
Apomorphine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Apramycin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Apramycin. Use caution during concomitant therapy.
Arsenic trioxide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Artemether	Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Atazanavir	The protease inhibitor, Atazanavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Atazanavir therapy is initiated, discontinued or altered.
Bleomycin	Tacrolimus (Topical) may enhance the adverse/toxic effect of Immunosuppressants. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Boceprevir	Boceprevir increases levels of tacrolimus by affecting CYP3A4 metabolism. Concomitant therapy requires close monitoring.
BRENTUXIMAB VEDOTIN	Avoid combination due to the potential enhancement of toxic effects of immunosuppressants.
Bromocriptine	Bromocriptine may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Bromocriptine therapy is initiated, discontinued or altered.
Carbamazepine	Carbamazepine may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Carbamazepine therapy is initiated, discontinued or altered.
Carboplatin	Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as carboplatin. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Carmustine	Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as carmustine. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Caspofungin	Caspofungin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Caspofungin therapy is initiated, discontinued or altered.
Chlorambucil	Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants sucb as chlorambucil. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Chloramphenicol	Chloramphenicol may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Chloramphenicol therapy is initiated, discontinued or altered.
Chlorpromazine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Cimetidine	Cimetidine may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Cimetidine therapy is initiated, discontinued or altered.
Cisapride	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. Cisapride may also increase the concentration of Tacrolimus in the blood.
Cisplatin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Cisplatin. Use caution during concomitant therapy.
Cladribine	Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as tacrolimus. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Clarithromycin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. The macrolide antibiotic, Clarithromycin, may also increase the blood concentration of Tacrolimus.
Clofarabine	Tacrolimus (topical) may enhance the adverse/toxic effect of immunosuppressants such as clofarabine. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Clomipramine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Clotrimazole	The antifungal, Clotrimazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Clotrimazole therapy is initiated, discontinued or altered.
Conivaptan	The strong CYP3A4 inhibitor, Conivaptan, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Conivaptan is initiated, discontinued or dose changed.
Crizotinib	Strong CYP3A4 inhibitors may increase levels of crizotinib. Consider alternative therapy.
Cyclosporine	Additive renal impairment may occur during concomitant therapy with cyclosporine. Combination therapy should be avoided.
Danazol	Danazol may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Danazol therapy is initiated, discontinued or altered.
Darunavir	The protease inhibitor, Darunavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Darunavir therapy is initiated, discontinued or altered.
Dasatinib	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Delavirdine	The strong CYP3A4 inhibitor, Delavirdine, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Delavirdine is initiated, discontinued or dose changed.
Desipramine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Diltiazem	Diltiazem may increase the serum concentration of tacrolimus by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of tacrolimus if diltiazem therapy is initiated, discontinued or dose changed.
Disopyramide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Dofetilide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Dolasetron	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Domperidone	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Doxepin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Dronedarone	Tacrolimus is a CYP3A substrate with a narrow therapeutic index thus concomitant therapy with dronedarone will increase plasma levels of tacrolimus. Monitor plasma concentrations and adjust dose accordingly.
Droperidol	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Erythromycin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. The macrolide antibiotic, erythromycin, may also increase the blood concentration of tacrolimus.
Ethinyl Estradiol	Ethinyl estradiol may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ethinyl estradiol therapy is initiated, discontinued or altered.
Felodipine	Felodipine increases tacrolimus levels
Flecainide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Fluconazole	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. The antifungal, fluconazole, may also increase serum concentrations of tacrolimus.
Fluoxetine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Flupenthixol	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Fosamprenavir	The protease inhibitor, Fosamprenavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Fosamprenavir therapy is initiated, discontinued or altered.
Foscarnet	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Fosphenytoin	The hydantoin decreases the effect of tacrolimus
Gatifloxacin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Gentamicin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Gentamicin. Use caution during concomitant therapy.
golimumab	Avoid combination due to the enhancement of side effects from immunosuppressants.
Halofantrine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Haloperidol	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Homoharringtonine	Avoid combination as there is potential to increase immunosuppressant adverse effects.
Ibutilide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Imatinib	The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Imatinib is initiated, discontinued or dose changed.
Imipramine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Indapamide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Indinavir	The protease inhibitor, Indinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Indinavir therapy is initiated, discontinued or altered.
Isoniazid	The strong CYP3A4 inhibitor, Isoniazid, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Isoniazid is initiated, discontinued or dose changed.
Isradipine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Itraconazole	The antifungal, Itraconazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Itraconazole therapy is initiated, discontinued or altered.
Ketoconazole	The antifungal, Ketoconazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ketoconzole therapy is initiated, discontinued or altered.
Lapatinib	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Levofloxacin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Lopinavir	The protease inhibitor, Lopinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Lopinavir therapy is initiated, discontinued or altered.
Loxapine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Lumefantrine	Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Maprotiline	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Mefloquine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Mesoridazine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Methadone	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Methylprednisolone	Methylprednisone may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Methylprednisone therapy is initiated, discontinued or altered.
