Tacrol0.1%

Tacrol 0.1% is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants

Drugs affecting the immune response

Tacrol 0.1% inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that Tacrol 0.1% binds to an intracellular protein, FKBP-12. A complex of Tacrol 0.1%-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).Tacrol 0.1% prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.In animals, Tacrol 0.1% has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

Usual Adult Dose for Organ Transplant- Rejection Prophylaxis KIDNEY TRANSPLANT: In combination with azathioprine: Initial dose: 0.1 mg/kg orally every 12 hours. Initiate within 24 hours of surgery, but delay until renal function has recovered. In combination with mycophenolate mofetil (MMF)/interleukin-2 (IL-2) receptor antagonist: Initial dose: 0.05 mg/kg orally every 12 hours. Initiate within 24 hours of surgery, but delay until renal function has recovered. LIVER TRANSPLANT: Initial dose: 0.05 to 0.075 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery. HEART TRANSPLANT: Initial dose: 0.0375 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery Usual Pediatric Dose for Organ Transplant- Rejection Reversal LIVER TRANSPLANT: Initial dose: 0.075 to 0.1 mg/kg orally every 12 hours

Since Tacrol 0.1% is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase Tacrol 0.1% whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease Tacrol 0.1% whole blood concentrations. Dose adjustments may be needed along with frequent monitoring of Tacrol 0.1% whole blood trough concentrations when Tacrol 0.1% is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation

Tacrol 0.1% capsules are contraindicated in patients with a hypersensitivity to Tacrol 0.1%. Tacrol 0.1% injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Tacrol 0.1% is transferred across the placenta. The use of Tacrol 0.1% during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. Tacrol 0.1% given orally to pregnant rabbits at 0.5 to 4.3 times the clinical dose and pregnant rats at 0.8 to 6.9 times the clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Tacrol 0.1% should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.Nursing Mothers: Tacrol 0.1% is excreted in human milk. As the effect of chronic exposure to Tacrol 0.1% in healthy infants is not established, patients maintained on Tacrol 0.1% should discontinue nursing taking into consideration importance of drug to the mother.

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that Tacrol 0.1% is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; and in adult rats, 16 times the recommended human IV dose (all based on body surface area corrections).

Store at 25°C

Pediatric Use: The safety and efficacy of Tacrol 0.1% in pediatric kidney and heart transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Tacrol 0.1%. Two randomized active-controlled trials of Tacrol 0.1% in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Tacrol 0.1%-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of Tacrol 0.1% in living related donor liver transplantation. Pediatric patients generally required higher doses of Tacrol 0.1% to maintain blood trough concentrations of Tacrol 0.1% similar to adult patients.Geriatric Use: Clinical trials of Tacrol 0.1% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Use in Renal Impairment: The pharmacokinetics of Tacrol 0.1% in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Tacrol 0.1% at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be requiredUse in Hepatic Impairment: The mean clearance of Tacrol 0.1% was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy volunteers with normal hepatic function. Close monitoring of Tacrol 0.1% trough concentrations is warranted in patients with hepatic impairment.The use of Tacrol 0.1% in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations of Tacrol 0.1%. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients