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2D Structure
Also known as: Fujimycin, 104987-11-3, Prograf, Tsukubaenolide, Protopic, Fk506
Molecular Formula
C44H69NO12
Molecular Weight
804.0  g/mol
InChI Key
QJJXYPPXXYFBGM-LFZNUXCKSA-N
FDA UNII
Y5L2157C4J

A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro.
Tacrolimus anhydrous is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of tacrolimus anhydrous is as a Calcineurin Inhibitor.
1 2D Structure

2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-prop-2-enyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone
2.1.2 InChI
InChI=1S/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19+,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1
2.1.3 InChI Key
QJJXYPPXXYFBGM-LFZNUXCKSA-N
2.1.4 Canonical SMILES
CC1CC(C2C(CC(C(O2)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C(CC(=O)C(C=C(C1)C)CC=C)O)C)C(=CC4CCC(C(C4)OC)O)C)O)C)OC)OC
2.1.5 Isomeric SMILES
C[C@@H]1C[C@@H]([C@@H]2[C@H](C[C@H]([C@@](O2)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@@H]([C@@H]([C@H](CC(=O)[C@@H](/C=C(/C1)\C)CC=C)O)C)/C(=C/[C@@H]4CC[C@H]([C@@H](C4)OC)O)/C)O)C)OC)OC
2.2 Other Identifiers
2.2.1 UNII
Y5L2157C4J
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Anhydrous Tacrolimus

2. Anhydrous, Tacrolimus

3. Fk 506

4. Fk-506

5. Fk506

6. Fr 900506

7. Fr-900506

8. Fr900506

9. Prograf

10. Prograft

11. Tacrolimus Anhydrous

12. Tacrolimus, Anhydrous

2.3.2 Depositor-Supplied Synonyms

1. Fujimycin

2. 104987-11-3

3. Prograf

4. Tsukubaenolide

5. Protopic

6. Fk506

7. Tacrolimus Anhydrous

8. Anhydrous Tacrolimus

9. Modigraf

10. Fk-506

11. Protopy

12. Lcp-tacro

13. Advagraf

14. Tacrolimus (fk506)

15. Fk 506

16. Fr-900506

17. Tacrolimus, Anhydrous

18. 8-deethyl-8-[but-3-enyl]-ascomycin

19. Tacrolimus (inn)

20. Fr900506

21. Astagraf Xl

22. Envarsus Xr

23. (-)-fk 506

24. Prograf (tn)

25. Tacrolimus [usan]

26. Chembl269732

27. Chebi:61049

28. Y5l2157c4j

29. Nsc-758659

30. K506

31. Ncgc00163470-03

32. Prograft

33. Tacrolimus [inn]

34. Avagraf

35. Envarsus

36. Graceptor

37. (3s,4r,5s,8r,9e,12s,14s,15r,16s,18r,19r,26as)-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(1e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propen-1-yl)-15,19-epoxy-3h-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4h,23h)tetrone

38. Fk-506 (tacrolimus)

39. Tacrolimus (anhydrous)

40. Sr-05000001879

41. Tacrolimus [usan:inn]

42. Hecoria

43. Talymus

44. Unii-y5l2157c4j

45. Ccris 7124

46. Mfcd00869853

47. Hsdb 8195

48. L 679934

49. Prograph

50. Tacro

51. Envarsus-xr

52. Tacrolimus [mi]

53. Schembl3088

54. Tacrolimus [mart.]

55. Dsstox_cid_26354

56. Dsstox_rid_81557

57. Tacrolimus [who-dd]

58. Dsstox_gsid_46354

59. Bspbio_001279

60. Chembl66247

61. L-679934

62. Gtpl6784

63. Dtxsid5046354

64. Chebi:93221

65. Hms503o21

66. Hms1792o21

67. Hms1990o21

68. Hms2093m19

69. Hms3403o21

70. Pharmakon1600-01503968

71. Ex-a1677

72. Tox21_112056

73. Bdbm50030448

74. Bdbm50079777

75. Lmpk04000003

76. Nsc758659

77. S5003

78. Akos005145901

79. Zinc169289411

80. Ac-1182

81. Am81227

82. Ccg-270494

83. Cs-1507

84. Db00864

85. Idi1_001040

86. Ncgc00163470-01

87. Ncgc00163470-02

88. Ncgc00163470-04

89. Ncgc00163470-05

90. Ncgc00163470-06

91. Ncgc00163470-07

92. Ncgc00163470-27

93. (3s,4r,5s,8r,9e,12s,14s,15r,16s,18r,19r,26as)-5,19-dihydroxy-3-{(1e)-1-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl}-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(prop-2-en-1-yl)-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-3h-15,19-epoxypyrido[2,1-c][1,4]oxazacyclotricosine-1,7,20,21(4h,23h)-tetrone

94. Hy-13756

95. Sbi-0052894.p002

96. Cas-104987-11-3

97. M2258

98. C01375

99. D08556

100. Ab01209746-01

101. Ab01209746_03

102. 581t933

103. Q411648

104. Q-201775

105. Sr-05000001879-1

106. Sr-05000001879-2

107. Sr-05000001879-5

108. Brd-k35452788-001-02-1

109. Brd-k69608737-001-03-7

110. Brd-k69608737-001-10-2

111. [(e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-14,16-

112. 15,19-epoxy-3h-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(23h)-tetrone,

113. (1r,9s,12s,13r,14s,17r,18e,21s,23s,24r,25s,27r)-1,14-dihydroxy-12-[(e)-1-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-prop-2-enyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

114. (3s,4r,5s,8r,9e,12s,14s,15r,16s,18r,19r,26as)-5,19-dihydroxy-3-{(e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-8-prop-2-en-1-yl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-3h-15,19-epoxypyrido[2,1-c][1,4]oxazacyclotricosine-1,7,20,21(4h,23h)-tetrone

115. (3s,4r,5s,8r,9e,12s,14s,15r,16s,18r,19r,26as)-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(1e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propen-1-yl)-15,19

116. (e)-(1r,9s,12s,13r,14r,21s,23s,24r,25s,27r)-17-allyl-1,14-dihydroxy-12-[(e)-2-((3r,4r)-4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0*4,9*]octacos-18-ene-2,3,10,16-tetraone

117. 15,19-epoxy-3h-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-((1e)-2-((1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl)-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propen-1-yl)-, (3s,4r,5s,8r,9e,12s,14s,15r,16s,18r,19r,26as)-

118. 15,19-epoxy-3h-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-, (3s-(3r*(e(1s*,3s*,4s*)),4s*,5r*,8s*,9e,12r*,14r*,15s*,16r*,18s*,19s*,26ar*))-

119. 15,19-epoxy-3h-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(1e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycyc

120. 15,19-epoxy-3h-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycycl Ohexyl]-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propen-1-yl)-, (3s,4r,5s,8r,9e,12s,14s,15r,16s,18r,19r,26as)-

121. 4,5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-heptadecahydro-5,19-dihydroxy-3-

122. Dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-,(3s,4r,5s,8r,12s,14s,15r,16s,18r,19r,26as)-

123. Lohexyl]-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propen-1-yl)-, (3s,4r,5s,8r,9e,12s,14s,15r,16s,18r,19r,26as)-

124. Tacrolimus Solution, 1.0 Mg/ml In Acetonitrile, Ampule Of 1 Ml, Certified Reference Material

2.4 Create Date
2005-06-08
3 Chemical and Physical Properties
Molecular Weight 804.0 g/mol
Molecular Formula C44H69NO12
XLogP32.7
Hydrogen Bond Donor Count3
Hydrogen Bond Acceptor Count12
Rotatable Bond Count7
Exact Mass803.48197664 g/mol
Monoisotopic Mass803.48197664 g/mol
Topological Polar Surface Area178 Ų
Heavy Atom Count57
Formal Charge0
Complexity1480
Isotope Atom Count0
Defined Atom Stereocenter Count14
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count2
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 8  
Drug NameAstagraf xl
PubMed HealthTacrolimus
Drug ClassesAntipsoriatic, Immune Suppressant
Drug LabelASTAGRAF XL is available for oral administration as hard gelatin capsules (tacrolimus extended-release capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include ethylcellulose NF, hypromello...
Active IngredientTacrolimus
Dosage FormCapsule, extended release
RouteOral
Strengtheq 5mg base; eq 0.5mg base; eq 1mg base
Market StatusPrescription
CompanyAstellas

