Tacrolimus

Tacrolimus is a prescription medication indicated for preventing organ rejection in heart, kidney, liver, or lung transplants.

• Tacrolimus is available under the following different brand names: Prograf, Astagraf XL, Hecoria, Envarsus XR

Adult and pediatric dosage

Capsule, immediate-release (Prograf, Hecoria)

• 0.5mg
• 1mg
• 5mg

Capsule, extended-release (Astagraf XL)

• 0.5mg
• 1mg
• 5mg

Tablet, extended-release (Envarsus XR)

• 0.75mg
• 1mg
• 4mg

Injectable solution (Prograf)

• 5mg/mL

Granules for oral suspension (Prograf)

• 0.2mg/packet
• 1mg/packet 

Heart Transplant 

Adult dosage

• IV: 0.01 mg/kg/day by continuous infusion initially 
• Oral (immediate-release): 0.075 mg/kg/day divided every 12 hours initially

Pediatric dosage

Prograf

• IV: 0.01 mg/kg/day by continuous infusion initially  
• Oral capsules and granules: 0.3 mg/kg/day divided into 2 doses, administered every 12 hours initially

Liver Transplant

Adult dosage

• IV: 0.03-0.05 mg/kg/day by continuous infusion initially  
• Oral (immediate-release), with corticosteroids only: 0.1-0.15 mg/kg/day divided every 12 hours initially

Pediatric dosage

Prograf

• IV: 0.03-0.05 mg/kg/day by continuous infusion initially  

Oral

• Capsules: 0.15-0.2 mg/kg/day divided every 12 hours initially  
• Granules: 0.2 mg/kg/day divided into 2 doses, administered every 12 hours initially

Kidney Transplant

Adult dosage

Prograf

• IV: 0.03-0.05 mg/kg/day IV by continuous infusion initially  
• Oral (with azathioprine): 0.2 mg/kg/day divided every 12 hours initially  
• Oral (with MMF/IL-2 receptor antagonist): 0.1 mg/kg/day divided every 12 hours initially

Astagraf XL

• With basiliximab induction
• 15 mg/kg orally once daily
• Without induction
• Preoperative: 0.1 mg/kg orally once daily
• Postoperative: 0.2 mg/kg orally once daily
• Postoperative oliguria: Initial postoperative dose should be administered above 6 hours and below 48 hours after transplantation but may be delayed until renal function shows evidence of recovery

Envarsus XR

• Administer Envarsus XR dose that is 80% of the total daily dose of the tacrolimus immediate-release product
• De novo kidney transplant
• Initiate at 0.14 mg/kg/day

Pediatric dosage

Prograf

• IV: 0.03-0.05 mg/kg/day by continuous infusion initially  
• Oral capsules and granules: 0.3 mg/kg/day divided into 2 doses, administered every 12 hours initially  

Lung Transplant

Adult dosage

Prograf

• IV: 0.01-0.03 mg/kg/day by continuous infusion initially  
• Oral (with azathioprine or MMF): 0.075 mg/kg/day divided every 12 hours initially

Pediatric dosage

Prograf

• IV: 0.01-0.03 mg/kg/day by continuous infusion initially  
• Oral capsules or granules: 0.03 mg/kg/day divided every 12 hours initially

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

Common side effects of Tacrolimus include:

• shaking,
• headache,
• diarrhea,
• constipation,
• nausea,
• vomiting,
• upset stomach,
• stomach pain,
• loss of appetite,
• trouble sleeping (insomnia), or
• tingling or swelling of the hands or feet. 

Serious side effects of Tacrolimus include:

• mental/mood changes,
• dizziness,
• change in the amount of urine,
• tiredness,
• pounding heartbeat,
• hearing problems (such as hearing loss, ringing in the ears),
• pain/redness/swelling of arms or legs,
• easy bruising/bleeding,
• muscle pain/cramps/weakness,
• yellowing skin or eyes,
• dark urine,
• persistent nausea or vomiting, and
• severe abdominal pain. 

Rare side effects of Tacrolimus include:

• none 

This is not a complete list of side effects and other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first,

• Tacrolimus has severe interactions with the following drugs:
• amphotericin B deoxycholate
  • cidofovir
  • elagolix
  • lefamulin
  • mifepristone
  • neomycin PO
  • saquinavir 
• Tacrolimus has serious interactions with at least 160 other drugs:
• Tacrolimus has moderate interactions with at least 287 drugs.
• Tacrolimus has minor interactions with at least 38 other drugs:

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns.

Contraindications

• Hypersensitivity to tacrolimus or any component of the formulation, including castor oil (Prograf) 

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Tacrolimus?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Tacrolimus?”

