Tacrolimus
Encyclopedia
Tacrolimus is an immunosuppressive
drug
that is mainly used 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 atopic dermatitis
(eczema
), severe refractory uveitis
after bone marrow
transplants, exacerbations of minimal change disease
, and the skin condition vitiligo
.
It is a 23-membered macrolide
lactone
discovered in 1984 from the fermentation broth of a Japan
ese soil
sample that contained the bacteria
Streptomyces tsukubaensis
. It reduces interleukin-2 (IL-2) production by T-cells.
, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis. The name tacrolimus is derived from 'Tsukuba
macrolide immunosuppressant'.
Tacrolimus 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.
, and is sold under the trade names Prograf given twice daily, Advagraf, a sustained release formulation allowing once daily dosing, and Protopic (Eczemus in Pakistan by Brookes Pharma), the topical formulation.
Advagraf is available in 0.5, 1, 3 and 5 mg capsules, the ointment is concentrations of 0.1% and 0.03%.
A second once-daily formulation of tacrolimus is in Phase 3 clinical trials in the U.S. and Europe. This formulation also has a smoother pharmacokinetic profile that reduces the peak-to-trough range in blood levels compared to twice-daily tacrolimus. Data from the first Phase 3 trial in stable kidney transplant patients showed that this once-daily formulation was non-inferior in efficacy and safety compared to twice-daily tacrolimus. A second Phase 3 trial in de novo patients is ongoing.
thus inhibiting both T-lymphocyte
signal transduction and IL-2 transcription. Although this activity is similar to ciclosporin
, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin. 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.
. Dosages are titrated to target blood levels. Typical starting doses for once daily tacrolimus are 0.15-0.20 mg/kg.
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.
, 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.
, particularly atopic dermatitis
. It suppresses inflammation in a similar way to steroid
s, 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 is applied on the active lesions until they heal off, but may also be used continuously in low doses (twice a week), and applied to the thinner skin over the face and eyelids. Clinical trials of up to one year have been conducted. Recently it has also been used to treat segmental vitiligo
in children, especially in areas on the face.
, blurred vision, liver and kidney
problems (tacrolimus nephrotoxicity
), hyperkalemia
, hypomagnesemia
, hyperglycemia
, diabetes mellitus
, itch
ing, lung damage (sirolimus
also causes lung damage), and various neuropsychiatric problems such as loss of appetite, insomnia
, Posterior reversible encephalopathy syndrome
, confusion, weakness, depression, cramps, neuropathy, seizure
s, tremor
s, and catatonia
.
In addition it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma
viral infections.
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/).
) 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.
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that is mainly used after allogeneic organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
to reduce the activity of the patient's immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
and so lower the risk of organ rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. It is also used in a topical preparation in the treatment of atopic dermatitis
Atopic dermatitis
Atopic dermatitis is an inflammatory, chronically relapsing, non-contagious and pruritic skin disorder...
(eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
), severe refractory uveitis
Uveitis
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
after bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
transplants, exacerbations of minimal change disease
Minimal change disease
Minimal Change Disease is a disease of the kidney that causes nephrotic syndrome and usually affects children .-Epidemiology:...
, and the skin condition vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
.
It is a 23-membered macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
discovered in 1984 from the fermentation broth of a Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
ese soil
Soil
Soil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics...
sample that contained the bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
Streptomyces tsukubaensis
Streptomyces tsukubaensis
Streptomyces tsukubaensis is a species of actinobacteria. It produces the immunosuppressive drug tacrolimus....
. It reduces interleukin-2 (IL-2) production by T-cells.
History
Tacrolimus was discovered in 1984; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975. Like ciclosporinCiclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis. The name tacrolimus is derived from 'Tsukuba
Tsukuba, Ibaraki
is a city located in Ibaraki Prefecture, Japan. It is known as the location of the , a planned city developed in the 1960s.As of 2008, the city has an estimated population of 207,394 and a population density of 730 persons per km². Its total area is 284.07 km².Mount Tsukuba, particularly well-known...
macrolide immunosuppressant'.
Tacrolimus was first approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in 1994 for use in liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.
Availability
The branded version of the drug is owned by Astellas PharmaAstellas Pharma
is a Japanese pharmaceutical company, formed on 1 April 2005 from the merger of and .Astellas' franchise areas are urology, immunology , dermatology, cardiology, and infectious disease...
, and is sold under the trade names Prograf given twice daily, Advagraf, a sustained release formulation allowing once daily dosing, and Protopic (Eczemus in Pakistan by Brookes Pharma), the topical formulation.
Advagraf is available in 0.5, 1, 3 and 5 mg capsules, the ointment is concentrations of 0.1% and 0.03%.
A second once-daily formulation of tacrolimus is in Phase 3 clinical trials in the U.S. and Europe. This formulation also has a smoother pharmacokinetic profile that reduces the peak-to-trough range in blood levels compared to twice-daily tacrolimus. Data from the first Phase 3 trial in stable kidney transplant patients showed that this once-daily formulation was non-inferior in efficacy and safety compared to twice-daily tacrolimus. A second Phase 3 trial in de novo patients is ongoing.
Pharmacology
Tacrolimus is chemically known as a macrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT. In detail, Tacrolimus 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 calcineurinCalcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
thus inhibiting both T-lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
signal transduction and IL-2 transcription. Although this activity is similar to ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin. 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.
Immunosuppression following transplantation
It has similar immunosuppressive properties to ciclosporin, but is much more potent. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with ciclosporin-based immunosuppression (30.7% vs 46.4%) in one study. Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation. Long term outcome has not been improved to the same extent. Tacrolimus is normally prescribed as part of a post-transplant cocktail including steroids, mycophenolate and IL-2 receptor inhibitorsBasiliximab
Basiliximab is a chimeric mouse-human monoclonal antibody to the α chain of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants...
. Dosages are titrated to target blood levels. Typical starting doses for once daily tacrolimus are 0.15-0.20 mg/kg.
Interactions
Also like ciclosporin it has a wide range of interactions, including that with grapefruitGrapefruit
The grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
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.
Ulcerative colitis
In recent years, Tacrolimus has been used to suppress the inflammation associated with ulcerative colitisUlcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
, a form of inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
. Although almost exclusively used in trial cases only, Tacrolimus has shown to be significantly effective in the suppression of outbreaks of UC.
Dermatological use
As an ointment (Protopic), tacrolimus is used in the treatment of eczemaEczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
, particularly atopic dermatitis
Atopic dermatitis
Atopic dermatitis is an inflammatory, chronically relapsing, non-contagious and pruritic skin disorder...
. It suppresses inflammation in a similar way to steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s, 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
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
), or other steroid related side-effects.
It is applied on the active lesions until they heal off, but may also be used continuously in low doses (twice a week), and applied to the thinner skin over the face and eyelids. Clinical trials of up to one year have been conducted. Recently it has also been used to treat segmental vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
in children, especially in areas on the face.
From oral and intravenous administration
Side effects can be severe and include infection, cardiac damage, hypertensionHypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, blurred vision, liver and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
problems (tacrolimus nephrotoxicity
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
), hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
, hypomagnesemia
Hypomagnesemia
Hypomagnesemia is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood. Usually a serum level less than 0.7 mmol/L is used as reference. The prefix hypo- means low . The middle 'magnes' refers to magnesium...
, hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
, diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, itch
Itch
Itch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
ing, lung damage (sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
also causes lung damage), and various neuropsychiatric problems such as loss of appetite, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, Posterior reversible encephalopathy syndrome
Posterior reversible encephalopathy syndrome
Posterior reversible encephalopathy syndrome , also known as reversible posterior leukoencephalopathy syndrome , is a syndrome characterised by headache, confusion, seizures and visual loss. It may occur due to a number of causes, predominantly malignant hypertension, eclampsia and some medical...
, confusion, weakness, depression, cramps, neuropathy, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
s, and catatonia
Catatonia
Catatonia is a state of neurogenic motor immobility, and behavioral abnormality manifested by stupor. It was first described in 1874: Die Katatonie oder das Spannungsirresein ....
.
In addition it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma
Polyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...
viral infections.
Carcinogenesis and mutagenesis
In people receiving immunosuppressants to reduce transplant graft rejection, an increase risk of malignancy is a recognised complication. The commonest cancers are non-Hodgkin's lymphoma and skin cancers. The risk appears to be related to the intensity and duration of treatment.From topical use
The most common adverse events associated with the use of Protopic, especially if used over a wide area, include a burning or itching sensation on the initial applications. Less common are flu-like symptoms, headache and cough and burning eyes.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/).
Cancer risks
Tacrolimus and a related drug for eczema (pimecrolimusPimecrolimus
Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis . It is currently available as a topical cream, once marketed by Novartis under the trade name Elidel.-Pharmacology:Pimecrolimus is an ascomycin macrolactam derivative...
) 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
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.
Contraindications and precautions
- Breast-feeding
- Hepatic disease
- Immunosuppression
- InfantInfantA newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
s - InfectionInfectionAn infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
- Intravenous administration
- Neoplastic disease, such as:
- Skin cancerSkin cancerSkin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
- Lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
- Skin cancer
- Occlusive dressing
- OliguriaOliguriaOliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
- PregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
- QT prolongation
- SunlightSunlightSunlight, in the broad sense, is the total frequency spectrum of electromagnetic radiation given off by the Sun. On Earth, sunlight is filtered through the Earth's atmosphere, and solar radiation is obvious as daylight when the Sun is above the horizon.When the direct solar radiation is not blocked...
(UV) exposure - GrapefruitGrapefruitThe grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
juice
External links
- Tacrolimus levels in Liver Transplants-Indian Study by Dr.Pradeep Naik,Dr.Dharmesh Kapoor, Dr.DCS Reddy
- Prograf prescribing information at Fujisawa
- Pimecrolimus (Elidel Cream) FDA adivisory page (for eczema treatment)
- Tacrolimus (FK506) product page from FermentekFermentekFermentek Ltd. is a biotechnological company, located in Atarot industrial zone, Jerusalem, Israel, specializing in the research, development and manufacture of biologically active, natural products isolated from microorganisms as well as from other natural sources such as plants and algae.The main...
- U.S. National Library of Medicine: Drug Information Portal - Tacrolimus