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Tacrolimus

PubChem CID
445643
Structure
Tacrolimus_small.png
Molecular Formula
Synonyms
  • tacrolimus
  • Fujimycin
  • 104987-11-3
  • Prograf
  • Tsukubaenolide
Molecular Weight
804.0 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-06-08
  • Modify:
    2025-01-11
Description
Tacrolimus (anhydrous) is a macrolide lactam containing a 23-membered lactone ring, originally isolated from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. It has a role as an immunosuppressive agent and a bacterial metabolite.
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 inhibits calcineurin which inhibits T-lymphocyte signal transduction and IL-2 transcription.
Tacrolimus anhydrous is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of tacrolimus anhydrous is as a Calcineurin Inhibitor.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Tacrolimus.png

1.2 3D Status

Conformer generation is disallowed since too many atoms

2 Names and Identifiers

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
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

QJJXYPPXXYFBGM-LFZNUXCKSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 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
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C44H69NO12
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

109581-93-3

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 KEGG ID

2.3.10 Lipid Maps ID (LM_ID)

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 NSC Number

2.3.15 PharmGKB ID

2.3.16 Pharos Ligand ID

2.3.17 RXCUI

2.3.18 Wikidata

2.3.19 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Anhydrous Tacrolimus
  • Anhydrous, Tacrolimus
  • FK 506
  • FK-506
  • FK506
  • FR 900506
  • FR-900506
  • FR900506
  • Prograf
  • Prograft
  • Tacrolimus
  • Tacrolimus Anhydrous
  • Tacrolimus, Anhydrous

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
804.0 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
2.7
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
12
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
803.48197664 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
803.48197664 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
178 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
57
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1480
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
14
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Melting Point

126 °C

3.2.2 Solubility

Insoluble
FDA label

3.2.3 LogP

3.3

3.2.4 Stability / Shelf Life

Stable under recommended storage conditions. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html

3.2.5 Optical Rotation

Colorless prisms from acetonitrile; mp 127-129 °C. Specific optical rotation: -84.4 deg at 23 °C/D (c = 1.02 in chloroform). Soluble in methanol, ethanol, acetone, ethyl acetate, chloroform, diethyl ether; sparingly soluble in hexane, petroleum ether. Insoluble in water. /Tacrolimus monohydrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1669

3.2.6 Collision Cross Section

267 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

269.55 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

277.08 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Immunosuppressive Agents; Dermatologic Agents
Human drug -> Prescription
Human drug -> Prescription; Discontinued; Active ingredient (TACROLIMUS)
Human drugs -> Immunosuppressants -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Other dermatological preparations -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug
Immunomodulators for non-malignant disease

3.3.2 Lipids

Polyketides [PK] -> Macrolides and lactone polyketides [PK04]

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 LC-MS

1 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M-H]-
Precursor m/z
802.475
Instrument
Thermo Q Exactive HF
Instrument Type
LC-ESI-QFT
Ionization Mode
negative
Collision Energy
HCD (NCE 20-30-40%)
Retention Time
1.023983
Top 5 Peaks

168.06561 100

167.0578 53.35

128.0705 52.87

502.31784 29.05

560.35931 26.11

Thumbnail
Thumbnail
2 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
804.4878
Instrument
SCIEX TripleTOF 6600
Instrument Type
LC-ESI-QTOF
Ionization Mode
positive
Collision Energy
35 eV
Retention Time
1.08035
Top 5 Peaks

768.45581 100

786.48315 42.19

576.30389 31.23

548.3219 23.42

718.42377 23.42

Thumbnail
Thumbnail

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Immediate-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. Extended-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving kidney transplants, in combination with other immunosuppressants, and may be used in patients converted from immediate-release formulations. Topical tacrolimus ointment is indicated as second-line therapy for short-term and non-continuous treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical treatments or for whom alternative treatments are not advisable. Both available strengths are indicated in adult patients, while only the lower strength (0.03%) formulation is indicated in pediatric patients between 2 and 15 years of age.
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.

7.2 LiverTox Summary

Tacrolimus is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after transplantation. Tacrolimus therapy can be associated with mild serum enzyme elevations, and it has been linked to rare instances of clinically apparent cholestatic liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Immunosuppressive Agents; Dermatologic Agents
Transplant Agents

7.4 FDA Medication Guides

1 of 3
Drug
Active Ingredient
TACROLIMUS
Form;Route
CAPSULE, EXTENDED RELEASE;ORAL
Company
ASTELLAS
Date
11/22/22
Drug
Active Ingredient
TACROLIMUS
Form;Route
CAPSULE, EXTENDED RELEASE;ORAL
Company
ASTELLAS
Date
09/14/2023
Drug
Active Ingredient
TACROLIMUS
Form;Route
CAPSULE, EXTENDED RELEASE;ORAL
Company
ASTELLAS
Date
09/14/2023
Drug
Active Ingredient
TACROLIMUS
Form;Route
CAPSULE, EXTENDED RELEASE;ORAL
Company
ASTELLAS
Date
9/14/23
2 of 3
Drug
Active Ingredient
TACROLIMUS
Form;Route
TABLET, EXTENDED RELEASE;ORAL
Company
VELOXIS PHARMS INC
Date
04/08/2024
3 of 3
Drug
Active Ingredient
TACROLIMUS
Form;Route
OINTMENT;TOPICAL
Company
LEO PHARMA AS
Date
2/25/19

7.5 WHO Essential Medicines

Drug
Drug Classes
Immunomodulators for non-malignant disease
Formulation
(1) Parenteral - General injections - IV: 5 mg per mL in 1 mL vial; (2) Oral - Liquid: 0.2 mg granules for oral suspension; 1 mg granules for oral suspension; (3) Oral - Solid: 0.5 mg (immediate-release); 0.75 mg (immediate-release); 1 mg (immediate-release); 2 mg (immediate-release); 5 mg (immediate-release)
Indication
Failure or rejection of transplanted organs or tissues

7.6 FDA Approved Drugs

7.7 FDA Orange Book

7.8 FDA National Drug Code Directory

7.9 Drug Labels

Drug and label
Active ingredient and drug

7.10 Clinical Trials

7.10.1 ClinicalTrials.gov

7.10.2 EU Clinical Trials Register

7.10.3 NIPH Clinical Trials Search of Japan

7.11 EMA Drug Information

1 of 7
View All
Medicine
Category
Human drugs
Therapeutic area
Graft Rejection
Active Substance
tacrolimus
INN/Common name
tacrolimus
Pharmacotherapeutic Classes
Immunosuppressants
Status
This medicine is authorized for use in the European Union
Company
Astellas Pharma Europe BV
Market Date
2007-04-23
2 of 7
View All
Medicine
Category
Human drugs
Therapeutic area
Graft Rejection
Active Substance
tacrolimus
INN/Common name
tacrolimus
Pharmacotherapeutic Classes
Immunosuppressants
Status
This medicine is authorized for use in the European Union
Company
Astellas Pharma Europe B.V.
Market Date
2009-05-15

7.12 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.

7.13 Drug Warnings

/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.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

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.

8.2 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.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
Y5L2157C4J
Active Moiety
TACROLIMUS ANHYDROUS
Pharmacological Classes
Established Pharmacologic Class [EPC] - Calcineurin Inhibitor Immunosuppressant
Pharmacological Classes
Mechanisms of Action [MoA] - Calcineurin Inhibitors
FDA Pharmacology Summary
Tacrolimus anhydrous is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of tacrolimus anhydrous is as a Calcineurin Inhibitor.
2 of 2
Non-Proprietary Name
TACROLIMUS
Pharmacological Classes
Calcineurin Inhibitor Immunosuppressant [EPC]; Calcineurin Inhibitors [MoA]

8.4 ATC Code

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
D11AH01
D11AX14

L - Antineoplastic and immunomodulating agents

L04 - Immunosuppressants

L04A - Immunosuppressants

L04AD - Calcineurin inhibitors

L04AD02 - Tacrolimus

D - Dermatologicals

D11 - Other dermatological preparations

D11A - Other dermatological preparations

D11AH - Agents for dermatitis, excluding corticosteroids

D11AH01 - Tacrolimus

8.5 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 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. 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 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.
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.
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.
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.

