Tacrolimus

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.
Hepatic impairment: Severe: Dosage reduction needed.

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.
Hepatic impairment: Severe: Dosage reduction needed.

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.
Hepatic impairment: Severe: Dosage reduction needed.

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.
Hepatic impairment: Severe: Dosage reduction needed.

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.
Hepatic impairment: Severe: Dosage reduction needed.

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.
Hepatic impairment: Severe: Dosage reduction needed.

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).
Hepatic impairment: Severe: Dosage reduction needed.

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).
Hepatic impairment: Severe: Dosage reduction needed.

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).
Hepatic impairment: Severe: Dosage reduction needed.

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.
Hepatic impairment: Severe: Dosage reduction needed.
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.

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.
Hepatic impairment: Severe: Dosage reduction needed.
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.

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.
Hepatic impairment: Severe: Dosage reduction needed.
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.

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 Populations: 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.

Should be taken on an empty stomach. Take on an empty stomach at least 1 hr before or 2-3 hr after meals. Avoid grapefruit & grapefruit juice.

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. Patient Counselling 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. Monitoring Parameters 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).

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.

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.

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, γ-interferon] and the expression of IL-2 receptor. It inhibits calcineurin activity by binding to an intracellular protein, FKBP-12, forming complex w/ Ca, calmodulin and calcineurin.
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).

Intravenous: Store between 5-25°C. Oral: Store at 25°C. Topical/Cutaneous: Store at 25°C.

Immunosuppressants / Other Dermatologicals

D11AH01 - tacrolimus ; Belongs to the class of agents for atopic dermatitis, excluding corticosteroids. Used in the treatment of atopic dermatitis.
L04AD02 - tacrolimus ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.