Patients & CaregiversHealthcare ProfessionalsWorldwide
HomeAbout MerckProductsNewsroomInvestor RelationsCareersResearchLicensingThe Merck Manuals
THE MERCK MANUAL MEDICAL LIBRARY: The Merck Manual of Diagnosis and Therapy
Tips for better results
ABCDEFGHI
JKLMNOPQR
STUVWXYZ
Tacrolimus Drug Information Provided by Lexi-Comp

Update Me

This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or standards of non-Merck sources.

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.

Medication Safety Issues

Sound-alike/look-alike issues:

Prograf® may be confused with Gengraf®, Prozac®

Temsirolimus may be confused with sirolimus, tacrolimus

Pronunciation

(ta KROE li mus)

U.S. Brand Names

  • Prograf®
  • Protopic®

Index Terms

  • FK506

Generic Available

No

Canadian Brand Names

  • Advagraf™
  • Prograf®
  • Protopic®

Pharmacologic Category

  • Immunosuppressant Agent
  • Topical Skin Product

Use: Labeled Indications

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

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

Use: Dental

Topical: Treatment of severe ulcerative or vesicobullous lesions (usually in consult with patient's physician)

Use: Unlabeled/Investigational

Potent immunosuppressive drug used in lung, small bowel transplant recipients; immunosuppressive drug for peripheral stem cell/bone marrow transplantation

Restrictions

An FDA-approved medication guide must be distributed when dispensing the outpatient prescription (new or refill) for tacrolimus ointment where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.

Pregnancy Risk Factor

C

Pregnancy Considerations

Tacrolimus crosses the placenta and reaches concentrations four times greater than maternal plasma concentrations. Neonatal hyperkalemia and renal dysfunction have been reported.The National Transplantation Pregnancy Registry (NTPR, Temple University) is a registry for pregnant women taking immunosuppressants following any solid organ transplant. The NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant recipients at 877-955-6877.

Lactation

Enters breast milk/contraindicated

Breast-Feeding Considerations

Concentrations in breast milk are equivalent to plasma concentrations; breast-feeding is not advised.

Contraindications

Hypersensitivity to tacrolimus or any component of the formulation

Warnings/Precautions

Boxed warnings:

• Injection/oral: See “Dosage form specific issues” below.

• Topical: See “Dosage form specific issues” below.

Dosage form specific issues:

• Injection/oral: Insulin-dependent post-transplant diabetes mellitus (PTDM) has been reported (1% to 20%); risk increases in African-American and Hispanic kidney transplant patients. [U.S. Boxed Warning]: Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression with 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. [U.S. Boxed Warning]: Should be administered under the supervision of a physician experienced in immunosuppressive therapy in a facility appropriate for monitoring and managing therapy.

• Topical: [U.S. Boxed Warning]: Topical calcineurin inhibitors have been associated with rare cases of malignancy (including skin and lymphoma), therefore it should be limited to short-term and intermittent treatment using the minimum amount necessary for the control of symptoms and only on involved areas. Use in children <2 years of age is not recommended, children ages 2-15 should only use the 0.03% ointment. Avoid use on malignant or premalignant skin conditions (eg cutaneous T-cell lymphoma). Should not be used in immunocompromised patients. Do not apply to areas of active bacterial or viral infection; infections at the treatment site should be cleared prior to therapy. Topical calcineurin agents are considered second-line therapies in the treatment of atopic dermatitis/eczema, and should be limited to use in patients who have failed treatment with other therapies. Patients with atopic dermatitis are predisposed to skin infections, and tacrolimus therapy has been associated with risk of developing eczema herpeticum, varicella zoster, and herpes simplex. If atopic dermatitis is not improved in <6 weeks, re-evaluate to confirm diagnosis. May be associated with development of lymphadenopathy; possible infectious causes should be investigated. Discontinue use in patients with unknown cause of lymphadenopathy or acute infectious mononucleosis. Acute renal failure has been observed (rarely) with topical use. Not recommended for use in patients with skin disease which may increase systemic absorption (eg, Netherton's syndrome). Minimize sunlight exposure during treatment. Safety not established in patients with generalized erythroderma. Safety of intermittent use for >1 year has not been established, particularly since the effect on immune system development is unknown.

