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Tacrolimus

Pronouncation: (tak-ROE-li-mus)
Class: Immunosuppressive, Immunomodulator

Trade Names:
Prograf
- Capsules 0.5 mg
- Capsules 1 mg
- Capsules 5 mg
- Injection 5 mg/mL

Trade Names:
Protopic
- Ointment 0.03%
- Ointment 0.1%

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.

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, t _½ ranged from 11.7 to 34.8 h, and bioavailability ranged from approximately 17% to 22%.

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 about 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 t _½ is approximately 31.9 to 48.1 h (PO and IV).

Special Populations

Hepatic Function Impairment

The mean Cl was substantially lower and t _½ prolonged in patients with severe hepatic function impairment.

Children

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

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.

Topical

As second-line therapy for the short-term and noncontinuous chronic 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.

Topical

Treatment of vitiligo in children; facial, flexural, and intertriginous psoriasis.

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, 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.

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 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.

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

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.
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

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, fosphenytoin, lansoprazole, macrolide antibiotics (eg, clarithromycin, erythromycin, troleandomycin), magnesium-aluminum hydroxide, methylprednisolone, metoclopramide, metronidazole, nefazodone, omeprazole, protease inhibitors (eg, indinavir, ritonavir, saquinavir), telithromycin, theophylline

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

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

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

Cyclosporine

Additive nephrotoxicity.

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.

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

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. 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.

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.

Lymphadenopathy

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

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.

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.
Patient should 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 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, take with a full glass of water. May be taken with food, but it is less effective.

Ointment
Advise patient or caregiver to carefully read the Medication Guide before using the first time and with each refill.
Advise patient or caregiver that ointment is applied 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 that if condition does not improve after 6 wk of treatment or if condition worsens, to contact health care provider.
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 sunscreens (minimum of SPF 15) and wear protective clothing over treated areas when exposure cannot be avoided.

More Tacrolimus resources:

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