8.6 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 15-O-Desmethyltacrolimus and 13-O-Desmethyltacrolimus.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

8.7 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 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (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. ...
O'Connor AD et al; Clin Toxicol (Phila) 46 (9): 838-40 (2008)

8.8 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. ...
Thomson AW et al; Ther Drug Monit 17 (6): 584-91 (1995)

8.9 Transformations

9 Use and Manufacturing

9.1 Uses

THERAPEUTIC CATEGORY: Immunosupressant; dermatological treatment of atopic eczema
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1669
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
MEDICATION

Use (kg; approx.) in Germany (2009): >25

Use (kg) in USA (2002): 45

Consumption (g per capita; approx.) in Germany (2009): 0.000305

Consumption (g per capita) in the USA (2002): 0.00016

Calculated removal (%): 6

9.1.1 Use Classification

Human drugs -> Immunosuppressants -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Other dermatological preparations -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

Obtained from Streptomyces tsukubaensis. /Tacrolimus hydrate/
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1590

9.3 Formulations / Preparations

Table: Tacrolimus Preparations
Route of Administration
Oral
Dosage Form
Capsules
Strength
0.5 mg (of anhydrous tacrolimus)
Brand or Generic Name (Manufacturer)
Prograf (Astellas)
Route of Administration
Oral
Dosage Form
Capsules
Strength
1 mg (of anhydrous tacrolimus)
Brand or Generic Name (Manufacturer)
Prograf (Astellas)
Route of Administration
Oral
Dosage Form
Capsules
Strength
5 mg (of anhydrous tacrolimus)
Brand or Generic Name (Manufacturer)
Prograf (Astellas)
Route of Administration
Parenteral
Dosage Form
For injection, concentrate, for IV infusion only
Strength
5 mg (of anhydrous tacrolimus) per mL
Brand or Generic Name (Manufacturer)
Prograf (Astellas)
American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 3770
Table: Tacrolimus Preparations
Route of Administration
Topical
Dosage Form
Ointment
Strength
0.03%
Brand or Generic Name (Manufacturer)
Protopic (Astellas)
Route of Administration
Topical
Dosage Form
Ointment
Strength
0.1%
Brand or Generic Name (Manufacturer)
Protopic (Astellas)
American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014
Oral: 0.2 mg, 1 mg tacrolimus (as monohydrate), granules for oral suspension (Modgraf)
Datapharm Communications Ltd; Electronic Medicines Compendium (eMC), Summary of Product Characteristics (SPC) for Modgraf (Last updated February 2014). Available from, as of June 17, 2014: https://www.medicines.org.uk/emc/medicine/22719/SPC/Modigraf+0.2mg+%26+1mg+granules+for+oral+suspension/
Oral: 0.5 mg, 1 mg, 5 mg of tacrolimus (as tacrolimus monohydrate) hard capsules (Perixis)
Datapharm Communications Ltd; Electronic Medicines Compendium (eMC), Summary of Product Characteristics (SPC) for Perixis (Last updated September 2013). Available from, as of June 17, 2014: https://www.medicines.org.uk/emc/medicine/28237/PIL/Perixis+0.5+1+5+mg+Hard+Capsules/
Oral: 0.5 mg, 1 mg, 5 mg tacrolimus (as monohydrate), prolonged-release hard capsules (Advagraf)
Datapharm Communications Ltd; Electronic Medicines Compendium (eMC), Summary of Product Characteristics (SPC) for Advagraf (Last updated December 2013). Available from, as of June 17, 2014: https://www.medicines.org.uk/emc/medicine/19814/SPC/Advagraf+0.5mg%2c+1mg%2c+3mg+and+5mg+Prolonged-release+hard+capsules/

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

1 of 3
View All
Pictogram(s)
Acute Toxic
Health Hazard
Signal
Danger
GHS Hazard Statements

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H372 (100%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

Precautionary Statement Codes

P203, P260, P264, P270, P280, P301+P316, P318, P319, P321, P330, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary
The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

10.1.2 Hazard Classes and Categories

Acute Tox. 3 (100%)

Repr. 2 (100%)

STOT RE 1 (100%)

Acute Tox. 3 (97.5%)

