Tacrolimus

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Key Terms: Intravenous line, Lymphatic system.

Definition

Tacrolimus belongs to a group of medicines known as immunosuppressive agents. It is used primarily to lower the body's natural immunity in order to prevent the rejection of organ transplants and to prevent graft-versus-host disease. Tacrolimus is also known as Prograf and FK506.

Purpose

Tacrolimus first saw use in transplant patients. By suppressing the activity of the immune system, tacrolimus makes it more likely that the recipient of a transplanted organ will accept that organ. It is especially used for kidney transplants.

In the fight against leukemia, grafts of stem cells from donors are sometimes given to the patient to encourage the blood of a recipient to begin production of normal cells. Tacrolimus may be given during the graft process because it seems to make the patient more receptive to the donated stem cells.

Description

Tacrolimus somehow suppresses, or prevents activity of, the cells in the lymphatic system, which are known as T cells. Under normal circumstances T cells mount an immune response to foreign materials in the body. However, during a transplant, T cells can cause the reaction that can lead to the rejection of a donor organ. The exact reason for the activity of tacrolimus is not understood.

Recommended Dosage

Given by mouth, in a capsule, or by intravenous line, tacrolimus doses range from about 0.03 milligrams to 0.05 milligrams per kilogram (1 kilogram equals approximately 2.2 pounds) of body weight per day. Individuals with liver or kidney problems must be given a lower dose.

Precautions

Tacrolimus should be taken without food and long after a meal. If there is food in the stomach it will interfere with the way the drug makes its way into the body. Grapefruit juice can increase the activity of tacrolimus and should be avoided.

Side Effects

Many serious side effects are associated with tacrolimus. Conditions affecting the brain brought on by the use of tacrolimus include coma (unconscious state) and delirium (uncontrolled and erratic conscious state). Most times the brain conditions are reversible. Headache, skin rashes, hair loss (alopecia), pain, sensitivity to light and shock (anaphylaxis) are all side effects. Kidney damage, which cannot be reversed, is also a danger.

Use of tacrolimus greatly increases the likelihood a person will get skin cancer and lymphoma. Anyone using the drug should be monitored closely for changes in the skin, and all normal precautions for avoiding skin cancer, such as avoiding direct exposure to ultraviolet light, should be taken.

Interactions

This drug interacts with a long list of other drugs. It is important to tell the physician in charge of the care plan, each and every drug being taken, so that interactions can be avoided. Tacrolimus prevents effective vaccination, and vaccinations should not be given while the drug is in use.

—Diane M. Calabrese

trade name: Prograf; drug class: immunosuppressant; action: inhibits T-lymphocyte activation leading to immunosuppression; use: prophylaxis of organ rejection in patients receiving allogenic liver transplants.

Brand names: Prograf®Protopic®

Chemical formula:

Drug Forms:
• Tacrolimus capsules (below)
• Tacrolimus Oral capsule
• Tacrolimus Solution for injection
• Tacrolimus Topical ointment

Español:
• Cápsulas de tacrolimo
• Tacrolimo, Cápsula oral
• Tacrolimo, Solución para inyección
• Tacrolimo, Pomada tópica

Tacrolimus capsules

What are tacrolimus capsules?

TACROLIMUS (Prograf®) is a medication used to decrease the immune system response. Tacrolimus is used to reduce immune responses and prevent rejection in patients who receive organ or bone marrow transplants. Tacrolimus may be used to treat other conditions such as dermatitis, eczema, or psoriasis. Generic tacrolimus capsules are not yet available.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• diabetes
• heart disease or heart failure
• high blood pressure
• infection
• kidney disease
• an unusual or allergic reaction to tacrolimus, castor oil, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I take this medicine?

Take tacrolimus capsules by mouth. Follow the directions on the prescription label. Swallow the capsules with a drink of water. Take with food or milk or take at bedtime to reduce stomach upset. Do not take with grapefruit juice. Taking tacrolimus with food can decrease the amount absorbed, but if you take every dose in the same way this will be acceptable. Take your doses at regular intervals. Do not take your medicine more often than directed.

