Tacrolimus

Uses

Tacrolimus ointment is used for short-term and intermittent long-term therapy in the treatment of patients with moderate to severe atopic dermatitis in whom the use of alternative, conventional therapies are deemed inadvisable because of potential risks, or in the treatment of patients who are not adequately responsive to or are intolerant of alternative, conventional therapies. Tacrolimus Ointment is also used for other skin conditions such as chronic cutaneous graft-vs-host disease, hand and foot eczema, allergic contact dermatitis, psoriasis, lichen planus, facial lichen, vulvar lichen sclerosus, pyoderma gangrenosum, leg ulcers in rheumatoid arthritis, steroid-induced rosacea & alopecia areata, annular erythema, chronic actinic dermatitis and recalcitrant facial erythema.

Tacrolimus is a calcineurin-inhibitor immunosuppressant used for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants

Tacrolimus is also used to associated treatment for these conditions: Graft Versus Host Disease (GVHD), Heart Transplant Rejection, Kidney Transplant Rejection, Liver Transplant Rejection, Oral Lichen Planus, Psoriasis, Pyoderma Gangrenosum, Rheumatoid Arthritis, Severe Atopic Dermatitis, Vitiligo, Moderate Atopic dermatitis, Refractory Atopic dermatitis, Refractory Rheumatoid arthritis, Severe Rheumatoid arthritis

How Tacrolimus works

The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents 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. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells.

Dosage

Tacrolimus dosage

Apply a thin layer of Tacrolimus ointment onto the affected skin areas twice daily and rub in gently and completely. Treatment should be continued for one week after clearing of signs and symptoms of atopic dermatitis. The safety of Tacrolimus ointment under occlusion which may promote systemic exposure has not been evaluated. Tacrolimus ointment should not be used with occlusive dressings.

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

Tacrolimus ointment should be applied as a thin layer to affected or commonly affected areas of the skin. Tacrolimus ointment may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Tacrolimus ointment should not be applied under occlusion because this method of administration has not been studied in patients.

Side Effects

Transient burning or heat sensation at the site of application is frequently observed. It tends to decrease after repeated applications. Other side-effects include skin erythema, flu-like symptoms, headache and skin infection. It does not cause skin atrophy despite prolonged application.

Toxicity

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD₅₀=134-194 mg/kg (rat).

Precaution

Cautions should be exercised while treatment with Tacrolimus ointment in patients with atopic dermatitis predisposed to superficial skin infections. The safety of Tacrolimus ointment has not been established in patients with generalized erythroderma.

Interaction

Formal topical drug interaction studies with Tacrolimus ointment have not been conducted. The concomitant administration of known CYP3A4 inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.

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

Food Interaction

• Avoid alcohol. Consuming alcohol may increase the rate of tacrolimus release from extended-release formulations.
• Avoid grapefruit products.
• Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of tacrolimus; therefore, monitoring tacrolimus whole blood trough concentrations may be warranted.
• Take at the same time every day.
• Take on an empty stomach. Take at least 1 hour before or 2 hours after a meal as coadministration with food decreases the rate and extent of absorption.
• Take separate from antacids. Coadministration of tacrolimus with aluminum or magnesium hydroxide antacids may increase the serum levels of tacrolimus, which poses a risk for toxicity.

[Moderate] ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations.

Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.br>
MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

Tacrolimus Hypertension interaction

[Moderate] The use of tacrolimus has been associated with hypertension.

Therapy with tacrolimus should be administered cautiously in patients with elevated blood pressure.

Close monitoring of blood pressure is recommended.

Tacrolimus Drug Interaction

Moderate: sulfamethoxazole / trimethoprim, apixaban, insulin glargine, atorvastatin, pantoprazole, valganciclovirMinor: calcium / vitamin dUnknown: aspirin, aspirin, diphenhydramine, mycophenolate mofetil, omega-3 polyunsaturated fatty acids, furosemide, metoprolol, metoprolol, mycophenolic acid, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Tacrolimus Disease Interaction

Major: diabetes mellitus, hepatic dysfunction, infections, QT interval prolongation, renal dysfunctionModerate: hyperkalemia, hypertension

Volume of Distribution

• 2.6 ± 2.1 L/kg [pediatric liver transplant patients]
• 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
• 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]

Elimination Route

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

Half Life

The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours.

Clearance

• 0.040 L/hr/kg [healthy subjects, IV]
• 0.172 ± 0.088 L/hr/kg [healthy subjects, oral]
• 0.083 L/hr/kg [adult kidney transplant patients, IV]
• 0.053 L/hr/kg [adult liver transplant patients, IV]
• 0.051 L/hr/kg [adult heart transplant patients, IV]
  
• 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients]
• 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients]
• 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
• 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]

Elimination Route

In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies of topically administered Tacrolimus in pregnant women. The experience with Tacrolimus ointment when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.

Nursing Mothers: Although systemic absorption of Tacrolimus following topical applications of Tacrolimus ointment is minimal relative to systemic administration, it is known that Tacrolimus is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Tacrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Tacrolimus ointment is contraindicated in patients with a history of hypersensitivity to Tacrolimus or any other component of the preparation.

Tacrolimus capsules are contraindicated in patients with a hypersensitivity to Tacrolimus. Tacrolimus 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

Special Warning

Pediatric Use: The safety and efficacy of Tacrolimus 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 Tacrolimus. Two randomized active-controlled trials of Tacrolimus in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of Tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Tacrolimus to maintain blood trough concentrations of Tacrolimus similar to adult patients.

Geriatric Use: Clinical trials of Tacrolimus 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 Tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Tacrolimus 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 required

Use in Hepatic Impairment: The mean clearance of Tacrolimus 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 Tacrolimus trough concentrations is warranted in patients with hepatic impairment.

The 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 trough concentrations of Tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients

Acute Overdose

Tacrolimus ointment is not for oral use. Accidental oral ingestion of Tacrolimus ointment may lead to adverse effects associated with systemic administration of Tacrolimus. If oral ingestion occurs, medical advice should be sought.

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 Tacrolimus 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).

Storage Condition

Store in a cool & dry place, protected from light.

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