Repr. 2 (93.8%)

STOT RE 1 (92.6%)

10.2 Fire Fighting

10.2.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html

10.3 Accidental Release Measures

10.3.1 Cleanup Methods

Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html

10.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html

10.3.3 Preventive Measures

Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html
Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html
Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

10.4 Handling and Storage

10.4.1 Storage Conditions

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: -20 °C Keep in a dry place. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html
Store at 25 °C (77 °F); excursions permitted to 15 °C-30 °C (59 °F-86 °F).
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
Store at room temperature 25 °C (77 °F); excursions permitted to 15 deg - 30 °C (59 deg - 86 °F).
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

10.5 Exposure Control and Personal Protection

10.5.1 Personal Protective Equipment (PPE)

Handle with gloves. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html
Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html

10.6 Stability and Reactivity

10.6.1 Hazardous Reactivities and Incompatibilities

Strong oxidizing agents. /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html

10.7 Regulatory Information

10.7.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tacrolimus, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 3, 2014: https://www.fda.gov/cder/ob/

10.8 Other Safety Information

10.8.1 Toxic Combustion Products

Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx). /FK-506 monohydrate/
Sigma-Aldrich; Material Safety Data Sheet for FK-506 monohydrate, Product Number: F4679, Version 4.8 (Revision Date 05/13/2014). Available from, as of June 17, 2014: https://www.sigmaaldrich.com/safety-center.html

11 Toxicity

11.1 Toxicological Information

11.1.1 Toxicity Summary

IDENTIFICATION AND USE: Tacrolimus is white to off-white crystalline powder. It is a calcineurin-inhibitor immunosuppressant available in several preparations. Tacrolimus in both oral capsules and a solution for IV injection is used for prophylaxis of organ rejection in patients receiving liver, kidney or heart transplants. Tacrolimus topical ointment is used as a second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children. HUMAN EXPOSURE AND TOXICITY: While most acute overdosages of tacrolimus at up to 30 times the intended dose have been asymptomatic and all patients recovered with no sequelae, some acute overdosages were followed by adverse reactions including tremors, abnormal renal function, hypertension, and peripheral edema. At therapeutic doses, patients receiving tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin, as well as an increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. While there are no adequate and well-controlled studies in pregnant women, the use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. ANIMAL STUDIES: Both rats and baboons showed a similar toxicologic profile following oral or intravenous administration of tacrolimus. Toxicity following intravenous administration was evident at lower doses than after oral administration for both rats and baboons. Toxicity was seen at lower doses in rats than in baboons. The primary target organs were the kidneys, pancreatic islets of Langerhans and exocrine pancreas, spleen, thymus, gastrointestinal tract, and lymph nodes. In addition, decreases in erythrocyte parameters were seen. Tacrolimus also produced reproductive and developmental toxicity in both rats and rabbits. In rats, chronic oral administration of tacrolimus at high doses resulted in changes in sex organs, and glaucoma/eye changes. Oral doses of tacrolimus at 1 and 3.2 mg/kg/day produced overt signs of parental toxicity and changes in the fertility and general reproductive performance of rats. Effects on reproduction included some embryo lethality, reduced number of implantations, increased incidence of post-implantation loss, and reduced embryo and offspring viability. In a rabbit teratology study, signs of maternal toxicity including reduced body weight were produced at all oral doses of tacrolimus administered (0.1, 0.32, or 1 mg/kg/day). Doses of 0.32 and 1 mg/kg/day produced signs of developmental toxicity, such as increased incidence of post-implantation losses, reduced number of viable fetuses, and increased incidences of morphological variations. In a rat teratology study, increased post-implantation loss was observed at 3.2 mg/kg/day. Maternal doses of 1 mg/kg/day decreased the body weight of F1 offspring. Decreased body weight, reduced survival number, and some skeletal alterations were seen in F1 offspring at maternal doses of 3.2 mg/kg/day. Tacrolimus did not exhibit genotoxic activity in vitro in bacterial asaays in Salmonella typhimurium and Escherichia coli or mammalian assays in Chinese hamster lung-derived cells assays. No evidence of mutagenicity was observed in vitro in the CHO/HGPRT assay (the Chinese hamster ovary cell assay (CHO), which measures forward mutation of the HGPRT locus) or in vivo in clastogenicity assays performed in mice. Tacrolimus also did not cause unscheduled DNA synthesis in rodent hepatocytes.

