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Pharmacologic class: Macrolide
Therapeutic class: Immunosuppressant
Pregnancy risk category C
FDA Box Warning
Immunosuppression may increase patient's susceptibility to infection and lymphoma development. Give under supervision of physician experienced in immunosuppressive therapy and management of organ transplant patients, in facility with adequate diagnostic and treatment resources. Physician responsible for maintenance therapy should have complete information needed for patient follow-up.
Be aware that long-term safety of topical calcineurin inhibitors hasn't been established.
Although a causal relationship hasn't been established, rare cases of malignancy (such as skin cancers and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including tacrolimus ointment. Therefore, continuous long-term use of tacrolimus ointment in any age-group should be avoided and application limited to areas of atopic dermatitis involvement. Tacrolimus ointment isn't indicated for use in children younger than age 2. Only 0.03% tacrolimus ointment is indicated for use in children ages 2 to 15.
Unknown. Thought to inhibit T-lymphocyte activation.
Capsules: 0.5 mg, 1 mg, 5 mg
Injection: 5 mg/ml
Topical ointment: 0.03%, 0.1%
Indications and dosages
➣ Prevention of organ rejection in patients with allogeneic liver transplants
Adults: Initially, 0.1 to 0.15 mg/kg/day P.O. in two divided doses q 12 hours. Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion.
Children: 0.15 to 0.2 mg/kg/day P.O. in two divided doses q 12 hours. Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion.
➣ Prevention of organ rejection in patients with allogeneic kidney transplants
Adults: Initially, 0.2 mg/kg/day P.O. in two divided doses q 12 hours when used in combination with azathioprine, or 0.1 mg/kg/day P.O. when used in combination with mycophenolate mofetil (MMF). Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion until oral dosing can be tolerated.
➣ Prevention of heart transplant rejection
Adults: Initially, 0.075 mg/kg/day P.O. q 12 hours in two divided doses in combination with azathioprine or MMF.
➣ Moderate to severe atopic dermatitis
Adults: 0.03% or 0.1% ointment applied b.i.d. to affected area, continued 1 week after dermatitis symptoms resolve
Children ages 2 and older: 0.03% ointment applied b.i.d. to affected area, continued 1 week after dermatitis symptoms resolve
• Hepatic or renal impairment
• Concurrent use of CYP3A inducers or inhibitors
• Black patients
• Hypersensitivity to drug or its components (including castor oil derivatives)
Use cautiously in:
• severe hepatic disease, renal impairment, diabetes mellitus, hypertension, hyperkalemia, hyperuricemia, lymphoma, serious infections
• skin barrier defect with increased potential for systemic absorption of tacrolimus ointment
• premalignant and malignant skin conditions (avoid use)
• concurrent use of cyclosporine, nelfinavir, or live vaccines (avoid use)
• concurrent use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, itraconazole, ketoconazole, ritonavir, telaprevir, voriconazole,) and strong inducers (such as rifampin, rifabutin) (not recommended)
• concurrent use of other substrates or CYP3A4 inhibitors that also have potential to prolong QT interval
• concurrent use of sirolimus (not recommended in liver and heart transplant; use with sirolimus in kidney transplant not established)
• concurrent use of other nephrotoxic drugs or drugs that cause hyperkalemia
• prolonged exposure to ultraviolet (UV) light and sunlight (avoid)
• pregnant or breastfeeding patients
• children younger than age 12 (age 2 for ointment use).
• Give oral form consistently with or without food but not with grapefruit juice.
• Give I.V. doses by infusion only. Be aware that I.V. use is reserved for patients who can't tolerate capsules orally.
• Start therapy within 24 hours of kidney transplantation and no earlier than 6 hours after liver or heart transplantation. Switch to oral dosing as soon as tolerable, starting 8 to 12 hours after I.V. dosing ends.
Before giving I.V., ensure that epinephrine 1:1,000 and oxygen are at hand in case of emergency.
• For I.V. use, dilute in normal saline solution or dextrose 5% in water to a concentration of 0.004 to 0.02 mg/ml. Give by infusion only.
• Be aware that ointment is used only as second-line therapy for the short-term and noncontinuous treatment of moderate to severe atopic dermatitis in nonimmunocompromised patients who have failed to respond adequately to other topical prescription treatments for atopic dermatitis.
• After applying ointment, don't place occlusive dressing or wrapping over affected area.
