tacrolimus (oral, iv)

Contraindicated in:

Hypersensitivity to tacrolimus or to castor oil (a component in the injection);
Lactation: Lactation.

Use Cautiously in:

Renal or hepatic impairment (dose ↓ may be required; if oliguria occurs, wait 48 hr before initiating tacrolimus);
Concurrent use with cyclosporine should be avoided;
Exposure to sunlight/UV light (may ↑ risk of malignant skin changes);
OB: Use only if potential maternal benefit justifies potential fetal risk (hyperkalemia and renal impairment may occur in the newborn).

Adv. Reactions/Side Effects ⬆ ⬇

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

CV: hypertension, peripheral edema, QTc interval prolongation

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

EENT: abnormal vision, amblyopia, tinnitus

Endo: hyperglycemia, hyperuricemia

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

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

GU: nephrotoxicity, urinary tract infection

Hemat: anemia, leukocytosis, leukopenia, thrombocytopenia, coagulation defects, pure red cell aplasia

Metab: hyperlipidemia

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

Neuro: paresthesia, neuropathy

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

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), LYMPHOMA/SKIN CANCER , fever, generalized pain, abnormal healing, chills

Interactions ⬆ ⬇

Drug-drug:

Risk of nephrotoxicity is ↑ by concurrent use of aminoglycosides, amphotericin B, cisplatin, or cyclosporine (allow 24 hr to pass after stopping cyclosporine before starting tacrolimus).
Concurrent use of potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists↑ risk of hyperkalemia.
The following drugs ↑ tacrolimus blood levels: azole antifungals, bromocriptine, calcium channel blockers, chloramphenicol, cimetidine, clarithromycin, cyclosporine, danazol, erythromycin, lansoprazole, magnesium/aluminum hydroxidemethylprednisolone, omeprazole, nefazodone, metoclopramide, protease inhibitors, and voriconazole.
Phenobarbital, phenytoin, caspofungin, sirolimuscarbamazepine, and rifampin may ↓ tacrolimus blood levels.
Vaccinations may be less effective if given concurrently with tacrolimus (avoid use of live-virus vaccines).

Drug-Natural Products:

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

Drug-Food:

Food↓ the rate and extent of GI absorption.
Grapefruit juice↑ absorption.

Availability ⬆ ⬇

(Generic available)

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
Immediate-release capsules: 0.5 mg; 1 mg; 5 mg
Solution for injection: 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.

Kidney Transplantation

PO (Adults ): Initial dose of immediate-release capsules (with azathioprine)—0.2 mg/kg/day in 2 divided doses; titrate to achieve recommended whole blood trough concentration; Initial dose of immediate-release capsules (with mycophenolate mofetil and IL-2 antagonist)—0.1 mg/kg/day in 2 divided doses; titrate to achieve recommended whole blood trough concentration; Extended-release capsules (Astagraf XL) (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—0.15–0.4 mg/kg/day in 2 divided doses.
IV (Adults ): Initial dose—0.03–0.1 mg/kg/day as a continuous infusion; titrate to achieve recommended blood concentration.
IV (Children ): 0.03–0.15 mg/kg/day.

Liver Transplantation

PO (Adults ): Initial dose of immediate–release capsules—0.1–0.15 mg/kg/day in 2 divided doses; titrate to achieve recommended blood concentration.
PO (Children ): Initial dose of immediate–release capsules—0.15–0.2 mg/kg/day in 2 divided doses; titrate to achieve recommended blood concentration.
IV (Adults and Children ): Same as for kidney transplant.

Heart Transplantation

PO (Adults ): Initial dose of immediate–release capsules—0.075 mg/kg/day in 2 divided doses; titrate to achieve recommended blood concentration.
IV (Adults ): Initial dose of immediate–release capsules—0.01 mg/kg/day as a continuous infusion; 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%).

Distribution: Crosses the placenta and enters breast milk.

Protein Binding: 99%.

Metabolism/Excretion: 99% metabolized by the liver; <1% excreted unchanged in the urine.

Half-Life: Liver transplant patients—11.7 hr; healthy volunteers—21.2 hr.

Canadian Brand Names ⬆ ⬇

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 ⬆ ⬇

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 more than 14 hrs after scheduled dose; do not double doses. Advise patient to read the Patient Information before starting tacrolimus and with each refill in case of changes. Instruct patient to inspect capsules with each new Rx, before taking. Contact health care professional if appearance of capsules or dose has changed.
- 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, increased thirst or hunger), infection (fever, sweats, chills, cough or flu-like symptoms, muscle aches, warm, red, painful areas on skin), neurotoxicity (vision changes, deliriums, or 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.
- 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.
- Inform patient of the risk of lymphoma or skin cancer with tacrolimus therapy.
- Advise patient of the risk of taking tacrolimus during pregnancy or breastfeeding. Caution female patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding and to 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.
- Emphasize the importance of repeated lab tests during tacrolimus therapy.

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Indications ⬇

Contraind./Precautions ⬆ ⬇