11.1.2 Hepatotoxicity

Tacrolimus therapy is associated with mild to moderate elevations in serum aminotransferase levels in 5% to 10% of patients. These elevations are usually mild, asymptomatic and self-limited, but are occasionally persistent and may require dose modification. Tacrolimus has also been implicated in instances of cholestatic hepatitis, but clinically apparent liver injury is rare. Because tacrolimus is used in the context of organ transplantation and often in liver transplantation, the causes of liver test abnormalities arising during therapy are many, and drug induced liver injury due to tacrolimus is sufficiently rare that its clinical features and typical course have not been defined.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

11.1.3 Drug Induced Liver Injury

Compound
tacrolimus
DILI Annotation
Less-DILI-Concern
Severity Grade
5
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.4 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited data indicate that amounts of systemically administered tacrolimus are low in breastmilk and probably do not adversely affect the breastfed infant. United States and European experts and guidelines consider tacrolimus to be probably safe to use during breastfeeding. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.

Topical tacrolimus presents a low risk to the nursing infant because it is poorly absorbed after topical application and peak blood concentrations are less than 2 mcg/L in most patients. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Current guidelines allow topical tacrolimus to be applied to the nipples just after nursing, with the nipples cleaned gently before nursing. Only water-miscible cream or gel products should be applied to the breast or nipple because ointments may expose the infant to high levels of mineral paraffins via licking, so pimecrolimus cream may be preferable to tacrolimus ointment for nipple application.

◉ Effects in Breastfed Infants

One infant was exclusively breastfed during maternal tacrolimus therapy throughout gestation to at least 2.5 months of age at which time the infant was developing normally physically and neurologically. An ultrasound examination of the infant's thymus was normal.

The National Transplantation Pregnancy Registry reported data gathered from 1991 to 2011 on mothers who breastfed their infants following organ transplantation. A total of 68 mothers with transplants (mostly kidney or liver) used tacrolimus while breastfeeding a total of 83 infants. Duration of nursing ranged from 1 week to 1.5 years and follow-up of the children ranged from weeks to 16 years. There were no reports of problems in any of the infants or children. As of December 2013, a total of 92 mothers had breastfed 125 infants for as long as 26 months with no apparent adverse effects in infants.

The breastfed infants of six women who took tacrolimus during pregnancy for organ transplantation were breastfed (4 exclusive, 2 partial) for 45 to 180 days and followed for periods of 2 to 30 months. The mothers' mean daily tacrolimus dosage during breastfeeding was 9.6 mg daily (range 4.5 to 15 mg daily). Four mothers were also taking azathioprine 100 to 150 mg daily, one was taking diltiazem, and one was taking prednisolone 15 mg and aspirin 75 mg daily. None of the infants had any clear tacrolimus-related side effects, although one had transient thrombocytosis that resolved despite continued breastfeeding. Developmental milestones were normal and no pattern of infections was noted.

Two mothers with systemic lupus erythematosus were reported who took tacrolimus 3 mg daily during pregnancy and lactation as well as prednisolone 30 or 40 mg daily. Three years after birth, both children were healthy. The durations of lactation were not stated.

In a case series of women who had liver transplants over a 25-year period, one woman breastfed (extent not stated) her infant while taking tacrolimus. No neonatal complications were noted.

A mother with a liver transplant was maintained on belatacept 10 mg/kg monthly, slow-release tacrolimus (Envarsus and Veloxis) 2 mg daily, azathioprine 25 mg daily, and prednisone 2.5 mg daily. She breastfed her infant for a year (extent not stated). The infant’s growth and cognitive milestones were normal.

An Australian case series reported 3 women with heart transplants who had a total of 5 infants, all of whom were breastfed (extent not stated) during maternal tacrolimus therapy. Daily dosages ranged from 3 to 13 mg daily. No adverse infant effects were reported up to the times of discharge.