Cautions

• Hypersensitivity reactions, including anaphylaxis reported with injection formulation, which contains polyoxyl 60 hydrogenated castor oil (HCO-60), a castor oil derivative; limit IV use to patients unable to take orally; monitor patient for 30 min after initiation of infusion and then at frequent intervals; discontinue infusion if anaphylaxis occurs; transition patient from IV to oral dosing as soon as the patient can tolerate oral administration
• Increased risk of infections and lymphoma, including latent virus activation (e.g., BK virus-induced nephropathy)
• Patients receiving immunosuppressants are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections; these infections may lead to serious, including fatal, outcomes; serious viral infections reported include, cytomegalovirus infections; CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at higher risk of developing CMV viremia and CMV disease; monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection (see Black Box Warnings)
• Medication errors (e.g., substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products) reported outside the U.S; which led to serious adverse reactions such as graft rejection, or other adverse reactions due to under-or over-exposure to tacrolimus; not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension; changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision
• Hypertension may occur; may treat with antihypertensives that are non-potassium-sparing diuretics; concurrent use of calcium channel blockers may require a tacrolimus dosage adjustment
• Mild-to-severe hyperkalemia may occur; avoid the use of potassium-sparing diuretics
• Myocardial hypertrophy was reported (reversible with dose reduction or discontinuation)
• QT prolongation reported; consider obtaining electrocardiograms and monitoring electrolytes periodically during treatment in patients with congestive heart failure, bradyarrhythmias, patients taking antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances, including hypokalemia, hypomagnesemia, or hypocalcemia
• Cases of pure red-cell aplasia were reported; if this is diagnosed, consider discontinuing tacrolimus
• Gastrointestinal perforation: all reported cases were considered a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm
• Increased risk of malignancy is related to intensity/duration of therapy; limit or avoid the sun and ultraviolet light exposure; use appropriate sun protection; post-transplant lymphoproliferative disorder related to EBV infection reported in immunosuppressed organ transplant patients; risk highest in young children
• African Americans may need to be titrated to higher dosages to achieve the target tacrolimus concentrations
• Graft rejection and other serious adverse effects have resulted from medication errors with extended-release dosage form; patients and caregivers are advised to recognize appearance extended-release tablets
• Monitor blood glucose: new onset of diabetes after transplants reported
• Acute and or chronic nephrotoxicity reported with therapy; monitor renal function; consider dosage reduction
• Neurotoxicity including the risk of posterior reversible encephalopathy syndrome (PRES) reported; monitor for neurologic abnormalities; reduce dosage or discontinue
• Posttransplant diabetes mellitus
  • The risk of post-transplant diabetes mellitus, especially in black and Hispanic patients; may occur in patients without a pretransplant history of diabetes mellitus
  • Insulin dependence may be reversible
  • Black patients may require higher doses in kidney transplant
  • Monitor blood glucose frequently
  • Discontinue cyclosporine 24 hours before starting tacrolimus
  • Combination immunosuppressant therapy 

Pregnancy and Lactation

• There is a pregnancy registry that monitors pregnancy outcomes in women exposed to the drug during pregnancy; the transplantation pregnancy registry international (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus; healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/
• Tacrolimus can cause fetal harm when administered to a pregnant woman; data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress; advise pregnant women of the potential risk to the fetus; administration of oral tacrolimus to pregnant rabbits and rats throughout organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on an mg/m2 basis)
• Risks during pregnancy are increased in organ transplant recipients; the risk of premature delivery following transplantation is increased; pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient; pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight, and fetal death; cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population; however, COP symptoms resolved postpartum and no long term effect on offsprings was reported
• Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes); monitor maternal blood glucose levels regularly
• Therapy may exacerbate hypertension in pregnant women and increase pre-eclampsia, monitor and control blood pressure
• Renal dysfunction, transient neonatal hyperkalemia, and low birth weight have been reported at the time of delivery in infants of mothers taking the drug
• There is an increased risk for premature delivery (less than 37 weeks) following transplantation and maternal exposure to the drug.
• Contraception
  • Therapy can cause fetal harm when administered to pregnant women; advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment
• Infertility
  • Based on findings in animals, male and female fertility may be compromised by treatment
• Lactation
  • Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk; effects of tacrolimus on the breastfed infant or milk production have not been assessed
  • Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during the postnatal period was associated with developmental toxicity in offspring at clinically relevant doses
  • The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for drugs and any potential adverse effects on the breastfed child from the drug or underlying maternal condition)