No

Immunosuppressant Agent

Potent immunosuppressive drug used in liver, kidney, heart, lung, small bowel transplant recipients; immunosuppressive drug for peripheral stem cell/bone marrow transplantation

C

Tacrolimus crosses the placenta and reaches concentrations four times greater than maternal plasma concentrations

Tacrolimus concentrations in breast milk are equivalent to plasma concentrations; breast-feeding is not advised while therapy is ongoing

Hypersensitivity to tacrolimus or any component; hypersensitivity to HCO-60 polyoxyl 60 hydrogenated castor oil (used in the parenteral dosage formulation) is a contraindication to parenteral tacrolimus therapy

Increased susceptibility to infection and the possible development of lymphoma may occur after administration of tacrolimus; it should not be administered simultaneously with cyclosporine; since the pharmacokinetics show great inter- and intrapatient variability over time, 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. Injection contains small volume of ethanol.

>10%:

Cardiovascular: Hypertension, peripheral edema

Central nervous system: Headache, insomnia, pain, fever

Dermatologic: Pruritus

Endocrine & metabolic: Hypo-/hyperkalemia, hyperglycemia, hypomagnesemia

Gastrointestinal: Diarrhea, nausea, anorexia, vomiting, abdominal pain

Hematologic: Anemia, leukocytosis

Hepatic: LFT abnormalities, ascites

Neuromuscular & skeletal: Tremors, paresthesias, back pain, weakness

Renal: Nephrotoxicity, increased BUN/creatinine

Respiratory: Pleural effusion, atelectasis, dyspnea

Miscellaneous: Infection

1% to 10%:

Central nervous system: Seizures

Dermatologic: Rash

Endocrine & metabolic: Hyperphosphatemia, hyperuricemia, pancreatitis

Gastrointestinal: Constipation

Genitourinary: Urinary tract infection

Hematologic: Thrombocytopenia

Neuromuscular & skeletal: Myoclonus

Renal: Oliguria

<1%: Hypertrophic cardiomyopathy, arthralgia, myalgia, hemolytic uremic syndrome, anaphylaxis, expressive aphasia, photophobia, secondary malignancy

Symptoms are extensions of pharmacologic activity and listed adverse effects

Symptomatic and supportive treatment required, hemodialysis is not effective

CYP3A3/4 enzyme substrate

Increased effect: Cyclosporine is associated with synergistic immunosuppression and increased nephrotoxicity

Increased toxicity: Nephrotoxic antibiotics, NSAIDs and amphotericin B potentially increase nephrotoxicity

Drugs which may INCREASE tacrolimus blood levels:

Calcium channel blockers: Diltiazem, nicardipine, verapamil

Antibiotic/antifungal agents: Clotrimazole, erythromycin, fluconazole, itraconazole, ketoconazole

Other drugs: Bromocriptine, cimetidine, clarithromycin, cyclosporine, danazol, methylprednisolone, metoclopramide, grapefruit juice

Drugs which may DECREASE tacrolimus blood levels:

Anticonvulsants: Carbamazepine, phenobarbital, phenytoin

Antibiotics: Rifabutin, rifampin

Polyvinyl-containing sets (eg, Venoset®, Accuset®) adsorb significant amounts of the drug, and their use may lead to a lower dose being delivered to the patient; tacrolimus capsules should be stored at controlled room temperature (15°C to 30°C). FK506 admixtures prepared in 5% dextrose injection or 0.9% sodium chloride injection should be stored in polyolefin containers or glass bottles. Infusion of FK506 through PVC tubings did not result in decreased concentration of the drug, however, loss by absorption may be more important when lower concentrations of FK506 are used. Stable for 48 hours in D₅W or NS in glass or polyolefin containers.

Binds to 40 FK binding protein resulting in inhibition of calcium-dependent signal transduction pathway in T cells, thereby blocking the secretion of IL-2 and other cytokines

Absorption: Highly variable following oral administration; food may reduce absorption

Peak serum concentrations 0.4-5.6 mg/mL after single oral dose of 0.15 mg/kg.

Distribution: Highly lipophilic and undergoes extensive tissue distribution; sequestered by erythrocytes which result in plasma concentrations 10- to 30-fold lower than whole blood concentrations

V_d: ~17 L/kg

Protein binding, plasma: ~88%

Metabolism: Extensive in the liver by cytochrome P-450 isozymes IA and 3A4

Bioavailability: Oral: Ranges from 5% to 67% (mean: ~27%)

Half-life, elimination: ~8.7 hours (mean)

Plasma clearance following intravenous administration: ~143 L/hour (mean)

Elimination: <1% of the parent compound excreted in the bile and urine

Children: 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.

Oral: 0.3 mg/kg/day divided every 12 hours; children generally require higher maintenance dosages on a mg/kg basis than adults

I.V. continuous infusion: 0.05-0.15 mg/kg/day

Adults:

Oral (usually 3-4 times the I.V. dose): 0.15-0.30 mg/kg/day in two divided doses administered every 12 hours and given 8-12 hours after discontinuation of the I.V. infusion. Lower tacrolimus doses may be sufficient as maintenance therapy.