Adverse Reactions

Oral, I.V.:

?15%:

Cardiovascular: Chest pain, hypertension, pericardial effusion (heart transplant)

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, hyper-/hypokalemia, hyperlipemia, hypomagnesemia, hypophosphatemia

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

Genitourinary: Urinary tract infection

Hematologic: Anemia, leukocytosis, leukopenia, thrombocytopenia

Hepatic: Ascites

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

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

Respiratory: Atelectasis, bronchitis, dyspnea, increased cough, pleural effusion

Miscellaneous: CMV infection, infection

<15%:

Cardiovascular: Abnormal ECG (QRS or ST segment abnormal), angina pectoris, cardiopulmonary failure, deep thrombophlebitis, heart rate decreased, hemorrhage, hemorrhagic stroke, hypervolemia, hypotension, generalized edema, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, thrombosis, vasodilation

Central nervous system: Abnormal dreams, abnormal thinking, agitation, amnesia, anxiety, chills, confusion, depression, dizziness, elevated mood, emotional lability, encephalopathy, hallucinations, nervousness, paralysis, psychosis, quadriparesis, seizure, 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, appetite increased, cramps, duodenitis, dysphagia, enlarged abdomen, esophagitis (including ulcerative), flatulence, gastritis, gastroesophagitis, GI perforation/hemorrhage, ileus, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, weight gain

Genitourinary: Bladder spasm, cystitis, dysuria, nocturia, oliguria, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis

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

Hepatic: Abnormal liver function tests, ALT/AST increased, bilirubinemia, cholangitis, cholestatic jaundice, GGT increased, hepatitis (including granulomatous), jaundice, liver damage, increase LDH

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

Ocular: Abnormal vision, amblyopia

Otic: Ear pain, otitis media, tinnitus

Renal: Albuminuria, renal tubular necrosis, toxic nephropathy

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

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

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%; tends to improve as lesions resolve), 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)

Oral, I.V., topical: Postmarketing and/or case reports (limited to important or life-threatening): Acute renal failure, alopecia, anaphylaxis, anaphylactoid reaction, angioedema, ARDS, arrhythmia, atrial fibrillation, atrial flutter, bile duct stenosis, blindness, cardiac arrest, cerebral infarction, cerebrovascular accident, deafness, delirium, depression, DIC, hemiparesis, hemolytic-uremic syndrome, hemorrhagic cystitis, hepatic necrosis, hepatotoxicity, hyperglycemia, leukoencephalopathy, lymphoproliferative disorder (related to EBV), myocardial hypertrophy (associated with ventricular dysfunction; reversible upon discontinuation), MI, neutropenia, pancreatitis (hemorrhagic and necrotizing), pancytopenia, paresthesia, photosensitivity reaction (topical), quadriplegia, QTc prolongation, respiratory failure, seizure, skin discoloration (topical), Stevens-Johnson syndrome, syncope, toxic epidermal necrolysis, thrombocytopenic purpura, torsade de pointes, TTP, veno-occlusive hepatic disease, venous thrombosis, ventricular fibrillation

Note: Calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) have been reported (with concurrent sirolimus).

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)

Drug Interactions

Alcohol (Ethyl): Tacrolimus may enhance the dermatologic adverse effect of Alcohol (Ethyl). Risk C: Monitor therapy

Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): May decrease the metabolism of Tacrolimus. Exceptions: Trazodone. Risk D: Consider therapy modification

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Tacrolimus. Exceptions: Miconazole. Risk D: Consider therapy modification

Calcium Channel Blockers (Dihydropyridine): May increase the serum concentration of Tacrolimus. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Tacrolimus. Risk C: Monitor therapy

Caspofungin: May decrease the serum concentration of Tacrolimus. Risk C: Monitor therapy

Cinacalcet: May decrease the serum concentration of Tacrolimus. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Fluconazole: May decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification

Grapefruit Juice: May decrease the metabolism of Tacrolimus. Risk X: Avoid combination

Macrolide Antibiotics: May increase the serum concentration of Tacrolimus. Exceptions: Dirithromycin [Off Market]; Spiramycin. Risk C: Monitor therapy

Metronidazole: May decrease the metabolism of Calcineurin Inhibitors. Risk C: Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Phenytoin: May increase the metabolism of Tacrolimus. Tacrolimus may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification

Rifamycin Derivatives: May increase the metabolism of Tacrolimus. Risk D: Consider therapy modification

Sirolimus: May enhance the adverse/toxic effect of Tacrolimus. An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. Risk D: Consider therapy modification

St Johns Wort: May decrease the serum concentration of Tacrolimus. Risk D: Consider therapy modification

Temsirolimus: May enhance the adverse/toxic effect of Tacrolimus. An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described with concomitant sirolimus and tacrolimus use. Risk D: Consider therapy modification

Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination

Vaccines (Dead Organisms): Immunosuppressants may diminish the therapeutic effect of Vaccines (Dead Organisms). Risk C: Monitor therapy

Vaccines (Live Organisms): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live Organisms). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Risk X: Avoid combination

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).

Storage

Injection: Prior to dilution, store at 5°C to 25°C (41°F to 77°F). Following dilution, stable for 24 hours in D5W or NS in glass or polyolefin containers.

Capsules and ointment: Store at room temperature of 15°C to 30°C (59°F to 86°F).

Reconstitution

Dilute with 5% dextrose injection or 0.9% sodium chloride injection to a final concentration between 0.004 mg/mL and 0.02 mg/mL.

Compatibility

Variable stability (consult detailed reference) in D5W, NS (only in glass or polyolefin containers).

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

Suppresses cellular immunity (inhibits T-lymphocyte activation), possibly by binding to an intracellular protein, FKBP-12

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

Oral:

Children: Notes: 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. If switching from I.V. to oral, the oral dose should be started 8-12 hours after stopping the infusion. Adjunctive therapy with corticosteroids is recommended early post-transplant.

Liver transplant: 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

Adults: Notes: If switching from I.V. to oral, the oral dose should be started 8-12 hours after stopping the infusion. Adjunctive therapy with corticosteroids is recommended early post-transplant.

Heart transplant: Initial dose: 0.075 mg/kg/day in 2 divided doses, given every 12 hours; begin oral dose no sooner than 6 hours post-transplant

Kidney transplant: 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

Liver transplant: 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

I.V.: Children and Adults: Note: I.V. route should only be used in patients not able to take oral medications and continued only until oral medication can be tolerated; anaphylaxis has been reported. Begin no sooner than 6 hours post-transplant; adjunctive therapy with corticosteroids is recommended.

Heart transplant: Initial dose: 0.01 mg/kg/day as a continuous infusion

Kidney, liver transplant: Initial dose: 0.03-0.05 mg/kg/day as a continuous infusion

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

Topical: Children ?2 years and Adults: Atopic dermatitis (moderate to severe): Apply minimum amount of 0.03% or 0.1% ointment to affected area twice daily; rub in gently and completely. Discontinue use when symptoms have cleared. If no improvement within 6 weeks, patients should be re-examined to confirm diagnosis.

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; Child-Pugh score ?10) appears to affect the metabolism of tacrolimus. The half-life of the drug was prolonged and the clearance reduced after I.V. administration. The bioavailability of tacrolimus 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 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: Oral

If dosed once daily (not common), administer in the morning. If dosed twice daily, doses should be 12 hours apart. If the morning and evening doses differ, the larger dose (differences are never >0.5-1 mg) should be given in the morning. If dosed 3 times/day, separate doses by 8 hours.

Administration: I.V.

Administer by I.V. continuous infusion only. Do not use PVC tubing when administering dilute solutions. Tacrolimus is dispensed in a 50 mL glass container with no overfill. It is usually intended to be administered as a continuous infusion over 24 hours.

Administration: Topical

Do not use with occlusive dressings. Burning at the application site is most common in first few days; improves as atopic dermatitis improves. Limit application to involved areas. Continue as long as signs and symptoms persist; discontinue if resolution occurs; re-evaluate if symptoms persist >6 weeks.

Administration: I.V. Detail

Do not mix with acyclovir or ganciclovir due to chemical degradation of tacrolimus (use different ports in multilumen lines). Do not alter dose with concurrent T-tube clamping. Adsorption of the drug to PVC tubing may become clinically significant with low concentrations.

Monitoring Parameters

Renal function, hepatic function, serum electrolytes (especially potassium), glucose and blood pressure, measure 3 times/week for first few weeks, then gradually decrease frequency as patient stabilizes. Whole blood concentrations should be used for monitoring (trough for oral therapy). Signs/symptoms of anaphylactic reactions during infusion should also be monitored. Patients should be monitored during the first 30 minutes of the infusion, and frequently thereafter.

Reference Range

Heart: Typical whole blood trough concentrations:

One week to 3 months: 8-20 ng/mL

Months 3-18: 6-18 ng/mL

Kidney transplant: Whole blood trough concentrations:

Months 1-3: 7-20 ng/mL

Months 4-12: 5-15 ng/mL

Liver transplant: Whole blood trough concentrations: Months 1-12: 5-20 ng/mL

Dietary Considerations

Capsule: Take on an empty stomach; be consistent with timing and composition of meals if GI intolerance occurs (per manufacturer).