2 of 8  
Drug NamePrograf
PubMed HealthTacrolimus
Drug ClassesAntipsoriatic, Immune Suppressant
Drug LabelPrograf is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include lactose monohydrate NF, hypromellose USP, croscarmellose so...
Active IngredientTacrolimus
Dosage FormCapsule; Injectable
RouteInjection; Oral
Strengtheq 0.5mg base; eq 5mg base; eq 1mg base; eq 5mg base/ml
Market StatusPrescription
CompanyAstellas

3 of 8  
Drug NameProtopic
PubMed HealthTacrolimus (On the skin)
Drug ClassesAntipsoriatic
Drug LabelPROTOPIC (tacrolimus) Ointment contains tacrolimus, a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It is for topical dermatologic use only. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R...
Active IngredientTacrolimus
Dosage FormOintment
RouteTopical
Strength0.1%; 0.03%
Market StatusPrescription
CompanyAstellas

4 of 8  
Drug NameTacrolimus
PubMed HealthTacrolimus
Drug ClassesAntipsoriatic, Immune Suppressant
Drug LabelPrograf is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include lactose monohydrate NF, hypromellose USP, croscarmellose so...
Active IngredientTacrolimus
Dosage FormOintment; Capsule
RouteOral; Topical
Strengtheq 5mg base; eq 0.5mg base; 0.1%; eq 1mg base; 0.03%
Market StatusPrescription
CompanyPanacea Biotec; Accord Hlthcare; Sandoz; Strides Pharma; Fougera Pharms; Dr Reddys Labs; Mylan

5 of 8  
Drug NameAstagraf xl
PubMed HealthTacrolimus
Drug ClassesAntipsoriatic, Immune Suppressant
Drug LabelASTAGRAF XL is available for oral administration as hard gelatin capsules (tacrolimus extended-release capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include ethylcellulose NF, hypromello...
Active IngredientTacrolimus
Dosage FormCapsule, extended release
RouteOral
Strengtheq 5mg base; eq 0.5mg base; eq 1mg base
Market StatusPrescription
CompanyAstellas

6 of 8  
Drug NamePrograf
PubMed HealthTacrolimus
Drug ClassesAntipsoriatic, Immune Suppressant
Drug LabelPrograf is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include lactose monohydrate NF, hypromellose USP, croscarmellose so...
Active IngredientTacrolimus
Dosage FormCapsule; Injectable
RouteInjection; Oral
Strengtheq 0.5mg base; eq 5mg base; eq 1mg base; eq 5mg base/ml
Market StatusPrescription
CompanyAstellas

7 of 8  
Drug NameProtopic
PubMed HealthTacrolimus (On the skin)
Drug ClassesAntipsoriatic
Drug LabelPROTOPIC (tacrolimus) Ointment contains tacrolimus, a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It is for topical dermatologic use only. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R...
Active IngredientTacrolimus
Dosage FormOintment
RouteTopical
Strength0.1%; 0.03%
Market StatusPrescription
CompanyAstellas

8 of 8  
Drug NameTacrolimus
PubMed HealthTacrolimus
Drug ClassesAntipsoriatic, Immune Suppressant
Drug LabelPrograf is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include lactose monohydrate NF, hypromellose USP, croscarmellose so...
Active IngredientTacrolimus
Dosage FormOintment; Capsule
RouteOral; Topical
Strengtheq 5mg base; eq 0.5mg base; 0.1%; eq 1mg base; 0.03%
Market StatusPrescription
CompanyPanacea Biotec; Accord Hlthcare; Sandoz; Strides Pharma; Fougera Pharms; Dr Reddys Labs; Mylan

