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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
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
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.
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International Brand Names
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Last full review/revision August 2008
Content last modified August 2008
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