tacrolimus (oral, IV)

General

Genetic Implications: Genetic Implications

Pronunciation:
ta-kroe-li-mus


Trade Name(s)

  • Advagraf Canadian Tradename
  • Astagraf XL
  • Envarsus XR
  • Prograf

Ther. Class.
immunosuppressants

Indications

Prevention of organ rejection in patients who have undergone allogenic liver, kidney, or heart transplantation (used concurrently with corticosteroids) (used concurrently with azathioprine or mycophenolate mofetil in kidney or heart transplants) (extended-release only indicated for kidney transplant).

Action

Inhibits T-lymphocyte activation.

Therapeutic Effect(s):

Prevention of transplanted organ rejection.

Pharmacokinetics

Absorption: Absorption following oral administration is erratic and incomplete (5–67%).

Distribution: Crosses the placenta and enters breast milk.

Protein Binding: 99%.

Metabolism and 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.

TIME/ACTION PROFILE (immunosuppression)

ROUTEONSETPEAKDURATION
POrapid1.3–3.2 hr†12 hr
PO-ERunknownunknown24 hr
IVrapidunknown8–12 hr
†Blood level.

Contraindication/Precautions

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).

Adverse 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

Metabolic: 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

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

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.

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. Genetic implication 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.

Availability (generic available)

Extended-release capsules (Astragraf XL): 0.5 mg, 1 mg, 3 mg Canadian Tradename, 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

Assessment

  • Assess for symptoms of PRES (headache, altered mental status, seizures, visual disturbances, hypertension) periodically during therapy. Confirm diagnosis by radiologic procedure. If PRES is suspected or diagnosed, maintain BP control and immediately reduce immunosuppression. Symptoms are usually reversed on reduction or discontinuation of immunosuppression.
  • Prevention of Organ Rejection:

    Monitor BP closely during therapy. Hypertension is a common complication of tacrolimus therapy and should be treated.

    • Observe patients receiving IV tacrolimus for the development of anaphylaxis (rash, pruritus, laryngeal edema, wheezing) for at least 30 min and frequently thereafter. If signs develop, stop infusion and initiate treatment.

Lab Test Considerations:

Tacrolimus blood level monitoring may be helpful in the evaluation of rejection and toxicity, dose adjustments, and assessment of compliance. For liver transplantation, most patients are stable when tacrolimus trough whole blood concentrations are maintained between 5–20 ng/mL. For kidney transplantation, during the first 3 mo, most patients maintained tacrolimus whole blood concentrations between 7–20 ng/mL and then between 5–15 ng/mL through 1 yr. For heart transplantation, from 1 to 3 mo, most patients maintained tacrolimus trough whole blood concentrations between 10–20 ng/mL and then between 5–15 ng/mL from ≥4 mo post-transplant.

  • Monitor serum creatinine, potassium, and glucose closely. ↑ serum creatinine and ↓ urine output may indicate nephrotoxicity. Genetic implication May also cause insulin-dependent post-transplant diabetes mellitus (incidence is higher in African American and Hispanic patients).
  • May also cause hyperuricemia, hypokalemia, hyperkalemia, hypomagnesemia, metabolic acidosis, metabolic alkalosis, hyperlipidemia, hyperphosphatemia, hypophosphatemia, hypocalcemia, and hyponatremia.
  • Monitor CBC. May cause anemia, leukocytosis, and thrombocytopenia.

Potential Diagnoses

Implementation

  • Do not confuse Prograf (tacrolimus) with Proscar (finasteride) or Prozac (fluoxetine).

    • Do not confuse immediate-release tacrolimus with extended-release tacrolimus.
  • Therapy should be provided by clinicians and in facilities experienced in transplant management.
  • Therapy with tacrolimus should be started no sooner than 6 hr post-transplantation. Concurrent therapy with corticosteroids is recommended in the early postoperative period.

    • Tacrolimus should not be used concomitantly with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hr before starting the other.
    • Oral therapy is preferred because of the risk of anaphylactic reactions with IV tacrolimus. IV therapy should be replaced with oral therapy as soon as possible.
    • Adults should be started at the lower end of the dose range; children require a higher doses to maintain blood trough concentrations similar to adults.
    • Immediate and extended-release capsules are not interchangeable.
  • PO 

    Oral doses can be initiated 8–12 hr after discontinuation of IV doses. Maybe taken with or without food, but with or without food should be consistent, 12 hrs apart, at the same time each day.

    • Take extended-release capsules at the same time each day, on an empty stomach at least 1 hr before or 2 hrs after breakfast. Swallow capsules whole; do not chew, divide, or crush. Administer  Prograf  granules immediately after preparing; do not store for later.
    • Administer initial oral doses no sooner than 6 hr after heart or liver transplant. For kidney transplants, may be administered within 24 hr of transplant but should be delayed until renal function has recovered.