4.2 Therapeutic Uses

Immunosuppressive Agents

National Library of Medicine's Medical Subject Headings. Tacrolimus. Online file (MeSH, 2014). Available from, as of April 30 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html


Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids. /Included in US product label/

NIH; DailyMed. Current Medication Information for Prograf (Tacrolimus) Capsule, Gelatin Coated; Prograf (Tacrolimus) Injection, Solution (Revised: September 2013). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b


Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Prograf be used concomitantly with adrenal corticosteroids. Therapeutic drug monitoring is recommended for all patients receiving Prograf. /Included in US product label/

NIH; DailyMed. Current Medication Information for Prograf (Tacrolimus) Capsule, Gelatin Coated; Prograf (Tacrolimus) Injection, Solution (Revised: September 2013). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b


Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids. /Included in US product label/

NIH; DailyMed. Current Medication Information for Prograf (Tacrolimus) Capsule, Gelatin Coated; Prograf (Tacrolimus) Injection, Solution (Revised: September 2013). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b


For more Therapeutic Uses (Complete) data for Tacrolimus (13 total), please visit the HSDB record page.


4.3 Drug Warning

/BOXED WARNING/ MALIGNANCIES AND SERIOUS INFECTIONS. Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression. Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Prograf. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

NIH; DailyMed. Current Medication Information for Prograf (Tacrolimus) Capsule, Gelatin Coated; Prograf (Tacrolimus) Injection, Solution (Revised: September 2013). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b


/BOXED WARNING/ WARNING: Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Protopic Ointment. Therefore: Continuous long-term use of topical calcineurin inhibitors, including Protopic Ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis; Protopic Ointment is not indicated for use in children less than 2 years of age; Only 0.03% Protopic Ointment is indicated for use in children 2-15 years of age.

NIH; DailyMed. DailyMed. Current Medication Information for Protopic (Tacrolimus) Ointment (Revised: May 2012). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8c2e5036-5f1b-4e71-bf87-5faef295fa96


Topical tacrolimus therapy should be avoided for malignant or premalignant skin conditions (e.g., cutaneous T-cell lymphoma (CTCL)), which may appear clinically similar to dermatitis.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014


Because of a potential increased risk for skin cancer, patients /using topical tacrolimus/ should be advised to limit exposure to sunlight or other UV light by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014


For more Drug Warnings (Complete) data for Tacrolimus (42 total), please visit the HSDB record page.


4.4 Drug 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 given FDA approval in 1994 for use in liver transplantation. Since then, this indication has expanded to 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.


FDA Label


Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.


Prophylaxis of transplant rejection in adult kidney or liver allograft recipients. Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.


Prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult and paediatric patients.


Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.


* Flare treatment:

Adults and adolescents (16 years of age and above)

Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.

Children (two years of age and above)

Treatment of moderate to severe atopic dermatitis in children (two years of age and above) who failed to respond adequately to conventional therapies such as topical corticosteroids.

* Maintenance treatment:

Maintenance treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (i. e. occurring four or more times per year) who have had an initial response to a maximum of six weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).


Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids. Treatment of moderate to severe atopic dermatitis in children (2 years of age and above) who failed to respond adequately to conventional therapies such as topical corticosteroids.

Maintenance treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (i. e. occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).


Prevention of solid organ transplant rejection, Treatment of solid organ transplant rejection


5 Pharmacology and Biochemistry
5.1 Pharmacology

Tacrolimus 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. Tacrolimus has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. 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.


5.2 MeSH Pharmacological Classification

Calcineurin Inhibitors

Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN. (See all compounds classified as Calcineurin Inhibitors.)