Metoclopramide	Metoclopramide may increase the concentration of Tacrolimus in the blood. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Metoclopramide therapy is initiated, discontinued or altered.
Metronidazole	Metronidazole increases the levels/toxicity of tacrolimus
Mibefradil	The calcium channel blocker, Mibefradil, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Mibefradil therapy is initiated, discontinued or altered.
Miconazole	The strong CYP3A4 inhibitor, Miconazole, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Miconazole is initiated, discontinued or dose changed.
Moxifloxacin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Mycophenolate mofetil	Tacrolimus may increase the plasma concentration of Mycophenolic acid. Monitor and adjust the dose of Mycophenolate mofetil to the therapeutic range.
Natalizumab	Tacrolimus may increase the toxic/adverse effects of Natalizumab. Concurrent administration should be avoided due to increased risk of infection.
Nefazodone	Nefazodone may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nefazodone therapy is initiated, discontinued or altered.
Nelfinavir	The protease inhibitor, Nelfinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nelfinavir therapy is initiated, discontinued or altered.
Neomycin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Neomycin. Use caution during concomitant therapy.
Netilmicin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Netilmicin. Use caution during concomitant therapy.
Nicardipine	The calcium channel blocker, Nicardipine, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nicardipine therapy is initiated, discontinued or altered.
Nifedipine	The calcium channel blocker, Nifedipine, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nifedipine therapy is initiated, discontinued or altered.
Nilotinib	May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
Norfloxacin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Nortriptyline	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Octreotide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Omeprazole	Omeprazole may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Omeprazole therapy is initiated, discontinued or altered.
Paclitaxel	Avoid combination of topical tacrolimus due to the potential enhancement of adverse effects of immunosuppressants.
Pentamidine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Perflutren	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Phenobarbital	Phenobarbital may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Phenobarbital therapy is initiated, discontinued or altered.
Phenytoin	Phenytoin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Phenytoin therapy is initiated, discontinued or altered.
Pimozide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Posaconazole	The strong CYP3A4 inhibitor, Posaconazole, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Posaconazole is initiated, discontinued or dose changed.
Probucol	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Procainamide	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Propafenone	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Protriptyline	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Quetiapine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Quinidine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. Quinidine, a strong CYP3A4 inhibitor, may also increase the serum concentration of Tacrolimus by inhibiting its metabolism and clearance.
Quinupristin	This combination presents an increased risk of toxicity
Ranolazine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Rifabutin	Carbamazepine may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Carbamazepine therapy is initiated, discontinued or altered.
Rifampin	Rifampin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Rifampin therapy is initiated, discontinued or altered.
Rilonacept	results in increased immunosuppressive effects; increases the risk of infection.
Risperidone	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Ritonavir	The protease inhibitor, Ritonavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ritonavir therapy is initiated, discontinued or altered.
Saquinavir	The protease inhibitor, Saquinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Saquinavir therapy is initiated, discontinued or altered.
Silodosin	The p-glycoprotein inhibitor, Tacrolimus, may increase the bioavailability of Silodosin. Increased Silodosin exposure may result in Silodosin toxicity. Concurrent use if not recommended.
Sirolimus	Sirolimus may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Sirolimus therapy is initiated, discontinued or altered.
Sotalol	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Sparfloxacin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
St. John's Wort	St. John's Wort may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if St. John's Wort therapy is initiated, discontinued or altered.
Streptomycin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Streptomycin. Use caution during concomitant therapy.
Sunitinib	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Telaprevir	Telaprevir increases levels by affecting CYP3A4 metabolism. Must monitor levels closely with concomitant therapy.
Telithromycin	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. Telithromycin, a strong CYP3A4 inhibitor, may also increase the serum concentration of Tacrolimus by inhibiting its metabolism and clearance.
Temsirolimus	Temsirolimus may decrease the blood concentration of Tacrolimus. Concomitant therapy may increase the adverse/toxic effects of both agents. Concomitant therapy should be avoided.
Teriflunomide	Avoid combination due to the increased toxic effects of immunosuppressants.
Tetrabenazine	May cause additive QTc-prolonging effects. Concomitant therapy should be avoided.
Thioridazine	May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
Thiothixene	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Tipranavir	Tipranavir may decrease the metabolism and clearance of Tacrolimus. Dose adjustments may be required. Monitor for Tacrolimus efficacy and toxicity during concomitant therapy.
Tobramycin	Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Tobramycin. Use caution during concomitant therapy.
Tofacitinib	Avoid combination due to the potential increase in immunosuppressant associated adverse effects.
Topotecan	The p-glycoprotein inhibitor, Tacrolimus, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Toremifene	Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Trastuzumab	Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Trimipramine	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Troleandomycin	The macrolide antibiotic, Troleandomycin, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Troleandomycin therapy is initiated, discontinued or altered.
Verapamil	The calcium channel blocker, Verapamil, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Verapamil therapy is initiated, discontinued or altered.
Voriconazole	Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of tacrolimus by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of tacrolimus if voriconazole is initiated, discontinued or dose changed.
Vorinostat	Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone	Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
Zuclopenthixol	Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

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