A woman with rheumatoid arthritis refractory to etanercept took sarilumab 200 mg every two weeks during pregnancy until 37 weeks of gestation. She was also taking prednisolone 10 mg and tacrolimus 3 mg daily. She delivered a healthy infant at 38 weeks of gestation and breastfed her infant. Prednisolone was continued postpartum, tacrolimus was restarted at 7 days postpartum, and sarilumab was restarted at 28 days postpartum. The mother continued to breastfeed until 6 months postpartum. The infant was vaccinated with multiple live vaccines after reaching six months old, including the Bacille-Calmette-Guerin vaccine, with no adverse effects.

A woman with a heart transplant took tacrolimus alone throughout pregnancy and postpartum while breastfeeding her infant (extent not stated) for one year. The child had normal weight gain, normal motor development, and no signs of metabolic disorders or significant infections. The age of the infant at evaluation was not stated.

◉ Effects on Lactation and Breastmilk

A study in renal transplant patients who were on a tacrolimus-based immunosuppression regimen found that women’s median serum prolactin levels were 14.4 mcg/L compared with women who were not taking tacrolimus (17.6 mcg/L). The difference was statistically significant. Median serum testosterone levels (0.121 vs 0.137 mcg/L) and serum cortisol levels (82.5 vs 105 mg/L) were also significantly lower in the tacrolimus group. The reduced prolactin may be caused by inhibition of the transcription of the human prolactin gene. Not all studies have found a reduction in serum prolactin with tacrolimus. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

11.1.5 Acute Effects

11.1.6 Interactions

With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with Prograf co-administration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Prograf in patients concomitantly receiving MPA-containing products.
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
Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with 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
Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations. Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when Prograf is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation.
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
Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these calcium channel blocking drugs and tacrolimus are used concomitantly.
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 Interactions (Complete) data for Tacrolimus (18 total), please visit the HSDB record page.

11.1.7 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1
Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
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 pharmacokinetics of tacrolimus are influenced by many factors, including genetic variability, acute infections, liver dysfunction, and interacting medications, which can result in elevated concentrations. The most appropriate management of acute tacrolimus toxicity has not been defined though case reports exist describing the therapeutic use of enzyme inducers to increase tacrolimus metabolism and decrease concentrations. ... The utilization of phenytoin to assist in decreasing tacrolimus concentrations in a case series of four solid organ transplant recipients with acute, symptomatic tacrolimus toxicity presenting with elevated serum creatinine, potassium, and tacrolimus trough concentrations greater than 30 ng/mL /is reported/. All four patients had the potential causative agents stopped or temporarily held and were given ... phenytoin for two to three days. Within three days of beginning phenytoin, all four patients had a decrease in tacrolimus concentration to less than 15 ng/mL, a return to or near baseline creatinine concentration, and lack of phenytoin-related side effects. Therefore, phenytoin appears to be a safe and potentially beneficial treatment option in patients with symptomatic tacrolimus toxicity.
Jantz AS et al; Case Rep Transplant. 2013;2013:375263. doi: 10.1155/2013/375263. Epub 2013

11.1.8 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Patients receiving immunosuppressants, including Prograf, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes.
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
/SIGNS AND SYMPTOMS/ Patients receiving immunosuppressants, including Prograf, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Boxed Warning]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
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
/SIGNS AND SYMPTOMS/ There are no adequate and well-controlled studies in pregnant women. ... The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction.
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
/SIGNS AND SYMPTOMS/ Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions ... including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed.
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 Human Toxicity Excerpts (Complete) data for Tacrolimus (11 total), please visit the HSDB record page.

