Tacrolimus


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Prophylaxis of organ transplant rejection Kidney transplant: Initial: 200-300 mcg/kg/day starting w/in 24 hr after transplant. Liver transplant: Initial: 100-200 mcg/kg/day starting approx 12 hr after transplant. Heart transplant: Initial: 75 mcg/kg/day after antibody induction and w/in 5 days after transplant and when patient is stable. Treatment of organ transplant rejection In patient resistant to conventional immunosuppressive agents: Kidney transplant: Initial: 200-300 mcg/kg/day. Liver transplant: Initial: 100-200 mcg/kg/day. Cardiac transplant: Initial: 150 mcg/kg/day. Lung transplant: Initial: 100-150 mcg/kg/day. Pancreas transplant: Initial: 200 mcg/kg/day. Intestine transplant: Initial: 300 mcg/kg/day. IV Prophylaxis of organ transplant rejection Kidney transplant: 50-100 mcg/kg/day. Liver transplant: 10-50 mcg/kg/day. Heart transplant: 10-20 mcg/kg/day. Topical Atopic dermatitis As 0.03% or 0.1% oint: Apply thinly to affected area(s) bid. If no improvement after 2 wk, consider further treatment options. Maintenance: As 0.1% oint: Apply thinly to affected area(s) twice wkly w/ 2-3 days between applications for up to 12 mth in patient who responded to up to 6 wk of bid treatment.
Dosage Details
Intravenous
Prophylaxis of cardiac graft rejection
Adult: Initially, 10-20 mcg/kg daily by continuous 24-hr infusion for up to 7 days.
Child: W/o antibody induction: Initially, 30-50 mcg/kg daily by continuous 24-hr infusion. Start 1st oral dose 8-12 hr after stopping infusion at a dose of 300 mcg/kg daily in 2 divided doses.

Intravenous
Prophylaxis of rejection in liver graft transplant
Adult: Initially, 10-50 mcg/kg daily by continuous 24-hr infusion for up to 7 days.
Child: 50 mcg/kg daily by continuous 24-hr infusion for up to 7 days. Convert to oral therapy as soon as clinically tolerated.

Intravenous
Prophylaxis of rejection in kidney graft transplant
Adult: Initially, 50-100 mcg/kg daily by continuous 24-hr infusion for up to 7 days.
Child: 75-100 mcg/kg daily by continuous 24-hr infusion for up to 7 days. Convert to oral therapy as soon as clinically tolerated.

Oral
Prophylaxis of rejection in kidney graft transplant
Adult: Initially, 200-300 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release). Start w/in 24 hr after transplant.
Child: As immediate-release tab/cap: Initially, 300 mcg/kg daily in 2 divided doses. Start w/in 24 hr after transplant. Adolescents: 200 mcg/kg daily.

Oral
Treatment for rejection of pancreas transplant
Adult: In patient resistant to conventional immunosuppressive agents: Initially, 200 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release).

Oral
Treatment of lung transplant rejection
Adult: In patient resistant to conventional immunosuppressive agents: Initially, 100-150 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release).

Oral
Treatment of liver transplant rejection
Adult: In patient resistant to conventional immunosuppressive agents: Initially, 100-200 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release).
Child: In patient resistant to conventional immunosuppressive agents: As immediate-release tab/cap: Initially, 300 mcg/kg daily in 2 divided doses.

Oral
Treatment of cardiac transplant rejection
Adult: In patient resistant to conventional immunosuppressive agents: Initially, 150 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release).
Child: In patient resistant to conventional immunosuppressive agents: As immediate-release tab/cap: Initially, 200-300 mcg/kg daily in 2 divided doses.

Oral
Prophylaxis of rejection in liver graft transplant
Adult: Initially, 100-200 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release). Start w/in 12 hr after transplant.
Child: As immediate-release tab/cap: Initially, 300 mcg/kg daily in 2 divided doses. Start approx 12 hr after transplant.

Oral
Treatment of kidney transplant rejection
Adult: In patient resistant to conventional immunosuppressive agents: Initially, 200-300 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release).
Child: In patient resistant to conventional immunosuppressive agents: As immediate-release tab/cap: Initially, 300 mcg/kg daily in 2 divided doses.

Oral
Prophylaxis of cardiac graft rejection
Adult: Initially, 75 mcg/kg daily, after antibody induction w/in 5 days after transplant and when patient is stable, given in 2 divided doses (immediate-release) or once daily (extended-release).
Child: As immediate-release tab/cap: Initially, 100-300 mcg/kg daily in 2 divided doses after antibody induction. Start w/in 5 days after transplant and when patient is stable.

Oral
Treatment for rejection of intestine transplant
Adult: In patient resistant to conventional immunosuppressive agents: Initially, 300 mcg/kg daily, given in 2 divided doses (immediate-release) or once daily (extended-release).

Topical/Cutaneous
Atopic dermatitis
Adult: As 0.03% or 0.1% oint: Apply thinly to affected area(s) bid. If no improvement after 2 wk, consider further treatment options. Maintenance: As 0.1% oint: Apply thinly to affected area(s) twice wkly w/ 2-3 days between applications for up to 12 mth in patient who responded to up to 6 wk of bid treatment.
Child: 2-16 yr As 0.03% oint: Apply thinly to affected area(s) bid for up to 3 wk. Maintenance: Apply thinly to affected area(s) twice wkly w/ 2-3 days between applications for up to 12 mth in patient who responded to up to 6 wk of initial treatment.
Special Patient Group
Patient w/o organ dysfunction: Initially, 2-4 mg daily given orally w/in 12 hr after transplant in combination w/ mycophenolate mofetil and corticosteroids, or w/ sirolimus and corticosteroids.
Hepatic Impairment
Oral
Severe: Dosage reduction needed.