What drug(s) may interact with tacrolimus capsules?

• aluminum hydroxide
• amiodarone
• bosentan
• bromocriptine
• certain medicines for HIV-infection such as protease inhibitors
• cimetidine
• corticosteroids
• cyclosporine
• diltiazem
• entecavir
• erythromycin
• grapefruit juice
• medicines for diabetes
• medicines for fungal infections
• medicines for seizures
• medicines to control the heart rhythm
• metoclopramide
• pamidronate
• rifabutin
• rifampin
• St. John's wort
• theophylline or aminophylline
• vaccines
• verapamil
• water pills (diuretics)
• ziprasidone
• zoledronic acid

Talk to your prescriber or health care professional before taking any of these medicines:
• aspirin
• acetaminophen
• ibuprofen
• ketoprofen
• naproxen

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking tacrolimus capsules?

Tacrolimus is a strong medication and can produce serious side effects. Discuss the potential risks and benefits with your prescriber or health care professional before you begin taking tacrolimus. Visit your prescriber or health care professional for regular checks on your progress. You will need to have laboratory tests to monitor your therapy with tacrolimus.

After you stop taking this medication, side effects can continue. Some side effects may not occur until years after the medicine was taken. These effects can include the development of certain types of cancer. Discuss this possibility with your prescriber or health care professional.

Tacrolimus will decrease your body's ability to fight infections. Call your prescriber or health care professional if you have a fever, chills, sore throat or other symptoms of a cold or flu. Do not treat these symptoms yourself. Try to avoid being around people who are sick. Do not have any vaccinations without your prescriber's approval. Avoid people who have recently received the oral polio vaccine.

Your blood sugar may increase while you are taking tacrolimus. Call your prescriber or health care professional for advice if you have any of the following symptoms: increased thirst, dry mouth, pass urine frequently, notice a fruity odor on your breath, or feel tired and lose your appetite.

Avoid taking aspirin, acetaminophen (Tylenol®), ibuprofen (Advil®), ketoprofen (Orudis KT®), or naproxen (Aleve®) products as these may mask a fever, unless instructed to by your prescriber or health care professional.

What side effects may I notice from taking tacrolimus capsules?

Tacrolimus therapy can produce many side effects. These mainly affect the urinary system and the nervous system. Contact your prescriber or health care professional about any unusual effects. Side effects that you should report to your prescriber or health care professional as soon as possible:
• signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
• signs of decreased red blood cells - unusual weakness or tiredness, fainting spells, lightheadedness
• blurred vision, increased sensitivity of the eyes to light
• burning or tingling in the hands or feet
• difficulty breathing, wheezing
• frequent urination
• increased thirst or hunger
• ringing in the ears
• skin rash or itching (hives)
• seizures (convulsions)
• stomach, back or general pain
• swelling of the feet or legs, unusual or sudden weight gain
• yellowing of skin or eyes

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• diarrhea or constipation
• difficulty sleeping, nightmares
• dizziness or drowsiness
• hair loss or unusual hair growth
• headache
• loss of appetite
• mood changes, depression, confusion
• muscle cramps
• nausea, vomiting
• tremor
• unusual sensitivity to touch

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open. Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Throw away any unused medicine after the expiration date.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

An immunosuppressive agent derived from Streptomyces tsukabaensis. It selectively binds FK-binding proteins and the complex inhibits calcineurin.

Tacrolimus
Systematic (IUPAC) name
3S-[3R*[E(1S*,3S*,4S*)] ,4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a -hexadecahydro-5, 19-dihydroxy -3-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14,16-dimethoxy -4,10,12,18-tetramethyl-8-(2-propenyl) -15,19-epoxy-3H-pyrido[2,1-c] [1,4] oxaazacyclotricosine-1,7,20,21(4H,23H) -tetrone, monohydrate
Identifiers
CAS number	104987-11-3
ATC code	L04AD02 D11AX14
PubChem	656830
DrugBank	APRD00276
ChemSpider	4976056
Chemical data
Formula	C44H69NO12
Mol. mass	804.018 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	20%, less after eating food rich in fat
Protein binding	75-99%
Metabolism	Hepatic CYP3A4
Half life	11.3 hours (range 3.5-40.6 hours)
Excretion	Mostly faecal
Therapeutic considerations
Pregnancy cat.	A
Legal status
Routes	Topical, oral, iv

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.