Patient Education

Take as directed, on an empty stomach. Be consistent with timing and consistency of meals if GI intolerance occurs (per manufacturer). Do not take within 2 hours before or after antacids. Do not alter dose and do not discontinue without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) during entire course of therapy unless instructed to restrict fluid intake. You will be susceptible to infection (avoid crowds and exposure to infection). If you have diabetes, monitor glucose levels closely (drug may alter glucose levels). You may experience nausea, vomiting, loss of appetite (small frequent meals, frequent mouth care may help); diarrhea (boiled milk, yogurt, or buttermilk may help); constipation (increased exercise, fluids, fruit, fluid, or fiber may help; if unresolved, consult prescriber); or muscle or back pain (mild analgesics may be recommended). Report chest pain; acute headache or dizziness; symptoms of respiratory infection, cough, or respiratory difficulty; unresolved GI effects; fatigue, chills, fever, unhealed sores, white plaques in mouth, irritation in genital area; unusual bruising or bleeding; pain or irritation on urination or change in urinary patterns; rash or skin irritation; or other unusual effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

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.

Additional Information

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

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

Tacrolimus administration has been associated with torsade de pointes. Use with caution in patients at higher risk for proarrhythmia. Correct any underlying conditions that may increase the risk of torsade de pointes prior to tacrolimus administration.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis, oral moniliasis, dysphagia, and esophagitis (including ulcerative).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Insomnia is common

Mental Health: Effects on Psychiatric Treatment

Contraindicated with ziprasidone; barbiturates and carbamazepine may decrease the effects of tacrolimus

Nursing: Physical Assessment/Monitoring

Assess other medications patient may be taking for effectiveness and interactions. Monitor blood pressure frequently. Assess results of laboratory tests prior to, during, and following therapy. Monitor response to therapy and adverse reactions. Patients with diabetes should be advised to monitor glucose levels closely (this medication may alter glucose levels). Monitor/instruct patient on appropriate use, interventions to reduce side effects, to monitor for signs of opportunistic infection, and adverse reactions to report.

Oncology: Vesicant

No

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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)

Pricing: U.S. (www.drugstore.com)

Capsules (Prograf)

0.5 mg (120): $245.99

1 mg (100): $399.99

5 mg (60): $1404.00

Ointment (Protopic)

0.03% (30): $111.92

0.03% (60): $211.40

0.1% (30): $104.71

0.1% (60): $204.73

0.1% (100): $339.92

Extemporaneously Prepared

Tacrolimus 0.5 mg/mL oral suspension: Mix the contents of six 5-mg tacrolimus capsules with equal amounts of Ora-Plus® and Simple Syrup, N.F., to make a final volume of 60 mL. The suspension is stable for 56 days at room temperature in glass or plastic amber prescription bottles.

Esquivel C, So S, McDiarmid S, Andrews W, and Colombani PM, “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).

Tacrolimus 1 mg/mL oral suspension: Mix the contents of six 5-mg capsules in approximately 5 mL of sterile water; add capsule contents to an empty amber bottle first, then add sterile water and agitate bottle until drug disperses and a slurry is formed. Add equal parts of Ora-Plus® (suspending agent) and Ora-Sweet® (sweetening agent) to a total volume of 30 mL. The suspension is stable for 4 months at room temperature in plastic amber prescription bottles.

Elefante A, Muindi J, West K, et al, “Long-Term Stability of a Patient-Convenient 1 mg/mL Suspension of Tacrolimus for Accurate Maintenance of Stable Therapeutic Levels,” Bone Marrow Transplant, 2006, 37(8):781-4.

References

Asante-Korang A, Boyle GJ, Webber SA, et al, “Experience of FK506 Immune Suppression in Pediatric Heart Transplantation: A Study of Long-Term Adverse Effects,” J Heart Lung Transplant, 1996, 15(4):415-22.

Atkison P, Joubert G, Barron A, et al, “Hypertrophic Cardiomyopathy Associated With Tacrolimus in Paediatric Transplant Patients,” Lancet, 1995, 345(8954):894-6.

Bronster DJ, Yonover P, Stein J, et al, “Demyelinating Sensorimotor Polyneuropathy After Administration of FK506,” Transplantation, 1995, 59(7):1066-8.

Cerra FB and Gruber SA, “Critical Care of the Transplant Patient,” Crit Care Clin, 6:813-1034.

Ehst BD and Warshaw EM, “Alcohol-Induced Application Site Erythema After Topical Immunomodulator Use and Its Inhibition by Aspirin,” Arch Dermatol, 2004, 140(8):1014-5.

Furlan V, Perello L, Jacquemin E, et al, “Interactions Between FK506 and Rifampicin or Erythromycin in Pediatric Liver Recipients,” Transplantation, 1995, 59(8):1217-8.

Hodak SP, Moubarak JB, Rodriguez I, et al, “QT Prolongation and Near Fatal Cardiac Arrhythmia After Intravenous Tacrolimus Administration: A Case Report,” Transplantation, 1998, 66(4):535-7.

