Tacrolimus

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 16.04.2021

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Definition
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Macrolide belonging to the group of calcineurin inhibitors, which is produced by the fungus Streptomyces tsukubaensis and is used as a systemic and topical immunosuppressive agent.

Pharmacodynamics (Effect)
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Tacrolimus inhibits the initial T-cell activation, the differentiation and proliferation of cytotoxic T-cells as well as specifically the expression of E-selectin (adhesion molecule on endothelial cells).

Applied topically, Tacrolimus binds to the cytoplasmic FK 506 binding protein-12 on the T-cell and thereby blocks the activity of the phosphatase calcineurin. Reduced activity of calcineurin inhibits the expression of the transcription factor NFAT (nuclear factor of activated T-cells), the proinflammatory cytokines IL-2, -3, -4 and -5, GM-CSF and interferon gamma.

Indication
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Systemic: prevention of rejection reactions after organ transplantation; for the treatment of autoimmune diseases, severe forms of psoriasis vulgaris and psoriatic arthritis.

Topical: moderate to severe atopic eczema, see under Eczema, atopic.

Non-approved topical indications (off-label use) for which well-documented experience reports are now available are seborrheic eczema, disseminated granuloma anulare, lichen planus (especially lichen planus mucosae), pyoderma gangraenosum, lupus erythematosus tumidus, REM syndrome, scarring pemphigoid, steroid rosacea.

Limited indication
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Systemic: pregnancy (risk of spina bifida).

Dosage and method of use
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  • Systemic: 0,1-0,2 mg/day/kg bw p.o. distributed over 2 single doses.

    Remember! Under the immunosuppression with Tacrolimus the ventricular wall and septum can thicken. Under therapy regular echocardiographic examinations are necessary. In women of childbearing age a pregnancy should be excluded before therapy and an effective contraception should be carried out under therapy!

  • Topical: 0.03% for children aged 2-16 years. 0.1% for adults/teenagers aged 16 years and older. The first three weeks: Apply thinly 2 times/day to the affected areas. From the 4th week: Apply thinly once/day to the eczema areas.

Undesirable effects
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Topical: Local irritation and burning, especially during the first two days of treatment. See table 1.

Interactions
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See Table 2.

Contraindication
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Systemic: Allergy to tacrolimus, pregnancy and lactation.

Topical: Known allergy to macrolides or other ingredients of the preparation Protopic. Pregnancy, lactation, Netherton syndrome, erythroderma. Bacterial, viral or mycotic infections of the skin (e.g. pyoderma, varicella, herpes simplex). Restraint with regard to dosage in liver diseases. Caution! Avoid UV exposure during ongoing therapy.

Recipe(s)
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  • To "stretch" finished dermatics with other vehicle systems is a practiced dermatological practice to achieve price advantages. This calculation mechanism however has to take into account the "auxiliary tax for pharmacies" according to which prescriptions have to be calculated. In case of a ready-to-use dermatological product the required package is not calculated grammatically but by the respective pack!
  • A standardized formulation is given in the new formulation form (NRF): Protopic ointment 0.1% (1 or 2 parts) + Lanette N 1 part/Aqua conservans 7 parts (1 part). The following formulation is a stable alternative not listed in the NRF: Protopic ointment 0,1% (1 part = 30,0 g) + low density polyethylene 2,5 + viscous paraffin ad 50,0 (vehicle type = lipophilic gel).

Preparations
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Prograf®, Protopic® 0.03% and 0.1%

Note(s)
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  • Remark. Caution is advised in case of long-term application as an increased local carcinoma risk has been proven in animal experiments.

  • Since 2006 the US-American product information carries a specially highlighted warning (black box) in which the lack of knowledge about the long-term safety of the agents with regard to the development of skin cancer and lymphoma is explicitly pointed out. See also Pimecrolimus.
  • After the market launch of the drugs, the occurrence of lymphoma was observed in patients treated topically with calcineurin inhibitors and glucocorticoids. However, this could not be confirmed in a subsequent study.
  • Several case reports have already reported on the successful use of Tacrolimus for the antipruritic therapy in diseases as lichen sclerosus et atrophicus, chronic hand eczema, scrotal eczema and graft-versus-host-disease.
  • Also in the case of psoriasis inversa, clinical improvements have been shown in individual cases after topical application of tacrolimus ( off-label use) (see below calcineurin inhibitors).
  • With Pimecrolimus, a Tacrolimus derivative, another lipophilic, immunosuppressive macrolactam derivative from the group of calcineurin inhibitors (see also Ciclosporin A) is approved for topical application.

Literature
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  1. Arellano FM et al (2006) Risk of Lymphoma Following Exposure to Calcineurin Inhibitors and Topical Steroids in Patients with Atopic Dermatitis. J Invest Dermatol (epub)
  2. Bohm M (2003) Successful treatment of anogenital lichen sclerosus with topical tacrolimus. Arch Dermatol 139: 922-924
  3. Braza TJ et al (2003) Tacrolimus 0.1% ointment for seborrhoic dermatitis: an open-label pilot study. Br J Dermatol 148:1242-1244
  4. Clayton TH et al (2003) Topical tacrolimus for facial psoriasis. Br J Dermatol 149: 419-420
  5. Drake L, Prendergast M, Maher R et al (2001) The impact of tacrolimus ointment on health-related quality of life of adults and pediatric patients with atopic dermatitis. J Am Acad Dermatol 44: 65-72
  6. Freeman AK et al (2003) Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol 48: 564-568
  7. Goldman D (2001) Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report. J Am Acad Dermatol 44: 995-998
  8. Kain S, Stephens CJ (2003) Successfull treatment of disseminated granuloma anulare with topical tacrolimus. Br J Dermatol 149(Suppl 64): 24
  9. Kunstfeld R (2003) Successful treatment of vulvar lichen sclerosus with topical tacrolimus. Arch Dermatol 139: 850-852
  10. Liu J Albers MW, Wandless TH et al (1992) Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry 31: 3896-3901
  11. Meshkinpour A (2003) An open pilot study using tacrolimus ointment in the treatment of seborrheic dermatitis. J Am Acad Dermatol 49: 145-147
  12. Niwa Y et al (2003) Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. Br J Dermatol 149: 960-967
  13. Plettenberg H et al (2003) Childhood vitiligo and tacrolimus: immunomodulating treatment for an autoimmune disease. Arch Dermatol 139: 651-654
  14. Ruzicka T et al (1997) A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. New Engl J Med 337: 816-821
  15. Schroer B, Lockey R (2003) Oral tacrolimus for severe recalcitrant atopic eczema. J Allergy Clin Immunol 111: 1409-1410
  16. Ständer S et al (2006) Diagnostic and therapeutic procedures in chronic pruritis. J Dtsch Dermatol Ges 4: 350-370
  17. Soter NA et al (2001) Tacrolimus ointment for the treatment of atopic dermatitis in adult patients. J Am Acad Dermatol 44: 39-46
  18. Ständer S et al (2003) Antipruritic effects of pimecrolimus and tacrolimus. dermatologist 54: 413-417
  19. Tanghetti EA (2003) Tacrolimus ointment 0.1% produces repigmentation in patients with vitiligo: results of a prospective patient series. Cutis 71: 158-162
  20. Travis LB (2003) Successful treatment of vitiligo with 0.1% tacrolimus ointment. Arch Dermatol 139: 571-574
  21. Wohlrab J (2006) Calcineurin inhibitors for the topical therapy of psoriasis. dermatologist 57: 685-689
  22. Wolf G (2008) Recipe tip: Stability of Tacrolimus in different vehicle systems. dermatologist 59: 678-679
  23. Yamamoto T et al (2003) Deep dermatophytosis during topical tacrolimus therapy for psoriasis. Acta Derm Venereol 83: 291-292

Tables
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Essential side effects of Tacrolimus

Organ System

Side effects (UAW)

Airways

bronchial asthma, bronchospasm, dyspnoea, atelectasis, pulmonary oedema, pleural effusion, rhinitis, sinusitis

Blood Lymph

anaemia (haemolytic or aplastic anaemia), blood formation disorders, blood coagulation disorders, thrombocytopenia, pancytopenia, leucopenia, leucocytosis, eosinophilia, splenomegaly, non-Hodgkin's lymphomas

GIT

Abdominal pain, gastrointestinal disorders, eosinophilic enteritis, cholestasis, hepatitis, increase in AP, transaminases, bilirubin

Urinary tract

Haematuria, oliguria, anuria, renal dysfunction, hydronephrosis, urea and creatinine increase, acute renal failure

Skin

abscesses, herpes simplex, ecchymosis, hirsutism, hyperhidrosis, alopecia, photosensitization, pruritus, exanthema, epidermolysis, Lyell syndrome, anaphylactic reactions, erythema nodosum, spinocellular carcinoma, thrombocytopenic purpura

Cardiovascular

Hypertension, edema, tachycardia, cardiac arrhythmia, hypertrophic cardiomyopathy

Nervous System

Anxiety, depression, psychosis, aphasia, encephalopathy, seizures, tremor, neuropathy, myasthenia, headache, quadriplegia, apoplexy

Sensory Organs

Amblyopia, cataract, visual disturbances, glaucoma, conjunctivitis, dizziness, tinnitus, deafness

Metabolism, Endocrine

Alkalosis, acidosis, electrolyte disorders, desiccosis, diabetes mellitus, glucose tolerance disorder, gout attack, gynecomastia

Support apparatus

Arthralgia, myalgia, muscle spasms, osteoporosis, rhabdomyolysis, aseptic bone necrosis

System reactions

fever, chills, sepsis


Essential interactions of Tacrolimus

Aciclovir

CNS toxicity ↑

Aminoglycosides

Renal damage

Amoxicillin

Tacrolimus mirror ↑

amphotericin B

Renal damage

Ciclosporin A

Renal damage

Cisplatin

Renal damage

Clarithromycin

Tacrolimus mirror ↑

Clotrimazole

Tacrolimus mirror ↑

Danazol

Tacrolimus mirror ↑

diuretics, potassium-sparing

Hyperkalemia ↑, avoid combination

Erythromycin

Renal damage

Fluconazole

Renal damage

Ganciclovir

CNS toxicity ↑

Ibuprofen

Renal damage

Imipenem

Tacrolimus mirror ↓

Potassium preparations

Hyperkalemia ↑, avoid combination

Ketoconazole

Renal damage

Live virus vaccines

Avoid combination

Methylprednisolone

Tacrolimus mirror ↑

Rifampicin

Tacrolimus mirror ↓

Authors

Last updated on: 16.04.2021