tacrolimus


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tacrolimus

 [tak″ro-li´mus]
an immunosuppressant derived from a species of Streptomyces, having actions similar to those of cyclosporine; administered orally or intravenously to prevent rejection of organ transplants and topically to treat moderate to severe atopic dermatitis.

tacrolimus

Advagraf, Prograf, Protopic

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.

Action

Unknown. Thought to inhibit T-lymphocyte activation.

Availability

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

Dosage adjustment

• Hepatic or renal impairment

• Concurrent use of CYP3A inducers or inhibitors

• Black patients

Contraindications

• Hypersensitivity to drug or its components (including castor oil derivatives)

Precautions

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).

Administration

• 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.

Adverse reactions

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

Interactions

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

Patient monitoring

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.

Patient teaching

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

(tə-krō′lə-məs)
n.
An immunosuppressive drug produced by the actinomycete Streptomyces tsukubaensis, C44H69NO12, used in combination with corticosteroids to prevent rejection of organ transplants.

tacrolimus

FK506, 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.

tacrolimus

A 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.

immunosuppressants

Drugs that prevent or reduce the immune response. They are used in the treatment of a variety of severe inflammations such as uveitis, scleritis, keratoconjunctivitis sicca, Behçet's syndrome, sympathetic ophthalmia, and to prevent corneal graft rejection. They include the corticosteroids (e.g. prednisolone), ciclosporin (cyclosporine), tacrolimus, and cytotoxic agents (e.g. azathioprine, chlorambucil, cyclophosphamide, methotrexate). It must be noted that immunosuppressants render the patient more susceptible to infection because immunity is reduced.
References in periodicals archive ?
The only adverse effect was a burning sensation expressed by a couple of owners for a few days on initiation of treatment, but resolved by itself after 4 days of continuous use, which is supported by Marsella and Nicklin (2002) who stated that it could be due to the molecular weight of Tacrolimus is such that it penetrates through inflamed skin and hardly penetrated the epidermis of normal skin.
We included all adult patients with more than three months after transplantation, with stable preswitch tacrolimus dose and blood levels for at least 4 weeks and at least three blood tacrolimus and serum creatinine blood levels before and after the switch.
The recipients with higher IL-18 serum levels had lower tacrolimus C/D ratios in liver transplantation [22].
In contrast to cyclosporine and tacrolimus, the serum concentration of MMF has not been measured.
Population pharmacokinetic modelling and Bayesian estimation of tacrolimus exposure: is this clinically useful for dosage prediction yet?
Four patients were diagnosed with polyneuropathy according to clinical and electrophysiological findings, three of whom had polyneuropathy caused by immunosuppressive drugs (cyclosporine, two patients; tacrolimus, one patient) and one had polyneuropathy caused by amyloidosis.
Biological samples are also taken, in order to dose the blood concentration of tacrolimus.
The present case was considered severely active because of the ferritin and IL-18 levels and was thought to be refractory; therefore, we decided to prescribe tacrolimus in combination with GC, including two courses of mPSL pulse therapy and MTX.
Patients indicated they applied topical tacrolimus a median of two times per week.
Tacrolimus is a macrolide lactone; calcineurin inhibitor, cause inhibition of IL-2 and T-cell derived cytokines like TNF-[alpha], and other interleukins.
In a study conducted by Schnopp et al.11 it was found out that tacrolimus was as effective as mometasone furoate in dyshidrotic plamar eczema.
This US FDA's approval is based on the company's Phase 3 clinical development programme, a randomised, double-blind, double-dummy, Phase III study in 543 de novo kidney transplant patients, which demonstrated comparable efficacy and safety compared to twice-daily tacrolimus (Prograf).