tacrolimus (systemic)

Contraindicated in:

Hypersensitivity to tacrolimus or to castor oil (a component in the injection);
Concurrent use with cyclosporine (↑ risk of nephrotoxicity);
Concurrent use of sirolimus (↑ risk of mortality and adverse reactions);
Lactation: Lactation.

Use Cautiously in:

Renal or hepatic impairment (dose ↓ may be required; if oliguria occurs, wait 48 hr before initiating tacrolimus);
Severe infection, graft-versus-host disease, or human leukocyte antigen mismatch (↑ risk of thrombotic microangiopathy);
Renal impairment (dose ↓ may be required; if oliguria occurs, wait 48 hr before initiating tacrolimus);
Hepatic impairment (dose ↓ may be required);
Exposure to sunlight/UV light (may ↑ risk of malignant skin changes);
OB: Hyperkalemia and renal impairment may occur in the newborn; use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Pedi: Higher end of dosing range is required to maintain adequate blood levels in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypertension, peripheral edema, QT interval prolongation

Derm: pruritus, rash, alopecia, herpes simplex, hirsutism, sweating, photosensitivity

EENT: abnormal vision, amblyopia, pharyngitis, tinnitus

Endo: hyperglycemia

F and E: hyperkalemia, hypokalemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia, hypocalcemia, hyponatremia, metabolic acidosis, metabolic alkalosis

GI: abdominal pain, anorexia, ascites, constipation, diarrhea, dyspepsia, ↑liver enzymes, nausea, vomiting, cholangitis, cholestatic jaundice, dysphagia, flatulence, GI BLEEDING, oral thrush

GU: nephrotoxicity, urinary tract infection

Hemat: anemia, leukocytosis, leukopenia, thrombocytopenia, coagulation defects, pure red cell aplasia, thrombotic microangiopathy (including hemolytic uremic syndrome and thrombotic thrombocytopenia purpura)

Metab: hyperlipidemia, hyperuricemia, ↑appetite

MS: arthralgia, pain, hypertonia, leg cramps, muscle spasm, myalgia, myasthenia, osteoporosis

Neuro: dizziness, headache, insomnia, paresthesia, tremor, abnormal dreams, agitation, anxiety, confusion, emotional lability, depression, hallucinations, neuropathy, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), psychoses, SEIZURES, somnolence

Resp: cough, pleural effusion, asthma, bronchitis, pneumonia, pulmonary edema

Misc: fever, chills, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), impaired wound healing, LYMPHOMA/SKIN CANCER

Interactions ⬆ ⬇

Drug-drug:

↑risk of nephrotoxicity with aminoglycosides, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors, or cyclosporine; allow 24 hr to pass after stopping cyclosporine before starting tacrolimus.
Potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists↑ risk of hyperkalemia.
Strong CYP3A4 inhibitors, including chloramphenicol, clarithromycin, cobicistat, itraconazole, ketoconazole, letermovir, nefazodone, posaconazole, protease inhibitors, and voriconazole, may significantly ↑ levels and risk of nephrotoxicity; ↓ tacrolimus dose by ../B/tu0.png when used with voriconazole or posaconazole; closely monitor tacrolimus whole blood trough concentrations.
Mild CYP3A4 inhibitors and moderate CYP3A4 inhibitors, including amiodarone, calcium channel blockers, cimetidine, clotrimazole, danazol, erythromycin, ethinyl estradiol, fluconazole, imatinib, isavuconazole, lansoprazole, nilotinib, and omeprazole, may ↑ levels and risk of toxicity; closely monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.
Magnesium/aluminum hydroxide and metoclopramide may ↑ levels and risk of toxicity; closely monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.
Strong CYP3A4 inducers, including carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin, may ↓ levels; ↑ tacrolimus dose and closely monitor tacrolimus whole blood trough concentrations.
Mild CYP3A4 inducers and moderate CYP3A4 inducers, including methylprednisolone or prednisone, may ↓ levels; closely monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.
Vaccinations may be less effective if given concurrently with tacrolimus; avoid use of live-virus vaccines.
May ↑ levels of mycophenolate mofetil or mycophenolic acid.
Caspofungin may ↓ levels; closely monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed.
Cannabidiol may ↑ levels and risk of toxicity; consider ↓ tacrolimus dose.

Drug-Natural Products:

Concomitant use with astragalus, echinacea, and melatonin may interfere with immunosuppression.
St. John's wort may ↓ levels; ↑ tacrolimus dose and closely monitor tacrolimus whole blood trough concentrations.
Schisandra sphenanthera may significantly ↑ levels; closely monitor tacrolimus whole blood trough concentrations.

Drug-Food:

Food↓ the rate and extent of GI absorption.
Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Availability ⬆ ⬇

(Generic available)

Immediate-release capsules: 0.5 mg; 1 mg; 5 mg
Extended-release capsules (Astragraf XL): 0.5 mg; 1 mg; 3 mg; 5 mg
Extended-release tablets (Envarsus XR): 0.75 mg; 1 mg; 4 mg
Granules for oral suspension: 0.2 mg/pkt; 1 mg/pkt
Solution for injection (contains alcohol): 5 mg/mL

Route/Dosage ⬆ ⬇

Because of the potential risk for anaphylaxis, the IV route of administration of tacrolimus should be reserved for those patients unable to take the drug orally. Extended-release capsules are not interchangeable with immediate-release capsules or other extended-release products. African American patients may require a higher dose to achieve desired tacrolimus trough concentrations. Patients with cystic fibrosis may also require a higher dose for lung transplantation due to a reduced bioavailability.

Kidney Transplantation

PO (Adults ): Immediate-release capsules (in combination with azathioprine): 0.2 mg/kg/day in 2 divided doses initially; titrate to achieve recommended whole blood trough concentration; Immediate-release capsules (in combination with mycophenolate mofetil and IL-2 antagonist): 0.1 mg/kg/day in 2 divided doses initially; titrate to achieve recommended whole blood trough concentration; Extended-release capsules (Astagraf XL) (in combination with basiliximab induction): 0.15 mg/kg once daily (to be started either before or within 48 hr of completion of transplant); Extended-release capsules (Astagraf XL) (without basiliximab induction): 0.1 mg/kg given as single dose preoperatively within 12 hr prior to reperfusion, followed by 0.2 mg/kg once daily started postoperatively at least 4 hr after preoperative dose and within 12 hr after reperfusion; Conversion from immediate-release capsules to extended-release capsules (Envarsus XR): Initiate extended-release treatment with a once daily dose that is 80% of the total daily dose of the immediate-release product (also appropriate for African American patients).
PO (Children ): Immediate-release capsules or suspension: 0.3 mg/kg/day in 2 divided doses initially; titrate to achieve recommended whole blood trough concentration.
IV (Adults ): 0.03–0.05 mg/kg/day as a continuous infusion initially; titrate to achieve recommended blood concentration.

Liver Transplantation

PO (Adults ): Immediate-release capsules: 0.1–0.15 mg/kg/day in 2 divided doses initially; titrate to achieve recommended blood concentration.
PO (Children ): Immediate-release capsules: 0.15–0.2 mg/kg/day in 2 divided doses initially; titrate to achieve recommended blood concentration. Suspension: 0.2 mg/kg/day in 2 divided doses initially; titrate to achieve recommended blood concentration.
IV (Adults ): 0.03–0.05 mg/kg/day as a continuous infusion initially; titrate to achieve recommended blood concentration.
IV (Children ): 0.03–0.05 mg/kg/day.

Heart Transplantation

PO (Adults ): Immediate-release capsules: 0.075 mg/kg/day in 2 divided doses initially; titrate to achieve recommended blood concentration.
PO (Children ): Immediate-release capsules or suspension (without antibody induction treatment): 0.3 mg/kg/day in 2 divided doses initially; titrate to achieve recommended whole blood trough concentration. Immediate-release capsules or suspension (with antibody induction treatment): 0.1 mg/kg/day in 2 divided doses initially; titrate to achieve recommended whole blood trough concentration.
IV (Adults ): 0.01 mg/kg/day as a continuous infusion initially; titrate to achieve recommended blood concentration.

