Tacrolimus

Pronunciation

Pronunciation: tak-ROE-li-mus
Class: Immunosuppressive, Immunomodulator

Trade Names

Prograf
- Capsules 0.5 mg
- Capsules 1 mg
- Capsules 5 mg
- Injection, solution, concentrate 5 mg/mL

Protopic
- Ointment 0.03%
- Ointment 0.1%

Protopic (Canada)

Pharmacology

Suppresses cell-mediated immune reactions and some humoral immunity, but exact mechanism is not known. The mechanism of action in atopic dermatitis is not known.

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Pharmacokinetics

Absorption

In healthy volunteers, as well as kidney and liver transplant patients, tacrolimus C max ranged from approximately 19.2 to 68.5 ng/mL, T max ranged from 1.5 to 3 h, AUC ranged from 203 to 3,300 ng•h/mL, half-life ranged from 11.7 to 34.8 h, and bioavailability ranged from approximately 17% to 23%.

Food effects

The rate and extent of absorption were greatest under fasted conditions. The presence and composition of food decreased the rate and extent of absorption. The effect was most pronounced with a high-fat meal. Mean AUC and C max were decreased 37% and 77%, respectively. T max was lengthened 5-fold. A high-carbohydrate meal decreased mean AUC and mean C max 28% and 65%, respectively.

Distribution

Tacrolimus Vd is approximately 0.85 to 1.94 L/kg. Protein binding is about 99%, mainly to albumin and alpha-1 acid glycoprotein.

Metabolism

Tacrolimus is extensively metabolized by the mixed function oxidation system, primarily the CYP-450 system (CYP3A). The major metabolite identified is 13-demethyl tacrolimus.

Elimination

Cl is about 0.04 to 0.083 L/h/kg. Less than 1% of an administered dose is excreted unchanged in the urine. The half-life is approximately 31.9 to 48.4 h (PO and IV).

Special Populations

Hepatic Function Impairment

The mean Cl was substantially lower and half-life prolonged in patients with severe hepatic impairment.

Children

Children younger than 12 yr of age need higher doses than adults to achieve similar trough concentrations.

Gender

No pharmacokinetic differences have been identified.

Race

Kidney transplant patients who are black require a higher tacrolimus dose to attain trough concentrations similar to white patients.

Indications and Usage

PO and IV

Prophylaxis of organ rejection in patients receiving allogenic liver, kidney, or heart transplants. Used in conjunction with adrenal corticosteroids. Used in conjunction with azathioprine or mycophenolate mofetil in heart and kidney transplant patients.

Topical

As second-line therapy for the short-term and noncontinuous long-term treatment of moderate to severe atopic dermatitis.

Unlabeled Uses

PO and IV

Prophylaxis of rejection for patients receiving bone marrow, pancreas, pancreatic island cell, and small bowel transplantation; treatment of autoimmune disease (ie, rheumatoid arthritis); prevention and treatment of acute graft-versus-host disease following hematopoietic stem cell transplantation; treatment of Crohn disease; treatment of pyoderma gangrenosum.

Topical

Treatment of vitiligo; cutaneous lupus erythematosis; facial, flexural, and intertriginous psoriasis; oral or genital lichen planus; pyoderma gangrenosum.

Contraindications

Hypersensitivity to tacrolimus or polyoxyl 60 hydrogenated castor oil, which is present in the injection, or any component of the product.

Dosage and Administration

Prophylaxis of Organ Rejection, Heart Transplants
Adults

PO 0.075 mg/kg/day in 2 divided daily doses every 12 h no sooner than 6 h after transplantation. IV 0.01 mg/kg/day as continuous infusion.

Prophylaxis of Organ Rejection, Kidney Transplants
Adults

PO 0.2 mg/kg/day (in combination with azathioprine) or 0.1 mg/kg/day (in combination with mycophenolate mofetil and interleukin-2 [IL-2] receptor antagonist) in 2 divided daily doses every 12 h, starting within 24 h of transplantation but delayed until renal function is recovered (eg, serum creatinine of 4 mg/dL or less). Black patients may require higher doses to achieve comparable blood concentration. IV 0.03 to 0.05 mg/kg/day as continuous infusion.

Prophylaxis of Organ Rejection, Liver Transplants
Adults

PO 0.1 to 0.15 mg/kg/day in 2 divided daily doses every 12 h no sooner than 6 h after transplantation. IV 0.03 to 0.05 mg/kg/day as continuous infusion.

Children

PO 0.15 to 0.2 mg/kg/day in 2 divided daily doses every 12 h. IV 0.03 to 0.05 mg/kg/day as continuous infusion.

Topical Dermatitis
Adults

Topical Apply thin layer of 0.03% or 0.1% to affected skin areas twice daily. Rub in gently and completely. Continue for 1 wk after clearing of atopic dermatitis.

Children (2 yr of age and older)

Topical Apply thin layer of 0.03% to affected skin areas twice daily. Rub in gently and completely. Continue for 1 wk after clearing of atopic dermatitis.

General Advice

  • Injection
  • For IV administration only. Not for intradermal, subcutaneous, IM, or intra-arterial administration.
  • Switch patients from the IV to the oral form of the medication as soon as possible.
  • When converting from IV to oral dosage form, give the first oral dose no sooner than 8 to 12 h after discontinuation of IV administration.
  • Topical
  • Do not use occlusive dressings with topical use.

Storage/Stability

Store capsules at 59° to 86°F. Store injection at 41° to 77°F. Store diluted solution in glass or polyethylene containers and discard after 24 h. Store ointment at 59° to 86°F. Keep tightly capped.

Drug Interactions

Amiodarone, antifungal agents (eg, clotrimazole, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), bromocriptine, calcium channel blockers (eg, diltiazem, felodipine, nicardipine, nifedipine, verapamil), chloramphenicol, cimetidine, cisapride, cyclosporine, danazol, ethinyl estradiol, HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), macrolide antibiotics (eg, clarithromycin, erythromycin, troleandomycin), magnesium-aluminum hydroxide, methylprednisolone, metoclopramide, metronidazole, nefazodone, protease inhibitors (eg, indinavir, ritonavir, saquinavir), proton pump inhibitors (eg, lansoprazole, omeprazole), telithromycin

Tacrolimus blood concentrations may be elevated, increasing the risk of toxicity.

Carbamazepine, caspofungin, fosphenytoin, phenobarbital, phenytoin, rifabutin, rifampin, sirolimus, St. John's wort

Tacrolimus blood concentrations may be reduced, increasing the risk of transplant rejection.

CYP3A4 inhibitors (eg, cimetidine, erythromycin, ketoconazole)

Use with caution during topical administration.

Ethanol

Risk of facial flushing may be increased with topical tacrolimus.

Hydantoins (eg, phenytoin)

Tacrolimus plasma levels may be reduced, while hydantoin concentrations may be increased.

Mycophenolate mofetil, sildenafil, simvastatin

Plasma levels may be elevated by tacrolimus, increasing the risk of adverse reactions.

Nephrotoxic agents (eg, aminoglycosides, amphotericin B, cisplatin, cyclosporine)

Additive nephrotoxicity.

Potassium-sparing diuretics

Avoid use with tacrolimus because of the potential for tacrolimus to cause hyperkalemia.

Sirolimus

Tacrolimus blood concentrations may be elevated. Coadministration of tacrolimus and sirolimus in combination with corticosteroids has been associated with fatal cases of bronchial anastomotic dehiscence in lung transplant patients. The combination is not recommended.

Vaccination (eg, BCG, measles, mumps, oral polio, rubella, TY 21a typhoid, yellow fever)

Vaccination may be less effective. Avoid use of live vaccines.

Ziprasidone

Risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased. Coadministration is contraindicated.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The incidences of the following oral/IV adverse reactions were reported with combined use of tacrolimus and steroids or azathioprine. The reported incidences for topical tacrolimus represent monotherapy.

CNS

Oral/IV

Headache, insomnia (64%); tremor (56%); asthenia (52%); paresthesia (40%); dizziness (19%); carpal tunnel syndrome, cerebral infection, feeling jittery, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome, progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder (postmarketing).

Topical

Headache (20%); insomnia (4%); asthenia (3%); anxiety, depression, dizziness, malaise, migraine, neuritis, paresthesia, vertigo (at least 1%).

Cardiovascular

Oral/IV

Hypertension (62%); chest pain (19%); pericardial effusion (15%); atrial fibrillation, atrial flutter, cardiac arrest, cardiac arrhythmia, deep limb venous thrombosis, ECG T wave abnormal, flushing, MI, myocardial hypertrophy associated with ventricular dysfunction, myocardial ischemia, pericardial effusion, QT prolongation, syncope, torsades de pointes, ventricular extrasystoles, ventricular fibrillation (postmarketing).

Topical

Angina pectoris, arrhythmia, cerebrovascular accident, hypertension, palpitations, peripheral vascular disorder, vasodilation (at least 1%).

Dermatologic

Oral/IV

Pruritus (36%); rash (24%); Stevens-Johnson syndrome, TEN (postmarketing).

Topical

Skin burning (58%); pruritus (46%); skin erythema (28%); skin infection (12%); skin tingling (8%); acne, hyperesthesia (7%); folliculitis, urticaria (6%); rash (5%); contact dermatitis, pustular rash, skin disorder, vesiculobullous rash (4%); cyst, dry skin, eczema herpeticum, exfoliative dermatitis (3%); eczema, face edema, fungal dermatitis, maculopapular rash, sunburn (2%); benign skin neoplasm (1%); alopecia, cellulitis, furunculosis, photosensitivity reaction, skin discoloration, sweating (at least 1%).

EENT

Oral/IV

Blindness, cortical blindness, loss of hearing (including deafness), photophobia (postmarketing).

Topical

Otitis media (12%); pharyngitis, rhinitis (6%); conjunctivitis (2%); ear pain, epistaxis, eye disorder, eye pain, laryngitis (at least 1%).

GI

Oral/IV

Diarrhea (72%); abdominal pain (59%); nausea (46%); constipation (36%); anorexia (34%); vomiting (29%); dyspepsia (28%); bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hemorrhagic pancreatitis, impaired gastric emptying, mouth ulceration, necrotizing pancreatitis, stomach ulcer (postmarketing).

Topical

Diarrhea (5%); dyspepsia (4%); abdominal pain, nausea (3%); gastroenteritis (2%); periodontal abscess, vomiting (1%); anorexia, constipation, gastritis, taste perversion, tooth disorder (at least 1%).

Genitourinary

Oral/IV

Abnormal kidney function (56%); urinary tract infection (34%); oliguria (19%); acute renal failure, hemolytic-uremic syndrome, hemorrhagic cystitis, micturition disorder (postmarketing).

Topical

Dysmenorrhea (4%); breast pain, creatinine increased, unintended pregnancy, vaginal moniliasis (at least 1%).

Hematologic-Lymphatic

Oral/IV

Anemia (50%); leukopenia (48%); leukocytosis (32%); thrombocytopenia (24%); DIC, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura (postmarketing).

Topical

Lymphadenopathy (3%); ecchymosis, leukocytosis, leukopenia (at least 1%).

Hepatic

Oral/IV

Fatty liver, hepatic cytolysis, hepatic necrosis, hepatotoxicity, venoocclusive liver disease (postmarketing).

Topical

ALT or AST increased, bilirubinemia, LFTs abnormal (at least 1%).

Lab Tests

Oral/IV

Creatinine increased (45%); LFTs abnormal (36%); BUN increased (30%).

Metabolic-Nutritional

Oral/IV

Hypophosphatemia (49%); hypomagnesemia (48%); hyperglycemia (47%); hyperkalemia (45%); peripheral edema (36%); hyperlipemia (31%); hypokalemia (29%); diabetes mellitus (26%); edema, hyperlipidemia (18%); cushingoid features (less than 15%); amylase increased (including pancreatitis), glycosuria, weight decreased (postmarketing).

Topical

Peripheral edema (36%); dehydration, hyperglycemia, hypoglycemia (at least 1%).

Musculoskeletal

Oral/IV

Back pain (30%); arthralgia (25%).

Topical

Myalgia (3%); back pain (2%); arthralgia, arthritis, neck pain (at least 1%).

Respiratory

Oral/IV

Pleural effusion (36%); dyspnea (29%); atelectasis (28%); cough (18%); bronchitis (17%); acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure (postmarketing).

Topical

Asthma (6%); sinusitis (4%); bronchitis (3%); cough increased, pneumonia (1%); dyspnea, hypoxia, lung disorder (at least 1%).

Miscellaneous

Oral/IV

Pain (63%); fever (48%); infection (45%); cytomegalovirus infection (32%); renal transplant incision-site complication (28%); ascites (27%); renal graft dysfunction (24%); Candida infection, impaired wound healing (less than 15%); feeling hot and cold, hot flushes, multiorgan failure, primary graft dysfunction (postmarketing).

Topical

Fever (21%); flu-like symptoms (18%); allergic reaction (12%); alcohol intolerance, infection (7%); accidental injury (6%); varicella zoster/herpes zoster (5%); herpes simplex, (4%); cyst (3%); pain (2%); lack of drug effect (1%); anaphylactoid reaction, angioedema, cheilitis, chills, edema, exacerbation of untreated area, hernia, procedural complication (routine procedure) (at least 1%).

Precautions

Warnings

Oral/IV

Increased risk of lymphoma and increased susceptibility to infection may be related to immunosuppression.

Administer under the supervision of an experienced health care provider and in an equipped facility.

Topical

Long-term safety of topical tacrolimus has not been established. Rare cases of malignancy (eg, lymphoma, skin cancer) have been associated with topical tacrolimus treatment. Avoid long-term use of tacrolimus ointment and limit application to areas of atopic dermatitis involvement. Not indicated in children younger than 2 yr of age. Only 0.03% strength is indicated for children 2 to 15 yr of age.