CNS: tremor, headache, insomnia, paresthesia, delirium, asthenia, neurotoxicities (including posterior reversible encephalopathy syndrome, delirium, seizures, and coma)
CV: hypertension, peripheral edema, myocardial hypertrophy
GI: nausea, vomiting, diarrhea, constipation, abdominal pain, ascites, anorexia
GU: hematuria, proteinuria, urinary tract infection, albuminuria, abnormal renal function, oliguria, renal failure, nephrotoxicity
Hematologic: anemia, leukocytosis, thrombocytopenia, agranulocytosis, hemolytic anemia, pure red cell aplasia
Metabolic: new-onset diabetes mellitus, hyperglycemia, hypomagnesemia, hypokalemia, hyperkalemia
Musculoskeletal: back pain
Respiratory: dyspnea, pleural effusion, atelectasis
Skin: burning (with ointment), rash, flushing, pruritus, alopecia
Other: pain, fever, chills, lymphadenopathy, serious infections (including cytomegalovirus infections and polyoma virus infections), lymphoma and other malignancies, anaphylaxis
Drug-drug. Bromocriptine, chloramphenicol, cimetidine, clarithromycin, clotrimazole, cyclosporine, danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, methylprednisolone, metoclopramide, metronidazole, nicardipine, omeprazole, protease inhibitors, verapamil: increased tacrolimus blood level
Cyclosporine: increased risk of nephrotoxicity
CYP450 inducers (such as carbamazepine, phenobarbital, phenytoin, rifampin): decreased tacrolimus metabolism Immunosuppressants (except adrenocorticoids): immunologic oversuppression
Live-virus vaccines: interference with immune response to vaccine
Mycophenolate mofetil: increased mycophenolate blood level
Nephrotoxic drugs (such as aminoglycosides, amphotericin B, cisplatin, cyclosporine): additive or synergistic effects
Drug-diagnostic tests. Blood urea nitrogen, creatinine, glucose: increased levels
Hemoglobin, magnesium, platelets, white blood cells: decreased levels
Liver function tests: abnormal values
Potassium: increased or decreased level
Drug-food. Any food: inhibited drug absorption
Grapefruit or grapefruit juice: increased drug blood level
Drug-herbs. Astragalus, echinacea, melatonin: decreased immunosuppression
St. John's wort: decreased tacrolimus blood level
Once I.V. infusion starts, watch closely for signs and symptoms of anaphylaxis.
• Monitor cardiac, liver, and kidney function test results. Watch for signs and symptoms of cardiovascular disorder, nephrotoxicity, and hepatic dysfunction.
Assess neurologic status for evidence of neurotoxicity (including posterior encephalopathy syndrome and seizures).
• Monitor potassium level closely. Stay alert for signs and symptoms of hyperkalemia.
• Monitor blood glucose. Watch for indications of hyperglycemia.
• Evaluate respiratory status regularly.
Teach patient to recognize and immediately report serious adverse reactions.
• Tell patient to take oral doses consistently with or without food, but not with grapefruit or grapefruit juice.
• Tell diabetic patient to expect increased blood glucose level, which may warrant further antidiabetic therapy. Advise him to monitor glucose level carefully.
• Instruct patient not to place occlusive dressings or wrappings over affected area after applying ointment. Tell him to use drug for 1 week after dermatitis symptoms resolve.
• Advise patient to avoid live vaccines and prolonged exposure to UV light or sunlight.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.
tacrolimus/tac·ro·li·mus/ (tak″ro-li´mus) a macrolide immunosuppressant having actions similar to those of cyclosporine; used to prevent rejection of organ transplants; also used topically to treat moderate to severe atopic dermatitis.
tacrolimusFK506, Prograf Immunology An immunosuppressant that inhibits IL-2 synthesis and binding; it is similar to, and synergistic with, cyclosporine, up to 50-fold more immunosuppressive than cyclosporine; it is used in BM, kidney, liver, lung, and other transplants Adverse effects Neurotoxicity–tremor, seizures, white matter disease, headache, nausea, paresthesias of hands, feet, insomnia; nephrotoxicity, hyperglycemia, hirsutism, paresthesia, ↑ lipids, ↑ K+, HUS, ↓ Mg2+. Cf Cyclosporine.
tacrolimusA potent immunosuppressant macrolide compound isolated from a bacterium. Tacrolimus is effective in reducing the risk of rejection of solid-organ transplants especially liver transplants. It has been successfully used as a monotherapy to prevent graft rejections and has virtually eliminated immunosuppression-related morbidity. It has also been found useful in ointment form for the treatment of moderate-to-severe atopic dermatitis in which it has been found as effective as strong topic steroids. Brand names are Prograf and Protopic.
drug class: immunosuppressant;
action: inhibits T-lymphocyte activation leading to immunosuppression;
use: prophylaxis of organ rejection in patients receiving allogenic liver transplants.