Lung Transplantation

PO (Adults ): Immediate-release capsules: 0.075 mg/kg/day in 2 divided doses initially; titrate to achieve recommended blood concentration.
PO (Children ): Immediate-release capsules or suspension (without antibody induction treatment): 0.3 mg/kg/day in 2 divided doses initially; titrate to achieve recommended whole blood trough concentration. Immediate-release capsules or suspension (with antibody induction treatment): 0.1 mg/kg/day in 2 divided doses initially; titrate to achieve recommended whole blood trough concentration.
IV (Adults ): 0.01–0.03 mg/kg/day as a continuous infusion initially; titrate to achieve recommended blood concentration.

US Brand Names ⬆ ⬇

Astagraf XL, Envarsus XR, Prograf

Action ⬆ ⬇

Inhibits T-lymphocyte activation.

Therapeutic effects:

Prevention of transplanted organ rejection.

Classifications ⬆ ⬇

Therapeutic Classification: Immunosuppressant agents

Pharmacokinetics ⬆ ⬇

Absorption: Absorption following oral administration is erratic and incomplete (5–67%). IV administration results in complete bioavailability.

Distribution: Widely distributed to tissues.

Protein Binding: 99%.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme. Primarily excreted in the feces (93%), with <1% being excreted unchanged in the urine.

Half-Life: Immediate release: 2–36 hr; Extended release: 38 hr.

Canadian Brand Names ⬆ ⬇

Advagraf, Envarsus PA

Time/Action Profile ⬆ ⬇

(immunosuppression)

ROUTE	ONSET	PEAK	DURATION
PO	rapid	1.3–3.2 hr‡	12 hr
PO-ER	unknown	unknown	24 hr
IV	rapid	unknown	8–12 hr

‡Blood level.

Patient/Family Teaching ⬆ ⬇

Advise patient to read the Patient Information before starting and with each refill in case of changes. Instruct patient to inspect capsules with each new Rx before taking. Instruct patient to take tacrolimus at the same time each day, with or without food, as directed. Do not skip or double up on missed doses. Do not discontinue medication without advice of health care professional. Take missed doses of extended-release capsule as soon as remembered unless >14 hr after scheduled dose; do not double doses. Contact health care professional if appearance of capsules or dose has changed. Emphasize the importance of repeated lab tests during therapy.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
- Advise patient to avoid grapefruit and grapefruit juice and alcohol during therapy.
- Reinforce the need for lifelong therapy to prevent transplant rejection. Review symptoms of rejection for transplanted organ and stress need to notify health care professional immediately if they occur.
- Advise patient to avoid eating raw oysters or other shellfish; make sure they are fully cooked before eating.
- Instruct patient to notify health care professional if signs of diabetes mellitus (frequent urination, ↑ thirst or hunger), infection (fever; sweats; chills; cough or flu-like symptoms; muscle aches; warm, red, painful areas on skin), neurotoxicity (vision changes, deliriums, tremors), or PRES occur.
- Advise patient to wear protective clothing and sunscreen to avoid photosensitivity reactions.
- Instruct patient to avoid exposure to chicken pox, measles, mumps, and rubella. If exposed, see health care professional for prophylactic therapy.
- Inform patient of the risk of lymphoma or skin cancer with tacrolimus therapy.
- Caution female patient to notify health care professional if pregnancy is planned or suspected, avoid breastfeeding during therapy, and discuss family planning with health care professional before starting therapy. May impair male and female fertility. Encourage female transplant recipients and females fathered by male transplant recipients to enroll in the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/; monitors outcomes of women exposed to tacrolimus.

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Indications ⬇

Contraind./Precautions ⬆ ⬇