TACROLIMUS

TACROLIMUS (tac-rol'i-mus) Prograf, Protopic Classifications: biologic response modifier; immunosuppressant; Therapeutic:immunosuppressant Prototype: Cyclosporine Pregnancy Category: C

Availability

0.5 mg, 1 mg, 5 mg capsules; 5 mg/mL injection; 0.1%, 0.03% ointment

Action

Inhibits helper T-lymphocytes by selectively inhibiting secretion of interleukin-2, interleukin-3, and interleukin-gamma; thus reduces transplant rejection.

Therapeutic Effect

Inhibits antibody production (thus subduing immune response) by creating an imbalance in favor of suppressor T-lymphocytes.

Uses

Liver rejection prophylaxis; rejection prophylaxis for other organ transplants (kidney, heart, bone marrow, pancreas, small bowel), moderate to severe atopic dermatitis (e.g., eczema).

Unlabeled Uses

Acute organ transplant rejection, severe plaque-type psoriasis.

Contraindications

Hypersensitivity to tacrolimus or castor oil; pregnancy (category C), lactation.

Cautious Use

Renal or hepatic insufficiency, hyperkalemia, QT prolongation; CHF; diabetes mellitus, gout, history of seizures, hypertension.

Route & Dosage

Rejection Prophylaxis Adult: PO 0.15–0.2 mg/kg/d in 2 divided doses q12h, start no sooner than 6 h after transplant; give first oral dose 8–12 h after discontinuing IV therapy IV 0.01–0.05 mg/kg/d as continuous IV infusion, start no sooner than 6 h after transplant, continue until patient can take oral therapy Child: PO 0.15–0.2 mg/kg/d IV 0.03–0.05 mg/kg/d Atopic Dermatitis Adult: Topical Apply thin layer to affected area b.i.d., continue until clearing of symptoms Child (2–15 y): Topical Apply thin layer of 0.03% ointment to affected area b.i.d., continue until clearing of symptoms Severe Plaque-Type Psoriasis Adult: PO Start with 0.05 mg/kg/d, increase to 0.1 mg/kg/d at week 3 and to 0.15 mg/kg/d at week 6 if necessary Renal Impairment Start with lower dose. Hemodialysis: Supplementation not necessary

Administration

Oral

• Discontinue cyclosporine at least 24 h before the first dose of tacrolimus.
• Convert patient from IV to oral therapy as soon as possible.
• Give first oral dose 8–12 h after discontinuing IV infusion.

Topical

• Ensure that skin is clean and completely dry before application.
• Apply a thin layer to the affected area and rub in gently and completely.
• Do not apply occlusive dressing over the site.

Intravenous PREPARE: IV Infusion: Dilute 5 mg/mL ampules with NS or D5W to a concentration of 0.004–0.02 mg/mL; use a less concentrated solution for pediatric patients.   ADMINISTER: IV Infusion: Give as continuous IV.   INCOMPATIBILITIES Y-site: Phenytoin.

• Store ampules between 5° and 25° C (41° and 77° F); store capsules at room temperature, 15°–30° C (59°–86° F).
• Store the diluted infusion in glass or polyethylene containers and discard after 24 h.

Adverse Effects (≥1%)

CNS: Headache, tremors, insomnia, paresthesia, hyperesthesia and/or sensations of warmth, circumoral numbness. CV: Mild to moderate hypertension. Endocrine: Hirsutism, hyperglycemia, hyperkalemia, hypokalemia, hypomagnesemia, hyperuricemia, decreased serum cholesterol. GI: Nausea, abdominal pain, gas, appetite changes, vomiting, anorexia, constipation, diarrhea, ascites. Hematologic: Anemia, leukocytosis, thrombocytopenia purpura. Urogenital: UTI, oliguria, nephrotoxicity. Respiratory: Pleural effusion, atelectasis, dyspnea. Special Senses: Blurred vision, photophobia. Skin: Flushing, rash, pruritus, skin irritation, alopecia, erythema, folliculitis, hyperesthesia, exfoliative dermatitis, hirsutism, photosensitivity, skin discoloration, skin ulcer, sweating. Body as a Whole: Pain, fever, peripheral edema, increased risk of cancer.

Interactions

Drug: Use with cyclosporine increases risk of nephrotoxicity. Erythromycin, metoclopramide may increase levels; caspofungin, rifampin may decrease levels. nsaids may lead to oliguria or anuria. Herbal: St. John's wort decreases efficacy. Food: Grapefruit juice (>1 qt/d) may increase plasma concentrations and adverse effects.

Pharmacokinetics

Absorption: Erratic and incompletely from GI tract; absolute bioavailability approximately 14–25%; absorption reduced by food. Peak: PO 1–4 h. Duration: IV 12 h. Distribution: Within plasma, tacrolimus is found primarily in lipoprotein-deficient fraction; 75–97% protein bound; distributed into red blood cells; blood:plasma ratio reported >4; animal studies have demonstrated high concentrations of tacrolimus in lung, kidney, heart, and spleen; distributed into breast milk. Metabolism: Extensively in liver (CYP3A4). Elimination: Metabolites primarily in bile. Half-Life: 8.7–11.3 h.

Nursing Implications

Assessment & Drug Effects

• Lab tests: Monitor serum electrolytes, blood glucose, uric acid, BUN, and creatinine clearance periodically.
• Monitor kidney function closely; report elevated serum creatinine or decreased urinary output.
• Monitor for neurotoxicity, and report tremors, changes in mental status, or other signs of toxicity.
• Monitor cardiovascular status and report hypertension.

Patient & Family Education

• Learn complete dosing instructions.
• Be aware of potential adverse effects.
• Minimize exposure to natural or artificial sunlight while using the ointment.
• Notify physician of S&S of neurotoxicity.

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Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug