Fujimycin/ FK-506/Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after an 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 tacrolimus is a macrolide 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.
Synonyms
- Anhydrous tacrolimus
- Tacrolimus
- Tacrolimus anhydrous
- Tacrolimus, anhydrous
Mechanism of Action of Tacrolimus
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 the 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 of genes that 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.
or
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 the 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.
Indications of Tacrolimus
- For use after an allogeneic organ transplant to reduce the activity of the patient’s immune system and so the risk of organ rejection. It was given FDA approval in 1994 for use in liver transplantation. Since then, this indication has expanded to kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.
- 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.
- Immunosuppressant; dermatological treatment of atopic eczema
- Treatment of vernal keratoconjunctivitis
- 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.
- Graft Versus Host Disease (GVHD)
- Heart Transplant Rejection
- Kidney Transplant Rejection
- Liver Transplant Rejection
- Oral Lichen Planus
- Psoriasis
- Pyoderma Gangrenosum
- Rheumatoid Arthritis
- Severe Atopic Dermatitis
- Vitiligo
- Moderate Atopic dermatitis
- Refractory Atopic dermatitis
- Refractory Rheumatoid arthritis
- Severe Rheumatoid arthritis
- Organ Transplant, Rejection Prophylaxis
- Organ Transplant, Rejection Reversal
- Crohn’s Disease
- Graft-versus-host disease
- Nephrotic Syndrome
- Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants; use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF)
Therapeutic Uses of Tacrolimus
- Immunosuppressive Agents
- 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.
- 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.
- 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.
- Protopic Ointment, both 0.03% and 0.1% for adults, and only 0.03% for children aged 2 to 15 years, is indicated as second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.
- Tacrolimus has been used in the management of fistulizing Crohn’s disease. Administration of oral tacrolimus has been effective for fistula improvement, but not for fistula remission in patients with perianal Crohn’s disease.
- Sandoz Tacrolimus (tacrolimus immediate release capsule) is indicated for: Treatment of active rheumatoid arthritis in adult patients for whom disease modifying anti-rheumatic drug (DMARD) therapy is ineffective or inappropriate.
- Tacrolimus has been shown to be effective in the treatment of psoriasis when used orally or topically. Drug Reference. 36th ed. London: The Pharmaceutical Press, 2009., p. 1848
- Tacrolimus has been reported to be effective in the management of myasthenia gravis in patients resistant to conventional therapy, or for whom standard therapy is contraindicated. here are reports of response to tacrolimus in patients with inflammatory bowel disease.
- In auto-immune chronic active hepatitis, some evidence suggests that tacrolimus may offer an alternative therapy when corticosteroids alone or with azathioprine do not suffice.
- Tacrolimus has been reported to be effective in inducing remission in patients with glomerular kidney disease; it has been used as monotherapy from the first presentation, as well as in patients refractory to standard therapy, and in those with the corticosteroid-dependent disease.
Contraindications of Tacrolimus
Contraindications and precautions include
- Breast-feeding
- Hepatic disease
- Immunosuppression
- Neoplastic disease
- Skin cancer
- Lung cancer
- Oliguria
- Pregnancy
- QT interval prolongation
- Sunlight (UV) exposure
- Grapefruit juice
- Skin Condition caused by Herpes Simplex Virus
- a herpes simplex infection
- a reduction in the body’s resistance to infection
- syndrome from birth with main symptom of scaly skin
- swollen lymph nodes
- malignant lymphoma
- low amount of potassium in the blood
- high blood pressure
- torsades de pointes
- a type of abnormal heart rhythm
- slow heartbeat
- prolonged QT interval on EKG
- chronic heart failure
- abnormal EKG with QT changes from birth
- severe liver disease
- damage to the kidneys
- delirium
- disorder of lymphoid tissue after transplant
- pregnancy
- malignant lymphoma
- a rupture in the wall of the stomach or intestine
- progressive multifocal leukoencephalopathy
- a type of brain infection
- a type of brain disorder called posterior reversible encephalopathy syndrome
- kidney problems due to BK polyomavirus
- pure red cell aplasia
Topical use
- Occlusive dressing
- Known or suspected malignant lesions
- Netherton’s syndrome or similar skin diseases
- Certain skin infections
Dosage of Tacrolimus
Strengths: 0.1%; 0.03% for tropical and 0.5 mg; 1 mg; 5 mg; 0.2 mg; 5 mg/mL; 4 mg; 0.75 mg tablet and injection
Atopic Dermatitis
- Apply a thin layer to the affected areas 2 times a day and rub in gently and completely; discontinue use when symptoms resolve
Atopic Dermatitis
- Less than 2 years: Safety and efficacy have not been established
2 to 15 years:
- 0.03% ointment: Apply a thin layer to the affected areas 2 times a day and rub in gently and completely; discontinue use when symptoms resolve
- 0.1% ointment: Safety and efficacy have not been established
16 years and older
- 0.03 or 0.1% ointment: Apply a thin layer to the affected areas 2 times a day and rub in gently and completely; discontinue use when symptoms resolve
Organ Transplant – Rejection Prophylaxis
KIDNEY TRANSPLANT > IMMEDIATE RELEASE
- In combination with azathioprine: Initial dose: 0.1 mg/kg orally every 12 hours; initiate within 24 hours of surgery but delay until renal function has recovered
- In combination with mycophenolate mofetil (MMF)/interleukin-2 (IL-2) receptor antagonist: Initial dose: 0.05 mg/kg orally every 12 hours; initiate within 24 hours of surgery, but delay until renal function has recovered
EXTENDED-RELEASE
- With Basiliximab Induction, MMF, and Corticosteroids: Initial dose: 0.15 to 0.2 mg/kg/day orally as a single dose. Give the first dose prior to or within 48 hours of transplant completion. May delay initiation until renal function has recovered.
