Pronunciation:

(ta KROE li mus)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Oral/injection: Potent immunosuppressive drug used in liver or kidney transplant recipients

Topical: Moderate to severe atopic dermatitis in patients not responsive to conventional therapy or when conventional therapy is not appropriate

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

Oral/injection: Insulin-dependent post-transplant diabetes mellitus (PTDM) has been reported (1% to 20%); risk increases in African-American and Hispanic kidney transplant patients. Increased susceptibility to infection and the possible development of lymphoma may occur after administration of tacrolimus. Nephrotoxicity and neurotoxicity have been reported, especially with higher doses; to avoid excess nephrotoxicity do not administer simultaneously with cyclosporine; monitoring of serum concentrations (trough for oral therapy) is essential to prevent organ rejection and reduce drug-related toxicity; tonic clonic seizures may have been triggered by tacrolimus. A period of 24 hours should elapse between discontinuation of cyclosporine and the initiation of tacrolimus. Use caution in renal or hepatic dysfunction, dosing adjustments may be required. Delay initiation if postoperative oliguria occurs. Use may be associated with the development of hypertension (common). Myocardial hypertrophy has been reported (rare). Each mL of injection contains polyoxyl 60 hydrogenated castor oil (HCO-60) (200 mg) and dehydrated alcohol USP 80% v/v. Anaphylaxis has been reported with the injection, use should be reserved for those patients not able to take oral medications.

Topical: Infections at the treatment site should be cleared prior to therapy. Patients with atopic dermatitis are predisposed to skin infections, including eczema herpeticum, varicella zoster, and herpes simplex. Discontinue use in patients with unknown cause of lymphadenopathy or acute infectious mononucleosis. Not recommended for use in patients with Netherton's syndrome. Safety not established in patients with generalized erythroderma.

Adverse Reactions:

Oral, I.V.:

15%

Cardiovascular: Chest pain, hypertension

Central nervous system: Dizziness, headache, insomnia, tremor (headache and tremor are associated with high whole blood concentrations and may respond to decreased dosage)

Dermatologic: Pruritus, rash

Endocrine & metabolic: Diabetes mellitus, hyperglycemia, hyperkalemia, hyperlipemia, hypomagnesemia, hypophosphatemia

Gastrointestinal: Abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting

Genitourinary: Urinary tract infection

Hematologic: Anemia, leukocytosis, thrombocytopenia

Hepatic: Ascites

Neuromuscular & skeletal: Arthralgia, back pain, weakness, paresthesia

Renal: Abnormal kidney function, increased creatinine, oliguria, urinary tract infection, increased BUN

Respiratory: Atelectasis, dyspnea, increased cough

3% to 15%:

Cardiovascular: Abnormal ECG, angina pectoris, deep thrombophlebitis, hemorrhage, hypotension, hypervolemia, generalized edema, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, thrombosis, vasodilation

Central nervous system: Abnormal dreams, abnormal thinking, agitation, amnesia, anxiety, chills, confusion, depression, emotional lability, encephalopathy, hallucinations, nervousness, psychosis, somnolence

Dermatologic: Acne, alopecia, cellulitis, exfoliative dermatitis, fungal dermatitis, hirsutism, increased diaphoresis, photosensitivity reaction, skin discoloration, skin disorder, skin ulcer

Endocrine & metabolic: Acidosis, alkalosis, Cushing's syndrome, decreased bicarbonate, decreased serum iron, diabetes mellitus, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hypoproteinemia, increased alkaline phosphatase

Gastrointestinal: Anorexia, cramps, dysphagia, enlarged abdomen, esophagitis, flatulence, gastritis, GI perforation/hemorrhage, ileus, increased appetite, oral moniliasis, rectal disorder, stomatitis, weight gain

Genitourinary: Urinary frequency, urinary incontinence, vaginitis, cystitis, dysuria

Hematologic: Bruising, coagulation disorder, decreased prothrombin, hypochromic anemia, leukopenia, polycythemia

Hepatic: Abnormal liver function tests, bilirubinemia, cholangitis, cholestatic jaundice, hepatitis, increased ALT, increased AST, increased GGT, jaundice, liver damage, increase LDH

Neuromuscular & skeletal: Hypertonia, incoordination, joint disorder, leg cramps, myalgia, myasthenia, myoclonus, neuropathy, osteoporosis

Ocular: Abnormal vision, amblyopia

Otic: Ear pain, otitis media, tinnitus

Renal: Albuminuria

Respiratory: Asthma, bronchitis, lung disorder, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

Miscellaneous: Abscess, abnormal healing, allergic reaction, flu-like syndrome, generalized spasm, hernia, herpes simplex, peritonitis, sepsis

Postmarketing and/or case reports: Acute renal failure, anaphylaxis, coma, deafness, delirium, hearing loss, hemolytic-uremic syndrome, leukoencephalopathy, lymphoproliferative disorder (related to EBV), myocardial hypertrophy (associated with ventricular dysfunction; reversible upon discontinuation), pancreatitis, QTc prolongation, seizure, Stevens-Johnson syndrome, thrombocytopenic purpura, torsade de pointes

Topical (as reported in children and adults, unless otherwise noted):

>10%:

Central nervous system: Headache (5% to 20%), fever (1% to 21%)

Dermatologic: Skin burning (43% to 58%), pruritus (41% to 46%), erythema (12% to 28%)

Respiratory: Increased cough (18% children)

Miscellaneous: Flu-like syndrome (23% to 28%), allergic reaction (4% to 12%)

1% to 10%:

Cardiovascular: Peripheral edema (3% to 4% adults)

Central nervous system: Hyperesthesia (3% to 7% adults), pain (1% to 2%)

Dermatologic: Skin tingling (2% to 8%), acne (4% to 7% adults), localized flushing (following ethanol consumption 3% to 7% adults), folliculitis (2% to 6%), urticaria (1% to 6%), rash (2% to 5%), pustular rash (2% to 4%), vesiculobullous rash (4% children), contact dermatitis (3% to 4%), cyst (1% to 3% adults), eczema herpeticum (1% to 2%), fungal dermatitis (1% to 2% adults), sunburn (1% to 2% adults), dry skin (1% children)

Endocrine & metabolic: Dysmenorrhea (4% women)

Gastrointestinal: Diarrhea (3% to 5%), dyspepsia (1% to 4% adults), abdominal pain (3% children), vomiting (1% adults), gastroenteritis (adults 2%), nausea (1% children)

Neuromuscular & skeletal: Myalgia (2% to 3% adults), weakness (2% to 3% adults), back pain (2% adults)

Ocular: Conjunctivitis (2% adults)

Otic: Otitis media (12% children)

Respiratory: Rhinitis (6% children), sinusitis (2% to 4% adults), bronchitis (2% adults), pneumonia (1% adults)

Miscellaneous: Varicella/herpes zoster (1% to 5%), lymphadenopathy (3% children)

1%: Alopecia, increased ALT, increased AST, anaphylactoid reaction, angina pectoris, angioedema, anorexia, anxiety, arrhythmia, arthralgia, arthritis, bilirubinemia, breast pain, cellulitis, cerebrovascular accident, cheilitis, chills, constipation, increased creatinine, dehydration, depression, dizziness, dyspnea, ear pain, ecchymosis, edema, epistaxis, exacerbation of untreated area, eye pain, furunculosis, gastritis, hernia, hyperglycemia, hypertension, hypoglycemia, hypoxia, laryngitis, leukocytosis, leukopenia, abnormal liver function tests, lymphadenopathy (0.8%), malaise, migraine, neck pain, neuritis, palpitation, paresthesia, peripheral vascular disorder, photosensitivity reaction, skin discoloration, diaphoresis, taste perversion, unintended pregnancy, vaginal moniliasis, vasodilation, vertigo

Overdosage/Toxicology:

Drug Interactions:

Antacids: Separate administration by at least 2 hours

Anticonvulsants: Carbamazepine, phenobarbital, phenytoin: May decrease tacrolimus blood levels

Calcium channel blockers (dihydropyridine): May increase tacrolimus serum concentrations; monitor.

Caspofungin: May decrease tacrolimus serum concentrations.

Cisapride (and metoclopramide): May increase serum concentration of tacrolimus

Cyclosporine: Concomitant use is associated with synergistic immunosuppression and increased nephrotoxicity; give first dose of tacrolimus no sooner than 24 hours after last cyclosporine dose. In the presence of elevated tacrolimus or cyclosporine concentration, dosing of the other usually should be delayed longer.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of tacrolimus. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of tacrolimus. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Ganciclovir: Nephrotoxicity may be additive with tacrolimus; use caution.

Potassium-sparing diuretics: Tacrolimus use may lead to hyperkalemia; avoid concomitant use

Rifabutin, rifampin: May decrease serum levels of tacrolimus.

Sirolimus: May decrease tacrolimus serum concentrations.

St John's wort: May decrease tacrolimus serum concentrations; avoid concurrent use.

Sucralfate: Separate administration by at least 2 hours

Vaccines (live): Vaccine may be less effective; avoid vaccination during treatment if possible

Voriconazole: Tacrolimus serum concentrations may be increased; monitor serum concentrations and renal function. Decrease tacrolimus dosage by 66% when initiating voriconazole.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Localized flushing (redness, warm sensation) may occur at application site of topical tacrolimus following ethanol consumption.

Food: Decreases rate and extent of absorption. High-fat meals have most pronounced effect (35% decrease in AUC, 77% decrease in Cmax). Grapefruit juice, CYP3A4 inhibitor, may increase serum level and/or toxicity of tacrolimus; avoid concurrent use.

Herb/Nutraceutical: St John's wort: May reduce tacrolimus serum concentrations (avoid concurrent use).

Stability:

Injection: Prior to dilution, store at 5°C to 25°C (41°F to 77°F). Polyvinyl-containing sets (eg, Venoset®, Accuset®) adsorb significant amounts of the drug, and their use may lead to a lower dose being delivered to the patient. FK506 admixtures prepared in 5% dextrose injection or 0.9% sodium chloride injection should be stored in polyolefin containers or glass bottles. Infusion of FK506 through PVC tubings did not result in decreased concentration of the drug, however, loss by absorption may be more important when lower concentrations of FK506 are used. Stable for 24 hours in D5W or NS in glass or polyolefin containers.

Capsules and ointment: Store at room temperature 25°C (77°F)

Compatibility:

Y-site administration: Compatible: Acyclovir, aminophylline, amphotericin B, ampicillin, ampicillin/sulbactam, benztropine, calcium gluconate, cefazolin, cefotetan, ceftazidime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, ciprofloxacin, clindamycin, co-trimoxazole, dexamethasone sodium phosphate, digoxin, diphenhydramine, dobutamine, dopamine, doxycycline, erythromycin lactobionate, esmolol, fluconazole, furosemide, ganciclovir, gentamicin, haloperidol, heparin, hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, insulin (regular), isoproterenol, leucovorin, lorazepam, methylprednisolone sodium succinate, metoclopramide, metronidazole, morphine, multivitamins, nitroglycerin, oxacillin, penicillin G potassium, perphenazine, phenytoin, piperacillin, potassium chloride, propranolol, ranitidine, sodium bicarbonate, sodium nitroprusside, sodium tetradecyl sulfate, tobramycin, vancomycin

Compatibility when admixed: Compatible: Cimetidine

Mechanism of Action:

Pharmacodynamics/Kinetics:

Absorption: Better in resected patients with a closed stoma; unlike cyclosporine, clamping of the T-tube in liver transplant patients does not alter trough concentrations or AUC

Oral: Incomplete and variable; food within 15 minutes of administration decreases absorption (27%)

Topical: Serum concentrations range from undetectable to 20 ng/mL (<5 ng/mL in majority of adult patients studied)

Protein binding: 99%

Metabolism: Extensively hepatic via CYP3A4 to eight possible metabolites (major metabolite, 31-demethyl tacrolimus, shows same activity as tacrolimus in vitro)

Bioavailability: Oral: Adults: 7% to 28%, Children: 10% to 52%; Topical: <0.5%; Absolute: Unknown

Half-life elimination: Variable, 21-61 hours in healthy volunteers

Time to peak: 0.5-4 hours

Excretion: Feces (~92%); feces/urine (<1% as unchanged drug)

Dosage:

Children:

Liver transplant: Patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. It is recommended that therapy be initiated at high end of the recommended adult I.V. and oral dosing ranges; dosage adjustments may be required.

Oral: Initial dose: 0.15-0.20 mg/kg/day in 2 divided doses, given every 12 hours; begin oral dose no sooner than 6 hours post-transplant; adjunctive therapy with corticosteroids is recommended; if switching from I.V. to oral, the oral dose should be started 8-12 hours after stopping the infusion

Typical whole blood trough concentrations: Months 1-12: 5-20 ng/mL

I.V.: Note: I.V. route should only be used in patients not able to take oral medications, anaphylaxis has been reported. Initial dose: 0.03-0.05 mg/kg/day as a continuous infusion; begin no sooner than 6 hours post-transplant; adjunctive therapy with corticosteroids is recommended; continue only until oral medication can be tolerated

Children 2 years: Moderate to severe atopic dermatitis: Topical: Apply 0.03% ointment to affected area twice daily; rub in gently and completely; continue applications for 1 week after symptoms have cleared

Adults:

Kidney transplant:

Oral: Initial dose: 0.2 mg/kg/day in 2 divided doses, given every 12 hours; initial dose may be given within 24 hours of transplant, but should be delayed until renal function has recovered; African-American patients may require larger doses to maintain trough concentration

Typical whole blood trough concentrations: Months 1-3: 7- 20 ng/mL; months 4-12: 5-15 ng/mL

I.V.: Note: I.V. route should only be used in patients not able to take oral medications, anaphylaxis has been reported. Initial dose: 0.03-0.05 mg/kg/day as a continuous infusion; begin no sooner than 6 hours post-transplant, starting at lower end of the dosage range; adjunctive therapy with corticosteroids is recommended; continue only until oral medication can be tolerated