11.1.9 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 52-week photocarcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation) with tacrolimus ointment at > or = 0.1% tacrolimus.
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
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/sq m/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.
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
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The carcinogenicity potential of FK506 /Sandoz Tacrolimus/ has been evaluated in mice and rats. Mice (56/sex) were administered FK506 as a dietary admix at doses of 0 (control), 0 (placebo), 0.3, 1 and 3 mg/kg/day. There was no evidence of any tumorigenic potential of FK506 in this study. Signs of toxicity were evident in the form of reduced bodyweight gain in both sexes receiving 3.0 mg/kg/day and for males receiving 1 mg/kg/day. For males receiving 3.0 mg/kg/day, there was a reduction in the efficiency of food utilization. An increase in mortality for males at 3.0 mg/kg/day was accompanied by pathological findings of minimal adipose tissue and fur staining, evidence of dysfunctional testes/epididymides, prostate glands and seminal vesicles. Males and females at 3.0 mg/kg/day also demonstrated reduced islets of Langerhans and increased basophilia and cellularity of islets. The no-effect level was considered to be 0.3 mg/kg/day in both sexes. In addition, 1 mg/kg/day was a no-effect level for females only.
Health Canada; Product Monograph for Sandoz Tacrolimus (Tacrolimus immediate release capsules), Drug Identification Number (DIN): 02416824 p59 (Revision date: 11/21/13). Available from, as of June 6, 2014: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The 104 week studies in rats administered tacrolimus at oral doses of 0.2, 0.5, 1.25, 2.5 and 5.0 mg/kg/day demonstrated no evidence of tumorigenicity.
Health Canada; Product Monograph for Sandoz Tacrolimus (Tacrolimus immediate release capsules), Drug Identification Number (DIN): 02416824 p59 (Revision date: 11/21/13). Available from, as of June 6, 2014: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
For more Non-Human Toxicity Excerpts (Complete) data for Tacrolimus (11 total), please visit the HSDB record page.

11.1.10 Non-Human Toxicity Values

LD50 Rat iv 23,600 ug/kg /Tacrolimus hydrate/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3344
LD50 Rat oral 134 mg/kg /Tacrolimus hydrate/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3344

11.1.11 Populations at Special Risk

The use of tacrolimus ointment is not recommended in patients having skin conditions with a skin barrier defect where there is the potential for increased systemic absorption of tacrolimus, including but not limited to, Netherton's syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft Versus Host Disease. Oral application is also not recommended. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions.
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 is a widely used immunosuppressive agent for the prophylaxis of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation (HSCT). Since tacrolimus is primarily metabolized by the liver, hepatic dysfunction may affect its metabolism. Hepatic veno-occlusive disease (VOD) is an early complication of HSCT that results in hepatic dysfunction, suggesting that VOD may affect tacrolimus metabolism. ... A case of hepatic VOD accompanied by a sustained high blood trough level of tacrolimus despite its discontinuation /is reported/. The findings of this case suggest that the elimination of tacrolimus can be markedly delayed in patients with hepatic VOD, and that the clinician should carefully modulate the drug dosage for these patients.
Shin SH et al; Blood Res 48 (1): 55-7 (2013)
Until long-term safety data are available some consider that it would be prudent if topical calcineurin inhibitors /including tacrolimus/ were: not used in children under 2 years of age, ... avoided in immunocompromised patients, avoided in patients with neoplasia, and avoided in those with skin disorders liable to lead to increased systemic absorption.
SWEETMAN, S.C. (ed.) Martindale-The Complete Drug Reference. 36th ed. London: The Pharmaceutical Press, 2009., p. 1843
Acute renal failure has been reported rarely in patients receiving topical tacrolimus. The risk of systemic absorption is increased in patients with epidermal barrier defects, especially following topical application of the drug to large body surface areas. Topical tacrolimus ointment should be used with caution in patients predisposed to renal impairment.
American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014

11.1.12 Protein Binding

~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL.

11.2 Ecological Information

11.2.1 Natural Pollution Sources

Tacrolimus is derived from a soil bacteria, Streptomyces tsukubaensis(1).
(1) Tanaka H et al; J Amer Chem Soc 103: 5031-33 (1987). Availble from, as of Oct 15, 2014: https://pubs.acs.org/doi/abs/10.1021/ja00250a050

11.2.2 Milk Concentrations

EXPERIMENTAL: ... Very small amounts of tacrolimus are excreted in the breast milk ... .
Hebert MF et al; Transplantation 95 (7): 908-15 (2013)
EXPERIMENTAL: 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.
Bramham K et al; Clin J Am Soc Nephrol 8 (4): 563-7 (2013)
EXPERIMENTAL: ... Infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. ...
Zheng S et al; Br J Clin Pharmacol 76 (6): 988-96 (2013)
EXPERIMENTAL: Although systemic absorption of tacrolimus following topical applications of Protopic Ointment is minimal relative to systemic administration, it is known that tacrolimus is excreted in human milk. ...
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

