Tacrolimus

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.

Oral
Severe: Dosage reduction needed.

Intravenous
Severe: Dosage reduction needed.

Tacrolimus Should be taken on an empty stomach. Avoid grapefruit & grapefruit juice.

Dilute w/ dextrose 5% inj or NaCl 0.9% inj to a final concentration between 0.004 mg/mL and 0.02 mg/mL.

Y-site: Aciclovir, phenytoin, ganciclovir.

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.

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

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.

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).

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.

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 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.

Description:
Mechanism of Action: 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).

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

Tab/cap/oint: Store at 25°C. Inj: Store between 5-25°C.

Immunosuppressants / Other Dermatologicals

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.

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.