Johnson MC, So S, March JW, et al, “QT Prolongation and Torsades de Pointes After Administration of FK506,” Transplantation, 1992, 53(4):929-30.

Jusko WJ, Piekoszewski W, Klintmalm GB, et al, “Pharmacokinetics of Tacrolimus in Liver Transplant Patients,” Clin Pharmacol Ther, 1995, 57(3):281-96.

Kaufman DB, Kaplan B, Kanwar YS, et al, “The Successful Use of Tacrolimus (FK506) in a Pancreas/Kidney Transplant Recipient With Recurrent Cyclosporine-Associated Hemolytic Uremic Syndrome,” Transplantation, 1995, 59(12):1737-9.

Kelly PA, Burckart GJ, and Venkataramanan R, “Tacrolimus: A New Immunosuppressive Agent,” Am J Health Syst Pharm, 1995, 52(14):1521-35.

Lubbe J and Milingou M, “Images in Clinical Medicine. Tacrolimus Ointment, Alcohol, and Facial Flushing,” N Engl J Med, 2004, 351(26):2740.

MacDonald AS and Sketris IS, “Tacrolimus in Transplantation,” Am J Health Syst Pharm, 1995, 52(14):1569-71.

McDiarmid SV, Colonna JO, Shaked A, et al, “Differences in Oral FK506 Dose Requirements Between Adults and Pediatric Liver Transplant Patients,” Transplantation, 1993, 55(6):1328-32.

Menegaux F, Keeffe EB, Andrews BT, et al, “Neurological Complications of Liver Transplantation in Adult Versus Pediatric Patients,” Transplantation, 1994, 58(4):447-50.

Minematsu T, Ohtani H, Sato H, et al, “Sustained QT Prolongation Induced by Tacrolimus in Guinea Pigs,” Life Sci, 1999, 65(14):PL197-202.

Mrvos R, Hodgman M, Dean B, et al, “FK506 Overdose: A Report of Four Cases,” Clin Toxicol, 1995, 33(5):487-8.

Natazuka T, Ogawa R, Kizaki T, et al, “Immunosuppressive Drugs and Hypertrophic Cardiomyopathy,” Lancet, 1995, 345(8965):1644.

Podesser BK, Rinaldi M, Yona NA, et al, “Comparison of Low and High Initial Tacrolimus Dosing in Primary Heart Transplant Recipients: A Prospective European Multicenter Study,” Transplantation, 2005, 79(1):65-71.

Przepiorka D, Suzuki J, Ippoliti C, et al, “Blood Tacrolimus Concentration Unchanged by Plasmapheresis,” Am J Hosp Pharm, 1994, 51(13):1708.

Schachner LA, Lamerson C, Sheehan MP, et al, "U.S. Tacrolimus Ointment Study Group: Tacrolimus Ointment 0.03% is Safe and Effective for the Treatment of Mild to Moderate Atopic Dermatitis in Pediatric Patients: Results From a Randomized, Double-Blind, Vehicle-Controlled Study," Pediatrics, 2005, 116(3):e334-42.

Starzl TE, Fung J, Jordan M, et al, “Kidney Transplantation Under FK506,” JAMA, 1990, 264(1):63-7.

Winkel E, DiSesa VJ, and Costanzo MR, “Advances in Heart Transplantation,” Dis Mon, 1999, 45(3):62-87.

Winkler M and Christians U, “A Risk-Benefit Assessment of Tacrolimus in Transplantation,” Drug Saf, 1995, 12(5):348-57.

International Brand Names

  • Advagraf (GB)
  • Limustin (MX)
  • Mustopic Oint (IN)
  • Proalid (MX)
  • Prograf (AE, AR, AU, BH, BR, CH, CL, CN, CO, CY, DE, DK, EG, FR, GB, GR, HK, IE, IL, IQ, IR, JO, JP, KP, KW, LB, LY, MX, MY, OM, PH, PL, PY, QA, SA, SE, SG, SY, TH, TW, UY, VE, YE)
  • Protopic (AT, BE, BG, CH, CL, CZ, DE, DK, EC, ES, FI, FR, GB, GR, HK, HN, IE, IL, IT, KP, MX, MY, NL, NO, PH, PT, RU, SE, SG, TR, TW)
  • Protopy (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
  • Tacrobell (KP)
  • Tacrol (PK)

Lexi-Comp.com

Last full review/revision August 2008

Content last modified August 2008

Back to Top
Audio
Figures
Photographs
Tables
Videos
Contact UsSite MapAccessibility StatementPrivacy PolicyTerms of UseCopyright 1995-2009 Merck & Co., Inc.