tacrolimus (FK506)
Prograf

Available forms
Available by prescription only
Capsules: 0.5 mg, 1 mg, 5 mg
Injection: 5 mg/ml

Indications and dosages
 Organ liver rejection prophylaxis. Adults: Initially, 0.05 to 0.1 mg/kg daily as a continuous I.V. infusion given no sooner than 6 hours after transplantation. Maintain I.V. route only until patient can tolerate oral administration (usually within 2 to 3 days); then give 0.15 to 0.3 mg/kg P.O. daily in two divided doses q 12 hours, beginning 8 to 12 hours after stopping infusion. May use oral dosing originally, if tolerated. Administer doses at lower end of range, if possible.
Children: 0.1 mg/kg I.V. daily or 0.3 mg/kg P.O. daily given no sooner than 6 hours after transplantation. Maintain I.V. route only until patient can tolerate oral administration (usually within 2 to 3 days); then give 0.3 mg/kg P.O. daily in two divided doses q 12 hours, beginning 8 to 12 hours after stopping infusion.

Pharmacodynamics
Immunosuppressant action: Exact mechanism unknown. Inhibits T-lymphocyte activation. Evidence suggests that drug binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin then forms, inhibiting the phosphatase activity of calcineurin. This effect may prevent the generation of nuclear factor of activated T cells, a nuclear component thought to initiate gene transcription for the formation of lymphocyte activation and, therefore, to cause immunosuppression.

Pharmacokinetics
Absorption: Absorption of oral drug from the GI tract varies. Absorption half-life in liver transplant patients is about 5 1/2 hours. Absolute bioavailability is 14% to 17%. Food reduces absorption and bioavailability.
Distribution: Bound to proteins, mainly albumin and alpha-1-acid glycoprotein, and is highly bound to erythrocytes. Protein-binding is between 75% and 99%. Distribution of drug between whole blood and plasma depends on several factors, such as hematocrit, temperature of separation of plasma, drug level, and plasma protein level.
Metabolism: Extensively metabolized by mixed-function oxidase system, primarily cytochrome P-450.
Excretion: Less than 1% of dose is excreted unchanged in urine. Ten possible metabolites have been identified in human plasma. Two metabolites, a demethylated and a double demethylated tacrolimus, are shown to retain 10% and 7%, respectively, of inhibitory effect of tacrolimus on T-lymphocyte activation.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug. I.V. form is contraindicated in those hypersensitive to castor oil derivatives. Use cautiously in patients with impaired renal or hepatic function.

Interactions
Drug-drug. Antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide: May interfere with tacrolimus metabolism. Reduce tacrolimus dosage if needed.
Carbamazepine, phenobarbital, phenytoin, rifamycins: Decreases tacrolimus levels. Increase tacrolimus dosage.
Immunosuppressants (except adrenal corticosteroids): Increases susceptibility to infection. Avoid use together.
Live-virus vaccines: Causes active infection. Avoid use together.
Nephrotoxic drugs (aminoglycosides, amphotericin B, cisplatin, cyclosporine): Increases risk of nephrotoxicity. Avoid use of tacrolimus and cyclosporine; stop one at least 24 hours before starting other. With elevated tacrolimus or cyclosporine levels, further dosing with other drug is usually delayed.
Drug-food. Any food: Inhibits drug absorption. Give drug on empty stomach.
Grapefruit juice: Increases drug blood levels in liver transplant patients. Tell patient not to use together.

Adverse reactions
CNS: headache, tremor, insomnia, paresthesia, asthenia, pain, fever.
CV: hypertension, peripheral edema.
GI: diarrhea, nausea, constipation, anorexia, vomiting, abdominal pain.
GU: abnormal renal function, urinary tract infection, oliguria.
Hematologic: anemia, leukocytosis,THROMBOCYTOPENIA.  
Musculoskeletal: back pain.
Respiratory: pleural effusion, atelectasis, dyspnea.
Skin: pruritus, rash.
Other: ascites, anaphylaxis.

Effects on lab test results
• May increase BUN, creatinine, AST, ALT, LDH, alkaline phosphatase, and glucose levels. May decrease magnesium level. May increase or decrease potassium level.
• May decrease hemoglobin and platelet count. May increase or decrease WBC count.

Overdose and treatment
There’s minimal experience with overdose. Patients who received inadvertent overdose developed no adverse reactions different from those reported at therapeutic doses.
 Provide supportive care and systemic treatment. Because of its poor aqueous solubility and extensive erythrocyte and plasma protein-binding, tacrolimus probably isn’t dialyzable to a significant extent.

Special considerations
• Give adult patients doses at lower end of dosing range. Adjust dosage based on assessment of rejection and tolerance. Lower doses may be sufficient as maintenance therapy. Tacrolimus should be used with adrenal corticosteroids in early posttransplant period.
• Tacrolimus therapy is usually delayed 48 hours or longer in patients with postoperative oliguria.
• Because of risk of anaphylaxis, reserve injection for patients unable to take capsules.
• Dilute I.V. form with normal saline solution injection or D₅W injection to a level between 0.004 and 0.02 mg/ml before use.
 ALERT Continuously observe patient receiving drug I.V. for at least 30 minutes after start of infusion and frequently thereafter. Stop infusion if signs or symptoms of anaphylaxis occur. Have an aqueous solution of epinephrine 1:1,000 and a source of oxygen available at patient’s bedside.
• Because of risk of hyperkalemia (mild to severe hyperkalemia has been noted in 10% to 44% of liver transplant recipients given tacrolimus), monitor serum potassium levels and don’t use potassium-sparing diuretics.
• Closely monitor patient with impaired renal function; dosage may need to be reduced. In patients with persistent elevations of serum creatinine level who are unresponsive to dosage adjustments, consider changing to another immunosuppressive therapy.
• Closely monitor patient experiencing posttransplant hepatic impairment because of increased risk of renal insufficiency related to high whole-blood levels of tacrolimus. Dosage adjustments may be needed.
 ALERT Patients receiving drug are at increased risk for developing lymphomas and other malignancies, particularly of skin. Risk appears to be related to intensity and duration of immunosuppression rather than to use of any specific drug.
• A lymphoproliferative disorder (LPD) related to Epstein-Barr virus (EBV) has been reported in immunosuppressed organ transplant recipients. LPD risk appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to tacrolimus after long-term immunosuppressive therapy.
• Antihypertensive therapy may be needed to control blood pressure elevations linked to drug use. Likewise, therapy may be needed to control blood glucose elevations linked to drug use.
• Black renal transplant patients may need higher doses to maintain comparable whole blood trough drug levels.
• Drug is being investigated for use in kidney, bone marrow, cardiac, pancreas, pancreatic islet cell, and small bowel transplantation. It also may be used to treat autoimmune disease and severe recalcitrant psoriasis.
• Store diluted infusion solution in glass or polyethylene container and discard after 24 hours. Don’t store in polyvinyl chloride container because of decreased stability and potential for extraction of phthalates.
Breast-feeding patients
• Drug appears in breast milk. Avoid use in breast-feeding women.
Pediatric patients
• Children without renal or hepatic dysfunction have needed and tolerated higher doses than adults to achieve similar blood levels. Children should receive high end of recommended adult I.V. and oral dosing ranges (0.1 mg/kg I.V. daily and 0.3 mg/kg P.O. daily). Dosage adjustments may be needed.

Patient education
• Tell patient to take capsules on empty stomach because food impairs drug absorption.
• Inform patient of need for repeated laboratory tests during therapy to watch for adverse reactions and monitor drug effectiveness.
• Advise woman of childbearing age to call if she becomes pregnant or plans to become pregnant.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use