Intravenous
Severe: Dosage reduction needed.
Administration
Should be taken on an empty stomach. Take at least 1 hr before or 2-3 hr after meals. Avoid grapefruit & grapefruit juice.
Reconstitution
Dilute w/ dextrose 5% inj or NaCl 0.9% inj to a final concentration between 0.004 mg/mL and 0.02 mg/mL.
Incompatibility
Y-site: Aciclovir, phenytoin, ganciclovir.
Special Precautions
Patient w/ risk factors for QT prolongation; skin disease which may increase systemic absorption (e.g. Netherton’s syndrome). Topical application on the face or neck, large areas of the body (i.e. >50% of the total BSA), or areas of broken skin. Avoid unsupervised switching of immediate- or extended-release formulation. Renal and hepatic impairment. Pregnancy and lactation.
Adverse Reactions
Systemic: Headache, tremor, paraesthesia, HTN, insomnia, nausea, diarrhoea, renal impairment; serum electrolyte disturbances (e.g. hyperkalaemia); hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia; leucopenia, anaemia, thrombocytopenia, agranulocytosis, haemolytic anaemia; anxiety, mood changes, dizziness, confusion, tinnitus, hearing loss, visual disturbances, peripheral neuropathies, convulsions; dyspepsia, constipation, GI haemorrhage and ulceration; dyspnoea, parenchymal lung disorders, pleural effusions, cough, nasal congestion and inflammation, pharyngitis; acne, alopecia, skin rashes, pruritus; muscle cramps, asthenia, arthralgia, febrile disorders, oedema, ascites, liver dysfunction; thromboembolic and ischaemic events, tachycardia; cardiac arrest, heart failure, ventricular arrhythmias, palpitations, ECG changes; cardiomyopathies (including ventricular hypertrophy); coagulation disorders, neutropenia, pancytopenia; acute resp distress syndrome, asthma, dysmenorrhoea, hypoproteinaemia, uterine bleeding, deep limb venous thrombosis, paralytic ileus, acute and chronic pancreatitis, peritonitis, haemolytic uraemic syndrome; CNS effects (e.g. CNS haemorrhage, coma, paralysis, amnesia, speech and language abnormalities); posterior reversible encephalopathy syndrome, post-transplant DM, pure red cell aplasia. Topical: Local irritation (e.g. pruritus, burning sensations), skin disorders (e.g. rosacea, acne); lymphadenopathy, flu-like symptoms. Rarely, hirsutism, thrombotic thrombocytopenic purpura, hypoprothrombinaemia; Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic artery thrombosis, veno-occlusive liver disease.
Potentially Fatal: Polyoma virus infections (e.g. polyoma virus associated nephropathy mostly due to BK virus and JC virus-associated progressive multifocal leucoencephalopathy); GI perforation.
Parenteral/PO/Topical: C
Patient Counseling Information
This drug may cause visual and neurological disturbances, if affected do not drive or operate machinery. Avoid excessive exposure to UV light and sunlight during treatment. Use of IUD may increase risk of infection.
MonitoringParameters
Monitor ECG, BP, fasting blood-glucose concentration, haematological, neurological (including visual) and coagulation parameters, electrolytes, hepatic and renal function, whole blood-tacrolimus trough concentration (esp during diarrhoea episodes).
Overdosage
Symptoms: Headache, nausea, vomiting, tremor, infections, lethargy, urticaria, increased BUN, elevated serum creatinine concentrations, increase in alanine aminotransferase levels. Management: Supportive and symptomatic treatment. May perform gastric lavage or admin activated charcoal if used shortly after intake.
Drug Interactions
Increased blood levels w/ HCV protease inhibitors (e.g. boceprevir, telaprevir), HIV protease inhibitors (e.g. saquinavir, ritonavir, nelfinavir), macrolide antibiotics (e.g. erythromycin), antifungal agents (e.g. fluconazole, ketoconazole, itraconazole, voriconazole), ciclosporin, lansoprazole, amiodarone, cimetidine, Mg-Al-hydroxide, metoclopramide. Decreased blood levels w/ rifampicin, phenytoin, metamizole, carbamazepine, isoniazid. May increase nephrotoxic or neurotoxic effects of NSAIDs, aminoglycosides, vancomycin, gyrase inhibitors, sulfamethoxazole+trimethoprim, ganciclovir, aciclovir. May reduce effect of live attenuated vaccines. Increased hyperkalaemic effect w/ K-sparing diuretics (e.g. spironolactone, amiloride, triamterene).
Food Interaction
Food decreases rate and extent of absorption, particularly high-fat meal. Increased blood levels w/ grapefruit juice, schisandra sphenanthera extracts. Decreased blood levels w/ St John’s wort. Enhanced visual and neurological effect w/ alcohol.
Action
Description: Tacrolimus is a potent macrolide which suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines [e.g. interleukin (IL)-2, IL-3, and γ-interferon] and the expression of the IL-2 receptor. It inhibits calcineurin activity by binding to an intracellular protein, FKBP-12; forming complex w/ Ca, calmodulin and calcineurin.
Pharmacokinetics:
Absorption: Incomplete and variable. Food, particulary high-fat meal, decreases rate and extent of absorption. Bioavailability: 20-25% (oral); approx 0.5% (topical). Time to peak plasma concentration: 0.5-6 hr.
Distribution: Widely distributed in tissues (IV). Crosses the placenta and enters breast milk. Volume of distribution: 0.5-4.7 L/kg (childn); 0.55-2.47 L/kg (adult). Plasma protein binding: Approx 99% (mainly to albumin and α1-acid glycoprotein.
Metabolism: Extensively metabolised in the liver by CYP3A4 isoenzyme.
Excretion: Mainly via faeces (approx 93%); urine (<1% as unchanged drug). Whole-blood elimination half-life: Approx 43 hr (healthy patient); approx 12-16 hr (transplant patient).
Chemical Structure

Chemical Structure Image
Tacrolimus

Source: National Center for Biotechnology Information. PubChem Database. Tacrolimus, CID=445643, https://pubchem.ncbi.nlm.nih.gov/compound/Tacrolimus (accessed on Jan. 23, 2020)

Storage
Tab/cap/oint: Store at 25°C. Inj: Store between 5-25°C.
ATC Classification
L04AD02 - tacrolimus ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.
D11AH01 - tacrolimus ; Belongs to the class of agents for atopic dermatitis, excluding corticosteroids. Used in the treatment of atopic dermatitis.
References
Anon. Tacrolimus (Systemic). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/11/2015.

Anon. Tacrolimus (Topical). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/11/2015.

Buckingham R (ed). Tacrolimus. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/11/2015.

Joint Formulary Committee. Tacrolimus. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/11/2015.

McEvoy GK, Snow EK, Miller J et al (eds). Tacrolimus (Topical). AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 04/11/2015.

McEvoy GK, Snow EK, Miller J et al (eds). Tacrolimus. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 04/11/2015.

Prograf Capsules and Injection. U.S. FDA. https://www.fda.gov/. Accessed 04/11/2015.

Protopic Ointment (Physicians Total Care, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/11/2015.

Tacrolimus Capsule (Accord Healthcare Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/11/2015.

Disclaimer: This information is independently developed by MIMS based on Tacrolimus from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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