Contents 1 History 2 Pharmacology 3 Indications 3.1 Immunosuppression following transplantation 3.2 Use in treating ulcerative colitis 3.3 Dermatological use 4 Contraindications and precautions 5 Side effects 5.1 From oral and intravenous administration 5.2 From topical use 5.3 Cancer risks 6 References 7 External links

History

Tacrolimus was discovered in 1984 by a Japanese team headed by T. Goto, T. Kino and H. Hatanaka; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.^[1] Like cyclosporin, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis.^[2] The name tacrolimus is derived from 'Tsukuba macrolide immunosuppressant'.^[3]

The drug is owned by Astellas Pharma Inc., and is sold under the tradenames Prograf, Advagraf, and Protopic. It is sometimes referred to as FK-506 (Fermentek catalogue number 506). It was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.

Pharmacology

Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.^[4] Although this activity is similar to cyclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporin.^[5] Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival.^[6]

Indications

Immunosuppression following transplantation

It has similar immunosuppressive properties to cyclosporin, but is much more potent in equal volumes. Also like cyclosporin it has a wide range of adverse interactions, including that with grapefruit which increases plasma-tacrolimus concentration. Several of the newer class of antifungals, especially of the azole class (fluconazole, posaconazole) also increase drug levels by competing for degradative enzymes. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with cyclosporin-based immunosuppression (30.7% vs 46.4%) in one study.^[5] Clinical outcome is better with tacrolimus than with emulsified cyclosporin during the first year of liver transplantation.^[7]

Use in treating ulcerative colitis

In recent years, Tacrolimus has been used to suppress the inflammation associated with ulcerative colitis, a form of inflammatory bowel disease. Although almost exclusively used in trial cases only, Tacrolimus has shown to be significantly effective in the suppression of outbreaks of UC.^[8][9]

Dermatological use

See also: Immunomodulators in the treatment of eczema

As an ointment (Protopic), tacrolimus is a recent addition in the treatment of eczema, particularly atopic dermatitis. It suppresses inflammation in a similar way to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that unlike steroids, it does not cause skin thinning (atrophy), or other steroid related side-effects. It may therefore be used continuously on the body (clinical trials of up to one year in length have occurred), and applied to the thinner skin over the face and eyelids^{[citation needed]}. Recently it has also been used to treat segmental vitiligo in children,especially on the face.^[10]

The most common adverse events associated with the use of Protopic included the sensation of skin burning, itching, flu-like symptoms, and headache. The use of Protopic should be avoided on known or suspected malignant lesions. The use of Protopic on patients with Netherton's syndrome or similar skin diseases is not recommended. Patients should minimize or avoid natural or artificial sunlight exposure. Skin infections should be cleared prior to application, and there may be an increased risk of certain skin infections. Protopic should not be used with occlusive dressings (http://www.protopic.com/).

Contraindications and precautions

• breast-feeding
• hepatic disease
• immunosuppression
• infants
• infection
• intravenous administration
• neoplastic disease, such as:
  • skin cancer
  • lung cancer
• occlusive dressing
• oliguria
• pregnancy
• QT prolongation

• sunlight (UV) exposure
• grapefruit juice^[11]

Side effects

From oral and intravenous administration

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion, loss of appetite, hyperglycemia, weakness, depression, cramps, and neuropathy, as well as potentially increasing the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections.