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Thieme References

13.5 Nature Journal References

13.6 Chemical Co-Occurrences in Literature

13.7 Chemical-Gene Co-Occurrences in Literature

13.8 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 FDA Orange Book Patents

14.4 Chemical Co-Occurrences in Patents

14.5 Chemical-Disease Co-Occurrences in Patents

14.6 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Protein Bound 3D Structures

15.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

15.2 Chemical-Target Interactions

15.3 Drug-Drug Interactions

15.4 Drug-Food Interactions

  • Avoid alcohol. Consuming alcohol may increase the rate of tacrolimus release from extended-release formulations.
  • Avoid grapefruit products.
  • Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of tacrolimus; therefore, monitoring tacrolimus whole blood trough concentrations may be warranted.
  • Take at the same time every day.
  • Take on an empty stomach. Take at least 1 hour before or 2 hours after a meal as coadministration with food decreases the rate and extent of absorption.
  • Take separate from antacids. Coadministration of tacrolimus with aluminum or magnesium hydroxide antacids may increase the serum levels of tacrolimus, which poses a risk for toxicity.

15.5 Pathways

16 Biological Test Results

16.1 BioAssay Results

17 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 LIPID MAPS Classification

18.5 KEGG: Lipid

18.6 KEGG: ATC

18.7 KEGG: Target-based Classification of Drugs

18.8 KEGG: Drug Groups

18.9 WHO ATC Classification System

18.10 FDA Pharm Classes

18.11 ChemIDplus

18.12 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.13 ChEMBL Target Tree

18.14 UN GHS Classification

18.15 NORMAN Suspect List Exchange Classification

18.16 CCSBase Classification

18.17 EPA DSSTox Classification

18.18 LOTUS Tree

18.19 FDA Drug Type and Pharmacologic Classification

18.20 EPA Substance Registry Services Tree

18.21 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. CAS Common Chemistry
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    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  6. European Chemicals Agency (ECHA)
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    (3S,4R,5R,8R,9Z,12R,14S,15R,16S,18R,19R,26aS)-8-allyl-5,19-dihydroxy-3-{(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-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
    https://echa.europa.eu/substance-information/-/substanceinfo/100.155.367
    (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1Z)-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
    https://echa.europa.eu/substance-information/-/substanceinfo/100.184.851
    (3S,4R,5R,8R,9Z,12R,14S,15R,16S,18R,19R,26aS)-8-allyl-5,19-dihydroxy-3-{(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-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 (EC: 627-021-3)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/159969
    (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1Z)-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 (EC: 658-056-2)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/189773
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  8. Hazardous Substances Data Bank (HSDB)
  9. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  10. ChEBI
  11. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  12. LiverTox
  13. LOTUS - the natural products occurrence database
    LICENSE
    The code for LOTUS is released under the GNU General Public License v3.0.
    https://lotus.nprod.net/
  14. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  15. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  16. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  17. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    fk_506
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  18. Chemical Probes Portal
  19. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  20. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  21. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  22. Therapeutic Target Database (TTD)
  23. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  24. DailyMed
  25. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  26. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  27. Drugs and Lactation Database (LactMed)
  28. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  29. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  30. EU Clinical Trials Register
  31. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  32. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  33. FDA Medication Guides
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  34. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  35. Japan Chemical Substance Dictionary (Nikkaji)
  36. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  37. LIPID MAPS
    Lipid Classification
    https://www.lipidmaps.org/
  38. Natural Product Activity and Species Source (NPASS)
  39. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  40. Metabolomics Workbench
  41. Nature Chemical Biology
  42. NIPH Clinical Trials Search of Japan
  43. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  44. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  45. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  46. Protein Data Bank in Europe (PDBe)
  47. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  48. Springer Nature
  49. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  50. Wikidata
  51. Wikipedia
  52. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  53. PubChem
  54. GHS Classification (UNECE)
  55. EPA Substance Registry Services
  56. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  57. PATENTSCOPE (WIPO)
  58. NCBI
CONTENTS