- With MMF and Corticosteroids, but Without Basiliximab Induction: Pre-operative dose: 0.1 mg/kg/day orally as a single dose within 12 hours prior to reperfusion; Post-operative dose: 0.2 mg/kg/day orally as a single dose. Give first post-operative dose within 12 hours after reperfusion but not less than 4 hours after the pre-operative dose.
IV
- Initial dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion
LIVER TRANSPLANT IMMEDIATE-RELEASE
- Initial dose: 0.05 to 0.075 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery.
IV
- Initial dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion
HEART TRANSPLANT IMMEDIATE-RELEASE
- Initial dose: 0.0375 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery
IV
- Initial dose: 0.01 mg/kg/day as a continuous IV infusion
Organ Transplant – Rejection Reversal
LIVER TRANSPLANT > IMMEDIATE RELEASE
- Initial dose: 0.075 to 0.1 mg/kg orally every 12 hours
INTRAVENOUS
- Initial dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion
Side Effects of Tacrolimus
More common
- signs of a hole in the digestive system (e.g., severe abdominal pain, burning pain, nausea, vomiting, chills or fever)
- agitation
- confusion
- cough
- diarrhea
- signs of a severe skin reaction such as blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort
- Abnormal dreams
- dizziness
- fever
- frequent urination
- a general feeling of discomfort or illness
- headache
- itching, skin rash
- joint pain
- loss of appetite
- loss of energy or weakness
- mental depression
- muscle aches and pains
- muscle trembling or twitching
- nausea
- pale skin
- runny nose
- seeing or hearing things that are not there
- seizures
- skin rash
- sore throat
- stomach pain
- swelling of the feet or lower legs
- trembling and shaking of the hands
- trouble sleeping
- unusual bleeding or bruising
- unusual tiredness or weakness
Common
- signs of kidney problems (e.g., increased urination at night, decreased urine production, blood in the urine)
- signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
- signs of progressive multifocal leukoencephalopathy (e.g., personality changes, progressive weakness on one side of the body, changes in memory, confusion)
- any mouth sores
- changes in memory and orientation
- clumsiness
- cold or flu-like symptoms (such as fever or sore throat)
- confusion
- constipation
- back pain
- changes in mood or emotions
- diarrhea
- difficulty sleeping or nightmares
- fever
- headache
- loss of appetite
- nausea
- stomach pain
- tiredness or fatigue
- trembling
- vomiting
- weakness
Rare
- signs of posterior encephalopathy syndrome (e.g., headache, seizures, visual disturbances, altered mental state)
- signs of reduced red blood cells (e.g., fatigue, a general feeling of being unwell, weakness, dizziness, fainting, pale skin, pale stool)
- swelling or tingling in your hands or feet
- symptoms of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odor)
- symptoms of a urinary tract infection (e.g., pain when urinating, urinating more often than usual, low back or flank pain)
- Blurred vision
- chest pain
- increased sensitivity to pain
- muscle cramps
- numbness or pain in the legs
- ringing in the ears
- sweating
- Enlarged heart
- flushing of the face or neck
- weight loss
Drug Interactions of Fujimycin/ FK-506
- alcohol
- alpha-blockers (e.g., alfuzosin, doxazosin, tamsulosin)
- antacids (e.g., aluminum hydroxide, magnesium carbonate)
- antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- antiseizure medications (e.g., clobazam, phenobarbital, phenytoin, valproic acid, )
- angiotensin-converting enzyme inhibitors (ACEIs; e.g., ramipril, lisinopril)
- angiotensin receptor blockers (ARBs; e.g., candesartan, irbesartan, losartan)
- antihistamines (e.g,. cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- BCG
- bosutinib
- bromocriptine
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- carbamazepine
- carvedilol
- celecoxib
- chloroquine
- clotrimazole
- colchicine
- cyclosporine
- dabrafenib
- dasatinib
- denosumab
- dexamethasone
- domperidone
- estrogens (e.g., conjugated estrogen, estradiol, Ethinyl estradiol)
- formoterol
- gliptin diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- grapefruit juice
- H2 antagonists (e.g., famotidine, ranitidine)
- imatinib
- macrolide antibiotics (e.g., erythromycin, clarithromycin)
- medications to treat cancer (e.g., carboplatin, cyclophosphamide, doxorubicin, ifosfamide, vincristine)
- methotrexate
- methylprednisolone
- nadolol
- nilotinib
- non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
- oxcarbazepine
- phenytoin
- potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene)
- propranolol
- proton pump inhibitors (e.g., lansoprazole, omeprazole)
- quinolone antibiotics (e.g., ciprofloxacin, norfloxacin, ofloxacin)
- St. John’s wort
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
- serotonin antagonists (anti-emetic medications; e.g., granisetron, ondansetron)
- sirolimus
- sotalol
- tramadol
- trimethoprim
- “statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- sulfamethoxazole
- sulfonylureas (e.g., gliclazide, glyburide)
- sunitinib
- tamoxifen
- tetracycline
- tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
- vaccines
- vardenafil
Pregnancy Category of Fujimycin/ FK-506
US FDA pregnancy category: Not assigned.
or
FDA Pregnancy Category – C
Pregnancy
Adequate studies have not been conducted on the use of tacrolimus by pregnant women. Reports of the use of tacrolimus during pregnancy has been associated with high blood potassium levels and kidney problems in the newborn. This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.
Breast-feeding
This medication passes into breast milk. Breast-feeding is not recommended while taking tacrolimus. If you are a breast-feeding mother and taking tacrolimus, it may affect your baby. Talk to your doctor.
References
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