Liver transplant:

Oral: Initial dose: 0.1-0.15 mg/kg/day in 2 divided doses, given every 12 hours; begin oral dose no sooner than 6 hours post-transplant; adjunctive therapy with corticosteroids is recommended; if switching from I.V. to oral, the oral dose should be started 8-12 hours after stopping the infusion

Typical whole blood trough concentrations: Months 1-12: 5-20 ng/mL

I.V.: Note: I.V. route should only be used in patients not able to take oral medications, anaphylaxis has been reported. Initial dose: 0.03-0.05 mg/kg/day as a continuous infusion; begin no sooner than 6 hours post-transplant starting at lower end of the dosage range; adjunctive therapy with corticosteroids is recommended; continue only until oral medication can be tolerated

Prevention of graft-vs-host disease: I.V.: 0.03 mg/kg/day as continuous infusion

Moderate to severe atopic dermatitis: Topical: Apply 0.03% or 0.1% ointment to affected area twice daily; rub in gently and completely; continue applications for 1 week after symptoms have cleared

Dosing adjustment in renal impairment: Evidence suggests that lower doses should be used; patients should receive doses at the lowest value of the recommended I.V. and oral dosing ranges; further reductions in dose below these ranges may be required

Tacrolimus therapy should usually be delayed up to 48 hours or longer in patients with postoperative oliguria

Hemodialysis: Not removed by hemodialysis; supplemental dose is not necessary

Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics

Dosing adjustment in hepatic impairment: Use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood levels of tacrolimus. The presence of moderate-to-severe hepatic dysfunction (serum bilirubin >2 mg/dL) appears to affect the metabolism of FK506. The half-life of the drug was prolonged and the clearance reduced after I.V. administration. The bioavailability of FK506 was also increased after oral administration. The higher plasma concentrations as determined by ELISA, in patients with severe hepatic dysfunction are probably due to the accumulation of FK506 metabolites of lower activity. These patients should be monitored closely and dosage adjustments should be considered. Some evidence indicates that lower doses could be used in these patients.

Administration:

Monitoring Parameters:

Reference Range:

Liver transplant: Whole blood trough concentration: 5-20 ng/mL

Kidney transplant: whole blood trough concentrations:

Months 1-3: 7-20 ng/mL

Months 4-12: 5-15 ng/mL

Dietary Considerations:

Patient Education:

Topical: Before applying, wash area gently and thoroughly. Apply in thin film to affected area. Do not cover skin with bandages. Wash hands only if not treating skin on the hands. Protect skin from sunlight or exposure to UV light. Consult prescriber if breast-feeding.

Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Additional Information:

Switch from I.V. to oral therapy: Threefold increase in dose

Pediatric patients: About 2 times higher dose compared to adults

Liver dysfunction: Decrease I.V. dose; decrease oral dose

Renal dysfunction: Does not affect kinetics; decrease dose to decrease levels if renal dysfunction is related to the drug

Anesthesia and Critical Care Concerns/Other Considerations:

Additional dosing considerations:

Switch from I.V. to oral therapy: Threefold increase in dose

Pediatric patients: About 2 times higher dose compared to adults

Liver dysfunction: Decrease I.V. dose; decrease oral dose

Renal dysfunction: Does not affect kinetics; decrease dose to decrease levels if renal dysfunction is related to the drug

Tacrolimus is associated with more neurotoxicity, nephrotoxicity, and glucose intolerance but less hypertension, dyslipidemia, gingival hyperplasia, or hirsutism than cyclosporine.

Cardiovascular Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Effects on Mental Status:

Mental Health: Effects on Psychiatric Treatment:

Oncology: Vesicant:

Dosage Forms:

Capsule (Prograf®): 0.5 mg, 1 mg, 5 mg

Injection, solution (Prograf®): 5 mg/mL (1 mL) [contains dehydrated alcohol 80% and polyoxyl 60 hydrogenated castor oil]

Ointment, topical (Protopic®): 0.03% (30 g, 60 g, 100 g); 0.1% (30 g, 60 g, 100 g)

Extemporaneously Prepared:

Esquivel C, So S, McDiarmid S, Andrews W, Colombani P. Suggested guidelines for the use of tacrolimus in pediatric liver transplant patients. Transplantation 1996, 61(5):847-8.

Foster JA, Jacobson PA, Johnson CE, et al. Stability of tacrolimus in an extemporaneously compounded oral liquid. (Abstract of Meeting Presentation) American Society of Health-System Pharmacists Annual Meeting 1996, 53:P-52(E).

International Brand Names: