Tacrolimus: Safe Use and Key Facts

Tacrolimus (Oral, IV, Topical)

Pronunciation: ta-kroe-li-mus

Brand Names:

Oral/IV: Astagraf XL, Prograf
Topical: Protopic

Classification:

Therapeutic: Immunosuppressants
Pregnancy Category: C

Indications

PO, IV: 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.
Topical: Moderate to severe atopic dermatitis in patients who do not respond to or cannot tolerate alternative, conventional therapies.

Action

Inhibits T-lymphocyte activation.

Therapeutic Effects:

Prevention of transplanted organ rejection
Improvement in signs/symptoms of atopic dermatitis

Pharmacokinetics

Absorption: Absorption following oral administration is erratic and incomplete (bioavailability ranges 5–67%); minimal amounts absorbed following topical use.
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

Route | Onset | Peak | Duration

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
Topical†	Unknown	1–2 weeks	Unknown

* Blood level

† Improvement in atopic dermatitis

Contraindications / Precautions

Contraindicated in:

Hypersensitivity to tacrolimus or to castor oil (a component in the injection)
Concurrent use with cyclosporine or sirolimus should be avoided
Congenital long QT syndrome
Lactation: Breastfeeding should be avoided
Weakened/compromised immune system
Malignant or pre-malignant skin condition
Pediatrics: Children under 2 years (safety not established)

Use cautiously in:

Heart failure, bradycardia, or electrolyte disorders (hypokalemia, hypomagnesemia, hypocalcemia)
Concurrent use of other drugs known to prolong the QT interval
Renal or hepatic impairment (dose may be required; if oliguria occurs, wait 48 hr before initiating tacrolimus)
Exposure to sunlight/UV light (may increase risk of malignant skin changes)
OB: Hyperkalemia and renal impairment may occur in the newborn; use only if benefit to mother justifies risk to the fetus
Pediatrics: Higher end of dosing range required to maintain adequate blood levels; superficial skin infections

Adverse Reactions / Side Effects

(Primarily noted for oral and intravenous use)

Central Nervous System (CNS):

Seizures
Dizziness
Headache
Insomnia
Tremor
Abnormal dreams
Agitation
Anxiety
Confusion
Depression
Emotional lability
Hallucinations
Posterior reversible encephalopathy syndrome (PRES)
Psychoses
Somnolence

EENT (Eyes, Ears, Nose, Throat):

Abnormal vision
Amblyopia
Sinusitis
Tinnitus

Respiratory:

Cough
Pleural effusion
Asthma
Bronchitis
Pharyngitis
Pneumonia
Pulmonary edema

Cardiovascular:

Hypertension
Peripheral edema
QTc interval prolongation

Gastrointestinal (GI):

Gastrointestinal bleeding
GI perforation
Abdominal pain
Anorexia
Ascites
Constipation
Diarrhea
Dyspepsia
Increased liver enzymes
Nausea
Vomiting
Cholangitis
Cholestatic jaundice
Dysphagia
Flatulence
Increased appetite
Oral thrush
Peritonitis

Genitourinary (GU):

Nephrotoxicity
Urinary tract infection

Dermatologic:

Pruritus
Rash
Alopecia
Herpes simplex
Hirsutism
Photosensitivity
Sweating

Endocrine/Metabolic:

Hyperglycemia
Hyperlipidemia

Fluids and Electrolytes:

Hyperkalemia
Hypomagnesemia
Hyperphosphatemia
Hypocalcemia
Hyponatremia
Hypophosphatemia
Metabolic acidosis
Metabolic alkalosis

Hematologic:

Anemia
Leukocytosis
Leukopenia
Thrombocytopenia
Coagulation defects
Pure red cell aplasia

Local (Topical use):

Burning
Stinging

Musculoskeletal:

Arthralgia
Hypertonia
Leg cramps
Muscle spasm
Myalgia
Myasthenia
Osteoporosis

Neurologic:

Paresthesia
Neuropathy

Miscellaneous:

Allergic reactions including anaphylaxis
Generalized pain
Abnormal healing
Chills
Fever
Infections (including activation of latent viral infections such as BK virus-associated nephropathy)
Increased risk of lymphoma and skin cancer

Drug Interactions

(Primarily noted for oral and IV use, but should be considered for topical use)

Drug–Drug Interactions:

Increased risk of nephrotoxicity with concurrent use of:
- Aminoglycosides
- Amphotericin B
- Cisplatin
- Cyclosporine (must wait 24 hours after stopping cyclosporine before starting tacrolimus)
Increased risk of hyperkalemia with:
- Potassium-sparing diuretics
- ACE inhibitors
- Angiotensin II receptor blockers
Strong CYP3A4 inhibitors (may significantly increase tacrolimus levels):
- Ketoconazole
- Itraconazole
- Voriconazole
- Ritonavir
- Clarithromycin
- Boceprevir
- Telaprevir
- Monitor whole blood tacrolimus trough concentrations closely
Other drugs that may increase tacrolimus levels:
- Bromocriptine
- Calcium channel blockers
- Chloramphenicol
- Cimetidine
- Lansoprazole
- Cyclosporine
- Amiodarone
- Danazol
- Ethinyl estradiol
- Erythromycin
- Magnesium/aluminum hydroxide
- Methylprednisolone
- Omeprazole
- Nefazodone
- Metoclopramide
- Protease inhibitors
- Avoid concurrent use with nelfinavir
Concurrent use of CYP3A4 substrates/inhibitors that also prolong the QT interval may increase the risk of QT prolongation.
Strong CYP3A4 inducers (may significantly decrease tacrolimus levels):
- Rifampin
- Rifabutin
Other drugs that may decrease levels:
- Phenobarbital
- Phenytoin
- Caspofungin
- Sirolimus
- Carbamazepine
Vaccinations:
- Live-virus vaccines should be avoided; vaccines may be less effective if given during tacrolimus therapy
May increase levels of:
- Mycophenolate mofetil
- Mycophenolic acid

Drug–Natural Products Interactions:

Concomitant use with:
- Astragalus
- Echinacea
- Melatonin
  May interfere with immunosuppression.
St. John’s wort may decrease tacrolimus blood levels.

Drug–Food Interactions:

Food may alter the rate and extent of gastrointestinal absorption.
Grapefruit juice increases absorption of tacrolimus.

Route / Dosage

Note: Due to the potential risk of anaphylaxis, the intravenous (IV) route should be reserved for patients unable to take tacrolimus orally.
Extended-release capsules are not interchangeable with immediate-release capsules.

Kidney Transplantation

PO (Adults):
- Immediate-release capsules (with azathioprine):
  0.2 mg/kg/day in 2 divided doses; titrate to achieve the recommended whole blood trough concentration.
- Immediate-release capsules (with mycophenolate mofetil and IL-2 antagonist):
  0.1 mg/kg/day in 2 divided doses; titrate to target levels.
- Extended-release capsules (with basiliximab induction):
  0.15 mg/kg once daily (start before or within 48 hours of transplant).
- Extended-release capsules (without basiliximab):
  0.1 mg/kg single dose preoperatively within 12 hours prior to reperfusion, then 0.2 mg/kg once daily starting postoperatively at least 4 hours after the preoperative dose and within 12 hours after reperfusion.
PO (Children):
0.15–0.4 mg/kg/day in 2 divided doses; titrate to achieve target trough concentration.
IV (Adults):
0.03–0.1 mg/kg/day as continuous infusion; adjust based on blood levels.
IV (Children):
0.03–0.15 mg/kg/day continuous infusion.

Liver Transplantation

PO (Adults):
0.1–0.15 mg/kg/day in 2 divided doses; titrate to target trough levels.
PO (Children):
0.15–0.2 mg/kg/day in 2 divided doses.
IV (Adults and Children):
Same as kidney transplantation.

Heart Transplantation

PO (Adults):
0.075 mg/kg/day in 2 divided doses; titrate accordingly.
IV (Adults):
0.01 mg/kg/day as a continuous infusion.

Atopic Dermatitis (Topical Use)

Adults:
Apply 0.03% or 0.1% ointment twice daily. Discontinue when symptoms resolve.
Children (2–15 years):
Apply 0.03% ointment twice daily. Discontinue when symptoms resolve.

Availability (Generic Available)

Capsules: 0.5 mg, 1 mg, 5 mg
Extended-release capsules (Astagraf XL): 0.5 mg, 1 mg, 5 mg
Injection: 5 mg/mL
Ointment: 0.03%, 0.1%

Nursing Implications

Assessment:

Posterior Reversible Encephalopathy Syndrome (PRES):
Monitor for headache, altered mental status, seizures, visual disturbances, and hypertension. Confirm diagnosis via imaging. If suspected or diagnosed, reduce immunosuppression immediately. Symptoms are typically reversible.
Organ Rejection Prevention:
Monitor blood pressure closely (hypertension is common).
Watch for anaphylaxis in patients receiving IV tacrolimus (rash, pruritus, laryngeal edema, wheezing)—monitor for at least 30 minutes. Stop infusion and treat if symptoms occur.
Atopic Dermatitis:
Assess skin lesions prior to and during therapy. Use only for short-term, lowest effective dose to reduce risk of skin cancer.

Lab Test Considerations:

Tacrolimus blood level monitoring is essential for evaluating:
- Rejection
- Toxicity
- Dose adjustments
- Compliance

Therapeutic Whole Blood Trough Concentrations:

Liver transplant: 5–20 ng/mL
Kidney transplant:
- First 3 months: 7–20 ng/mL
- After 3 months: 5–15 ng/mL
Heart transplant:
- Week 1–3 months: 8–20 ng/mL
- After 3 months to 18 months: 6–18 ng/mL
Monitor:
- Serum creatinine, potassium, glucose — increases may indicate nephrotoxicity
- Possible post-transplant insulin-dependent diabetes mellitus (higher incidence in African American and Hispanic patients)
- Other lab abnormalities:
  - Hyperuricemia
  - Hypokalemia / Hyperkalemia
  - Hypomagnesemia
  - Metabolic acidosis / alkalosis
  - Hyperlipidemia
  - Hypophosphatemia / Hyperphosphatemia
  - Hypocalcemia
  - Hyponatremia
Monitor CBC: risk of anemia, leukocytosis, and thrombocytopenia.

Potential Nursing Diagnoses

Risk for infection (related to adverse reactions)

Implementation Guidelines

Do not confuse:
- Prograf (tacrolimus) with Prozac (fluoxetine)
Prescriber qualifications:
Should only be prescribed by healthcare professionals experienced in immunosuppressive therapy and organ transplantation.
Start tacrolimus therapy no sooner than 6 hours post-transplantation.
Use with corticosteroids is recommended early post-op.
Avoid co-administration with cyclosporine:
Must discontinue one at least 24 hours before starting the other.
Oral therapy is preferred over IV due to anaphylaxis risk.
Switch to oral as soon as feasible.
Dosing considerations:
- Adults should start at lower end of dose range
- Children need higher doses to reach adult blood levels
Immediate- vs. extended-release capsules are NOT interchangeable
PO Administration:
- Oral doses may begin 8–12 hours after stopping IV
- Can be taken with or without food, but maintain consistency
- Extended-release capsules: take at the same time daily, at least 1 hour before or 2 hours after breakfast
- Swallow whole – do not crush, chew, or split
Topical Use:
- Avoid continuous long-term use

IV Administration Guidelines

Route: Continuous infusion
Diluent: 0.9% NaCl or D5W
Concentration: 0.004–0.02 mg/mL
Storage:
- Stable for 24 hours in polyethylene or glass containers
- Do not store in PVC containers
Infusion Rate: Administer total daily dose over 24 hours

Patient / Family Teaching

Instruct the patient to take tacrolimus at the same time each day, with or without food, exactly as directed.
Do not skip or double up on missed doses.
Do not discontinue the medication without guidance from a healthcare professional.
If a dose of the extended-release capsule is missed, take it as soon as remembered unless more than 14 hours have passed after the scheduled time—do not double the dose.
Advise the patient to read the Patient Information Leaflet before starting tacrolimus and with each refill, in case of updates.
Instruct the patient to inspect the appearance of the capsules with each new prescription. Contact a healthcare professional if the appearance or dose seems different.
Avoid grapefruit, grapefruit juice, and alcohol during tacrolimus therapy.
Reinforce that lifelong therapy is necessary to prevent organ rejection.
Educate the patient about early symptoms of organ rejection and stress the importance of immediate medical attention if they occur.
Avoid raw oysters or other shellfish; consume only if fully cooked to reduce the risk of infection.
Instruct patients to contact their healthcare provider if they experience signs of:
- Diabetes mellitus (e.g., frequent urination, increased thirst or hunger)
- Infection (e.g., fever, sweats, chills, cough or flu-like symptoms, muscle aches, or painful/red skin areas)
- Posterior Reversible Encephalopathy Syndrome (PRES)
Advise wearing protective clothing and sunscreen to prevent photosensitivity reactions.
Instruct patients to avoid exposure to chickenpox, measles, mumps, and rubella. If exposed, contact a healthcare professional immediately for possible prophylactic treatment.
Advise the patient to inform their healthcare provider about all prescription and over-the-counter (OTC) medications, vitamins, or herbal products they are using.
Consult a healthcare professional before starting any new medication.
Educate the patient on the risk of lymphoma or skin cancer associated with tacrolimus therapy.
Discuss the potential risks during pregnancy and breastfeeding. Use only if the benefits outweigh the risks.
Emphasize the importance of regular lab tests to monitor tacrolimus levels and prevent complications.

Topical (Protopic Ointment) Instructions

Contact a healthcare professional if symptoms do not improve after 6 weeks, worsen, or if a skin infection develops.
Use the ointment only on areas affected by atopic dermatitis.
Discontinue use when the signs and symptoms of atopic dermatitis resolve.
Limit sun exposure during treatment, including artificial UV light (e.g., tanning beds).

Evaluation / Desired Outcomes

Successful prevention of transplanted organ rejection
Improvement or resolution of atopic dermatitis symptoms

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