From topical use

A common side effect of tacrolimus ointment, if used over a wide area, is to cause a burning or itching sensation on the first one or two applications. Less common side effects include flu-like symptoms, headache, cough and burning eyes.^[12]

Cancer risks

Further information: Eczema#Immunomodulators

Tacrolimus and a related drug for eczema (pimecrolimus) were suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the drug, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. However, current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.^[13]

Dermatologists agree that the drug should be used as a second-line remedy only after conventional methods of treatment have failed.^{[citation needed]}

References

1. ^ Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1987). "FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics.". J Antibiot (Tokyo) 40 (9): 1249–55. PMID 2445721. 
2. ^ Pritchard D (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens.". Drug Discov Today 10 (10): 688–91. doi:10.1016/S1359-6446(05)03395-7. PMID 15896681.  Supports source organism, but not team information
3. ^ Ponner, B, Cvach, B (Fujisawa Pharmaceutical Co.): Protopic Update 2005
4. ^ Liu J, Farmer J, Lane W, Friedman J, Weissman I, Schreiber S (1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.". Cell 66 (4): 807–15. doi:10.1016/0092-8674(91)90124-H. PMID 1715244. 
5. ^ ^{a b} McCauley, Jerry (2004-05-19). "Long-Term Graft Survival In Kidney Transplant Recipients". Slide Set Series on Analyses of Immunosuppressive Therapies. Medscape. http://www.medscape.com/viewarticle/474429. Retrieved on 2006-06-06. 
6. ^ M.M. Abou-Jaoude, R. Naim, J. Shaheen, N. Naufal, S. Abboud, M. AlHabash, M. Darwish, A. Mulhem, A. Ojjeh, and W.Y. Almawi (2005). "Tacrolimus (FK506) versus cyclosporin microemulsion (Neoral) as maintenance immunosuppresion therapy in kidney transplant recipients.". Transplantation Proceedings 37: 3025–3028. doi:10.1016/j.transproceed.2005.08.040. 
7. ^ J.G. O'Grady, A. Burroughs, P. Hardy, D. Elbourne, A. Truesdale, and The UK and Ireland Liver Transplant Study Group (2002). "Tacrolimus versus emulsified cyclosporin in liver transplantation: the TMC randomised controlled trial.". Lancet 360: 1119–1125. doi:10.1016/S0140-6736(02)11196-2. 
8. ^ Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU (2006). "Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up.". Am J Gastroenterol 101: 1048-1056. doi:10.1111/j.1572-0241.2006.00524.x. PMID 16573777. 
9. ^ Baumgart DC, MacDonald JK, Feagan BG (2008). "Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis.". Cochrane Database Syst Rev 16: CD007216. doi:10.1002/14651858.CD007216. PMID 18646177. 
10. ^ Nanette B. Silverberg, Peggy Lin, Lisa Travis, Jeanne Farley-Li, Anthony J. Mancini, Annette M. Wagner, Sarah L. Chamlin and Amy S. Paller(Nov.2004)."Tacrolimus ointment promotes repigmentation of vitiligo in children: A review of 57 cases". Journal of the American Academy of Dermatology, Volume 51, Issue 5,Pages 760-766.
11. ^ Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K (2006). "Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient". Drug Metab Pharmacokinet 21 (2): 122–5. doi:10.2133/dmpk.21.122. PMID 16702731. 
12. ^ Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ; US Tacrolimus Ointment Study Group (2005). "Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis". J Am Acad Derm 53 (2 suppl 2): S186–94. doi:10.1016/j.jaad.2005.04.062. PMID 16021174. 
13. ^ N H Cox and Catherine H Smith (December 2002). "Advice to dermatologists re topical tacrolimus" (DOC). Therapy Guidelines Committee. British Association of Dermatologists. http://www.bad.org.uk/healthcare/guidelines/Advice_re_topical_tacrolimus.doc. 

External links

• Prograf prescribing information at Fujisawa
• Tacrolimus (Protopic Cream) FDA advisory page (for eczema treatment)
• Pimecrolimus (Elidel Cream) FDA adivisory page (for eczema treatment)
• Offers more information on possible cancer risks of Protopic (Tacrolimus)
• Tacrolimus (FK506) product page from Fermentek

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