IV Administration

  • Continuous Infusion:   Diluent:  Dilute in 0.9% NaCl or D5W. Concentration: 0.004–0.02 mg/mL. May be stored in polyethylene or glass containers for 24 hr following dilution. Do not store in PVC containers. Do not administer solutions that are discolored or contain particulate matter.
  • Rate: Administer daily dose as a continuous infusion over 24 hr.
  • Y-Site Compatibility:
    • alemtuzumab
    • alfentanil
    • amifostine
    • MORE...
      • amikacin
      • aminocaproic acid
      • aminophylline
      • amiodarone
      • amphotericin B deoxycholate
      • amphotericin B lipid complex
      • amphotericin B liposome
      • anidulafungin
      • argatroban
      • azithromycin
      • aztreonam
      • benztropine
      • bivalirudin
      • bleomycin
      • bumetanide
      • buprenorphine
      • busulfan
      • butorphanol
      • calcium acetate
      • calcium chloride
      • calcium gluconate
      • carboplatin
      • carmustine
      • caspofungin
      • cefazolin
      • cefotaxime
      • cefotetan
      • cefoxitin
      • ceftazidime
      • ceftriaxone
      • cefuroxime
      • chloramphenicol
      • chlorpromazine
      • ciprofloxacin
      • cisatracurium
      • cisplatin
      • clindamycin
      • cyclophosphamide
      • cyclosporine
      • cytarabine
      • dacarbazine
      • dactinomycin
      • daptomycin
      • daunorubicin hydrochloride
      • dexamethasone
      • dexmedetomidine
      • dexrazoxane
      • digoxin
      • diltiazem
      • diphenhydramine
      • dobutamine
      • docetaxel
      • dopamine
      • doxorubicin hydrochloride
      • doxorubicin liposomal
      • doxycycline
      • droperidol
      • enalaprilat
      • ephedrine
      • epinephrine
      • epirubicin
      • ertapenem
      • erythromycin
      • esmolol
      • etoposide
      • etoposide phosphate
      • famotidine
      • fenoldopam
      • fentanyl
      • fluconazole
      • fludarabine
      • foscarnet
      • fosphenytoin
      • gemcitabine
      • gentamicin
      • glycopyrrolate
      • granisetron
      • haloperidol
      • heparin
      • hetastarch
      • hydralazine
      • hydrocortisone
      • hydromorphone
      • idarubicin
      • ifosfamide
      • imipenem/cilastatin
      • insulin
      • irinotecan
      • isoproterenol
      • ketorolac
      • labetalol
      • leucovorin
      • levofloxacin
      • levorphanol
      • lidocaine
      • linezolid
      • lorazepam
      • magnesium sulfate
      • mannitol
      • meperidine
      • meropenem
      • mesna
      • methotrexate
      • methylprednisolone
      • metoclopramide
      • metoprolol
      • metronidazole
      • micafungin
      • midazolam
      • milrinone
      • mitomycin
      • mitoxantrone
      • morphine
      • moxifloxacin
      • multivitamins
      • mycophenolate
      • nafcillin
      • nalbuphine
      • naloxone
      • nicardipine
      • nitroglycerin
      • nitroprusside
      • norepinephrine
      • octreotide
      • ondansetron
      • oxacillin
      • oxaliplatin
      • oxytocin
      • paclitaxel
      • palonosetron
      • pamidronate
      • pancuronium
      • pemetrexed
      • penicillin G potassium
      • pentamidine
      • phenylephrine
      • piperacillin/tazobactam
      • potassium acetate
      • potassium chloride
      • potassium phosphates
      • procainamide
      • prochlorperazine
      • promethazine
      • propranolol
      • quinupristin/dalfopristin
      • remifentanil
      • rocuronium
      • sodium acetate
      • sodium bicarbonate
      • sodium phosphates
      • streptozocin
      • succinylcholine
      • sufentanil
      • teniposide
      • theophylline
      • thiotepa
      • tigecycline
      • tirofiban
      • tobramycin
      • topotecan
      • vancomycin
      • vasopressin
      • vecuronium
      • verapamil
      • vinblastine
      • vincristine
      • vinorelbine
      • voriconazole
      • zidovudine
      • zoledronic acid
  • Y-Site Incompatibility:
    • acyclovir
    • allopurinol
    • azathioprine
    • MORE...
      • cefepime
      • dantrolene
      • diazepam
      • esomeprazole
      • folic acid
      • ganciclovir
      • iron sucrose
      • levothyroxine
      • phenytoin
      • thiopental

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.
  • Rep:  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.

Evaluation/Desired Outcomes

Prevention of transplanted liver, kidney, or heart rejection.

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