Immunosuppressive Agents

Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
TACROLIMUS ANHYDROUS
5.3.2 FDA UNII
Y5L2157C4J
5.3.3 Pharmacological Classes
Calcineurin Inhibitors [MoA]; Calcineurin Inhibitor Immunosuppressant [EPC]
5.4 ATC Code

L04AD02


L04AD02


L04AD02


L04AD02


D11AH01


D11AX14


L04AD02

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355


D - Dermatologicals

D11 - Other dermatological preparations

D11A - Other dermatological preparations

D11AH - Agents for dermatitis, excluding corticosteroids

D11AH01 - Tacrolimus


L - Antineoplastic and immunomodulating agents

L04 - Immunosuppressants

L04A - Immunosuppressants

L04AD - Calcineurin inhibitors

L04AD02 - Tacrolimus


5.5 Absorption, Distribution and Excretion

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 1710%; in adults liver transplant patients is 226%; in healthy subjects is 185%. The absolute bioavailability in pediatric liver transplant patients was 3124%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.


Route of Elimination

In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.630.7%, urinary elimination accounted for 2.31.1%.


Volume of Distribution

2.6 2.1 L/kg [pediatric liver transplant patients]

1.07 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]

3.1 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]

3.7 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]

3.9 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]

3.1 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]


Clearance

0.040 L/hr/kg [healthy subjects, IV]

0.172 0.088 L/hr/kg [healthy subjects, oral]

0.083 L/hr/kg [adult kidney transplant patients, IV]

0.053 L/hr/kg [adult liver transplant patients, IV]

0.051 L/hr/kg [adult heart transplant patients, IV]

0.138 0.071 L/hr/kg [pediatric liver transplant patients]

0.12 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients]

0.038 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]

0.042 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]

0.034 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]

0.017 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]

0.016 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]


The aim of this study was to assess tacrolimus levels in breast milk and neonatal exposure during breastfeeding. An observational cohort study was performed in two tertiary referral high-risk obstetric medicine clinics. Fourteen women taking tacrolimus during pregnancy and lactation, and their 15 infants, 11 of whom were exclusively breast-fed, were assessed. Tacrolimus levels were analyzed by liquid chromatography-tandem mass spectrometry. Samples from mothers and cord blood were collected at delivery and from mothers, infants, and breast milk postnatally where possible. All infants with serial sampling had a decline in tacrolimus level, which was approximately 15% per day (ratio of geometric mean concentrations 0.85; 95% confidence interval, 0.82-0.88; P<0.001). Breast-fed infants did not have higher tacrolimus levels compared with bottle-fed infants (median 1.3 ug/L [range, 0.0-4.0] versus 1.0 ug/L (range, 0.0-2.3), respectively; P=0.91). Maximum estimated absorption from breast milk is 0.23% of maternal dose (weight-adjusted). Ingestion of tacrolimus by infants via breast milk is negligible. Breastfeeding does not appear to slow the decline of infant tacrolimus levels from higher levels present at birth.

PMID:23349333 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613954 Bramham K et al; Clin J Am Soc Nephrol 8 (4): 563-7 (2013)


Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. Mean (+ or - SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 + or - 1.8 ng ml(-1)) were 71 + or - 18% (range 45-99%) of maternal concentrations (9.0 + or - 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 + or - 0.04 ng ml(-1)) and unbound drug concentrations (0.003 + or - 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 + or - 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood.

PMID:23528073 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845323 Zheng S et al; Br J Clin Pharmacol 76 (6): 988-96 (2013)


Ten colostrum samples were obtained from six women in the immediate postpartum period (0-3 days) with a mean drug concentration of 0.79 ng/mL (range 0.3-1.9 ng/mL). The median milk:maternal plasma ratio was 0.5.

Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 1385


The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a US study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67). There was no evidence based on blood concentrations that tacrolimus accumulates systemically upon intermittent topical application for periods of up to 1 year. As with other topical calcineurin inhibitors, it is not known whether tacrolimus is distributed into the lymphatic system.

NIH; DailyMed. DailyMed. Current Medication Information for Protopic (Tacrolimus) Ointment (Revised: May 2012). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8c2e5036-5f1b-4e71-bf87-5faef295fa96


For more Absorption, Distribution and Excretion (Complete) data for Tacrolimus (9 total), please visit the HSDB record page.