Solid organ transplantation: Oral: 0.15-0.30 mg/kg/day in two divided doses administered every 12 hours; lower tacrolimus doses may be sufficient as maintenance therapy

Peripheral stem cell/bone marrow transplantation: Oral (usually ~2-3 times the intravenous dose): 0.06-0.09 mg/kg/day (maximum: 0.12 mg/kg/day) in two divided doses administered every 12 hours and given 8-12 hours after discontinuation of the intravenous infusion; adjust doses based on trough serum concentrations

I.V.:

Solid organ transplantation: Initial (given at least 6 hours after transplantation): 0.05-0.10 mg/kg/day; corticosteroid therapy is advised to enhance immunosuppression. Patients should be switched to oral therapy as soon as possible (within 2-3 days).

Peripheral stem cell/bone marrow transplantation: Initial: 0.03 mg/kg/day as a continuous intravenous infusion

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) appears to affect the metabolism of FK506. The half-life of the drug was prolonged and the clearance reduced after I.V. administration. The bioavailability of FK506 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 FK506 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. See the following dosing considerations:

Switch from I.V. to oral therapy: Threefold increase in dose

T-tube clamping: No change 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

Dialysis: Not removed

Inhibitors of hepatic metabolism: Decrease dose

Inducers of hepatic metabolism: Monitor drug level; increase dose

Renal function, hepatic function, serum electrolytes, glucose and blood pressure, hypersensitivity indicators, neurological responses, and other clinical parameters; monitoring of serum concentrations (trough for oral therapy), see Warnings/Precautions; measure 3 times/week for first few weeks, then gradually decrease frequency as patient stabilizes

Whole blood: Trough level: 7-20 ng/mL (ELISA). Plasma levels are generally 0.02-0.2 times whole blood levels; increased precision with whole blood levels.

Plasma: Trough levels: 0.5-2 ng/mL (ELISA, plasma, extracted at 37°C) for all transplant procedures (liver, heart, lung, kidney, small bowel) whole blood measurements produce concentration 5-40 times higher than those in serum due to high binding to RBCs (therapeutic range: 5-10 ng/mL, although levels >20 mg/mL may be desirable for short periods to prevent rejection)

Insomnia is common

Barbiturates and carbamazepine may decrease the effects of tacrolimus

No information available to require special precautions

No effects or complications reported

Take as directed, preferably 30 minutes hour before or 30 minutes after meals. 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 unless instructed to restrict fluid intake) during entire course of therapy. You will be susceptible to infection (avoid crowds and people with infections or contagious diseases). If you are diabetic, monitor glucose levels closely (may alter glucose levels). You may experience nausea, vomiting, loss of appetite (frequent small meals, frequent mouth care may help); diarrhea (boiled milk, yogurt, or buttermilk may help); constipation (increased exercise or dietary fruit, fluid, or fiber may help, if not consult prescriber); muscle or back pain (mild analgesics may be recommended). Report chest pain; acute headache or dizziness; symptoms of respiratory infection, cough, or difficulty breathing; unresolved gastrointestinal 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 related to this medication. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

For I.V. administration, tacrolimus is dispensed in a 50 mL glass container or nonpolyvinyl chloride container; it is intended to be infused over at least 12 hours; polyolefin administration sets should be used

Capsule: 1 mg, 5 mg

Injection, with alcohol and surfactant: 5 mg/mL (1 mL)

Tacrolimus oral suspension can be compounded at a concentration of 0.5 mg/mL; an extemporaneous suspension can be prepared by mixing 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.

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).

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.

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.

Jusko WJ, Piekoszewski W, Klintmalm GB, et al, "Pharmacokinetics of Tacrolimus in Liver Transplant Patients," Clin Pharmacol Ther, 1995, 57(3):281-96.

Kaufman DB, Kaplan B, Kanwar YS, et al, "The Successful Use of Tacrolimus (FK506) in a Pancreas/Kidney Transplant Recipient With Recurrent Cyclosporine-Associated Hemolytic Uremic Syndrome," Transplantation, 1995, 59(12):1737-9.

Kelly PA, Burckart GJ, and Venkataramanan R, "Tacrolimus: A New Immunosuppressive Agent," Am J Health Syst Pharm, 1995, 52(14):1521-35.

MacDonald AS and Sketris IS, "Tacrolimus in Transplantation," Am J Health Syst Pharm, 1995, 52(14):1569-71.

McDiarmid SV, Colonna JO, Shaked A, et al, "Differences in Oral FK506 Dose Requirements Between Adults and Pediatric Liver Transplant Patients," Transplantation, 1993, 55(6):1328-32.

Menegaux F, Keeffe EB, Andrews BT, et al, "Neurological Complications of Liver Transplantation in Adult Versus Pediatric Patients," Transplantation, 1994, 58(4):447-50.

Mrvos R, Hodgman M, Dean B, et al, "FK506 Overdose: A Report of Four Cases," Clin Toxicol, 1995, 33(5):487-8.

Natazuka T, Ogawa R, Kizaki T, et al, "Immunosuppressive Drugs and Hypertrophic Cardiomyopathy," Lancet, 1995, 345(8965):1644.

Przepiorka D, Suzuki J, Ippoliti C, et al, "Blood Tacrolimus Concentration Unchanged by Plasmapheresis," Am J Hosp Pharm, 1994, 51(13):1708.

Starzl TE, Fung J, Jordan M, et al, "Kidney Transplantation Under FK506," JAMA, 1990, 264(1):63-7.

Winkler M and Christians U, "A Risk-Benefit Assessment of Tacrolimus in Transplantation," Drug Saf, 1995, 12(5):348-57.