Monitor

Monitor tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters to evaluate rejection, toxicity, dose adjustments, and compliance. Assess serum creatinine, potassium, and fasting glucose regularly. Perform routine monitoring of metabolic and hematologic systems.


Pregnancy

Category C .

Lactation

Excreted in breast milk. Avoid breast-feeding.

Children

Children generally require higher doses to maintain trough tacrolimus levels similar to adults (oral and IV). Safety and efficacy not established in children younger than 2 yr of age (topical).

Renal Function

May require reduced doses; monitor closely.

Hepatic Function

Patients with hepatic disease may require reduced doses (Child-Pugh class 10 or higher).

Anaphylactic reactions

May occur with IV injection.

Diabetes mellitus

Insulin-dependent posttransplant diabetes mellitus has been reported.

Hyperglycemia

Frequently occurs with tacrolimus; may require treatment.

Hypertension

May occur. Antihypertensive therapy may be required.

Immunosuppression

Avoid use in immunocompromised patients (topical). Safety and efficacy not established.

Infections

Lymphoproliferative disorder related to Epstein-Barr virus infection and activation of latent viral infections (including BK virus associated neuropathy and JC virus associated PML) has been reported in patients on immunosuppressants.

Lymphadenopathy

Investigate the etiology of lymphadenopathy occurring in patients receiving the topical ointment.

Malignancies

Increased risk of developing malignancies, particularly of the skin, in patients treated with tacrolimus.

Myocardial hypertrophy

Has been reported; manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness.

Nephrotoxicity

May occur; particularly when used in high doses.

Netherton syndrome

Topical use is not recommended.

Neurotoxicity

Neurotoxicity (including headache and tremor) and other changes in motor function, mental status, and sensory function have been reported.

Topical infections

Resolve clinical infections at treatment sites before starting topical therapy.

Viral infections

The topical ointment may be associated with increased risk of varicella zoster virus infection (eg, chickenpox or shingles), herpes simplex virus infection, or eczema herpeticum.

Overdosage

Symptoms

Maximum tolerated dose not established; transient urticaria and lethargy observed in 1 case of acute overdose.

Patient Information

  • Advise patient to use product exactly as prescribed.
  • Capsules and Injection
  • Warn patient not to alter the dose or discontinue the medication without consulting health care provider.
  • Advise patient to report any serious adverse reactions to health care provider.
  • Inform patient of the need for frequent laboratory tests to assess the efficacy of the treatment regimen and of the need to keep appointments.
  • Direct patient to avoid contact with others who may have any type of infection.
  • Direct patient to take capsules 30 min before or 2 h after meals. If the medication causes GI upset, instruct patient to take with a full glass of water. May be taken with food, but it is less effective.
  • Inform patients that tacrolimus can cause diabetes mellitus and advise them to inform health care provider if they develop frequent urination or increased thirst or hunger.
  • Inform patients of the increased risk of neoplasia.
  • Advise patients that exposure to sunlight and UV light should be limited by wearing protective clothing and using sunscreen with a high protection factor because of the increased risk for skin cancer.
  • Ointment
  • Advise patient or caregiver to carefully read the Medication Guide before using the first time and with each refill.
  • Advise patient or caregiver to apply ointment topically to skin lesions twice daily.
  • Teach patient or caregiver proper technique for applying ointment: wash hands; apply a thin film of ointment to cover involved areas; wash hands after applying unless hands are also being treated.
  • Advise patient or caregiver to be sure skin is completely dry before applying ointment after a bath or shower.
  • Advise patient to stop therapy after signs and symptoms of dermatitis have resolved. If symptoms return, follow health care provider's advice.
  • Caution patient not to cover treated areas with bandages, dressings, or wraps.
  • Warn patient to avoid contact with the eyes.
  • Advise patient that if ointment comes in contact with the eyes, to wash eyes with large amounts of cool water and to contact health care provider if eye irritation persists.
  • Advise patient that burning sensations, stinging, soreness, or itching at the application site are the most common adverse reactions and to notify health care provider if symptoms become severe or persist for more than several days.
  • Advise patient to contact health care provider if condition does not improve after 6 wk of treatment or if condition worsens.
  • Advise patient to check with health care provider before using any other topical agents (eg, medicated soaps, astringents, cosmetics) on treated skin.
  • Warn patient to avoid unnecessary exposure to sun and sunlamps while using this medication. Advise patient to use sunscreen (minimum of SPF 15) and wear protective clothing over treated areas when exposure cannot be avoided.

Copyright © 2009 Wolters Kluwer Health.

Hide
(web3)