5.6 Metabolism/Metabolites

The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5. Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring. 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.


Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. 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.

NIH; DailyMed. Current Medication Information for Prograf (Tacrolimus) Capsule, Gelatin Coated; Prograf (Tacrolimus) Injection, Solution (Revised: September 2013). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b


Fk_506 has known human metabolites that include 13-O-Desmethyltacrolimus and 15-O-Desmethyltacrolimus.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560


5.7 Biological Half-Life

The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.53.8 hours, in pediatric kidney transplant patients was 10.25.0 (range 3.4-25) hours.


In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, ... the elimination half-life based on radioactivity was 48.1+ or - 15.9 hours whereas it was 43.5 + or- 11.6 hours based on tacrolimus concentrations. ... When administered PO, the elimination half-life based on radioactivity was 31.9 + or- 10.5 hours whereas it was 48.4 + or - 12.3 hours based on tacrolimus concentrations ... .

NIH; DailyMed. Current Medication Information for Prograf (Tacrolimus) Capsule, Gelatin Coated; Prograf (Tacrolimus) Injection, Solution (Revised: September 2013). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b


... A case of tacrolimus toxicity in a non-transplant patient /is presented/. ... /The/ patient's tacrolimus dose was 2.1 mg/kg/day for 4 days (therapeutic 0.03 to 0.05 mg/kg/day). Her tacrolimus elimination half-life was 16.5 hours, compared to a mean half-life in healthy volunteers of 34.2 +/- 7.7 hours. ...

PMID:18608277 O'Connor AD et al; Clin Toxicol (Phila) 46 (9): 838-40 (2008)


5.8 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.


Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Tacrolimus is commercially available for topical use as a 0.03 or 0.1% ointment. The exact mechanism(s) of action of tacrolimus in the treatment of atopic dermatitis has not been elucidated but appears to involve inhibition of the activation of T cells. Tacrolimus also has been shown to inhibit release of mediators from skin mast cells and basophils and to downregulate the expression of high-affinity receptors for immunoglobulin E (IgE) on Langerhans cells. Although tacrolimus is not genotoxic and does not interact directly with DNA, the drug may impair local immunosurveillance.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014


Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds 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 inhibited. This effect may prevent 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 (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

NIH; DailyMed. Current Medication Information for Prograf (Tacrolimus) Capsule, Gelatin Coated; Prograf (Tacrolimus) Injection, Solution (Revised: September 2013). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b


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 effect has been shown to prevent 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 (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-a, 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 down regulate the expression of FceRI on Langerhans cells.

NIH; DailyMed. DailyMed. Current Medication Information for Protopic (Tacrolimus) Ointment (Revised: May 2012). Available from, as of June 17, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8c2e5036-5f1b-4e71-bf87-5faef295fa96


Tacrolimus, formerly known as FK506, is a macrolide antibiotic with immunosuppressive properties. Although structurally unrelated to cyclosporin A (CsA), its mode of action is similar. It exerts its effects principally through impairment of gene expression in target cells. Tacrolimus bonds to an immunophilin, FK506 binding protein (FKBP). This complex inhibits calcineurin phosphatase. The drug inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis. Tacrolimus also potentiates the actions of glucocorticoids and progesterone by binding to FKBPs contained within the hormone receptor complex, preventing degradation. The agent may enhance expression of the transforming growth factor beta-1 gene in a fashion analogous to that demonstrated for CsA. T cell proliferation in response to ligation of the T cell receptor is inhibited by tacrolimus. Type 1 T helper cells appear to be preferentially suppressed compared with type 2 T helper cells. T cell-mediated cytotoxicity is impaired. B cell growth and antibody production are affected indirectly by the suppression of T cell-derived growth factors necessary for these functions. Antigen presentation appears to be spared. ...

PMID:8588225 Thomson AW et al; Ther Drug Monit 17 (6): 584-91 (1995)