Tacrolimus

What is Tacrolimus?

• Tacrolimus is a calcineurin-inhibitor immunosuppressant used largely as a means of prophylaxis against cellular rejection after transplantation.

Tacrolimus-2D-skeletal

What are the uses of this medicine?

• Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant.
• Tacrolimus capsules are a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.

How does this medicine work?

• Tacrolimus (ta kroe' li mas), also known as FK506, is a macrolide antibiotic which also has profound immunosuppressive properties, particularly affecting T cells and the cellular immune response.
• Tacrolimus acts as a calcineurin inhibitor which is responsible for activating an important signal transduction molecule in the pathway of T cell activation.
• The result of the inhibition is a decrease in maturation of T lymphocytes and reduction in lymphokine production, including IL-2.
• Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity.
• The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Who Should Not Use this medicine ?

This medicine cannot be used in patients who:

• are allergic to tacrolimus or any of the ingredients in tacrolimus capsules.

What drug interactions can this medicine cause?

Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work. Especially tell your healthcare provider if you take:

• sirolimus (RAPAMUNE®): You should not take tacrolimus capsules if you take sirolimus.
• cyclosporine (GENGRAF®, NEORAL®, and SANDIMUNE®)
• medicines called aminoglycosides that are used to treat bacterial infections
• ganciclovir (CYTOVENE® IV, VALCYTE®)
• amphotericin B (ABELCET®, AMBISOME®)
• cisplatin
• antiviral medicines called nucleoside reverse transcriptase inhibitors
• antiviral medicines called protease inhibitors
• water pill (diuretic)
• medicine to treat high blood pressure
• nelfinavir (VIRACEPT®)
• telaprevir (INCIVEK®)
• boceprevir
• ritonavir (KALETRA®, NORVIR®, TECHNIVIETM, VIEKIRA PAKTM, VIEKIRA, XRTM)
• letermovir (PREVYMISTM)
• ketoconazole
• itraconazole (ONMELTM, SPORANOX®)
• voriconazole (VFEND®)
• clarithromycin (BIAXIN®, BIAXIN XL®, PREVPAC®)
• rifampin (RIFADIN®, RIFAMATE®, RIFATER®, RIMACTANE®)
• rifabutin (MYCOBUTIN®)
• amiodarone (NEXTERONE®, PACERONE®)
• Avoid eating grapefruit or drinking grapefruit juice.

Is this medicine FDA approved?

• Tacrolimus was first approved by the US Food and Drug Administration (FDA) in 1994, for use in liver transplantation; the indications were extended to include kidney transplants.
• Generic versions of tacrolimus were approved in the US in 2017.

How should this medicine be used?

Recommended dosage:

For Kidney Transplant patients With Azathioprine:

• 0.2 mg/kg/day, divided in two doses, administered every 12 hours
• Month 1-3: 7-20 ng/mL
• Month 4-12: 5-15 ng/mL

• For Kidney Transplant patients With MMF/IL-2 receptor antagonist:
• 0.1 mg/kg/day, divided in two doses, administered every 12 hours
• Month 1-12: 4-11 ng/mL

For Liver Transplant With corticosteroids only:

• 0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours
• Month 1-12: 5-20 ng/mL

For Heart Transplant With azathioprine or Mycophenolate mofetil(MMF):

• 0.075 mg/kg/day, divided in two doses, administered every 12 hours
• Month 1-3: 10-20 ng/mL
• Month ≥ 4: 5-15 ng/mL

PEDIATRIC PATIENTS: Liver Transplant:

• 0.15-0.2 mg/kg/day capsules divided in two doses, every 12 hours
• Month 1-12: 5-20 ng/mL

Administration:

• Take tacrolimus capsules with or without food.
• Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.
• Take tacrolimus capsules at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.
• Taking tacrolimus capsules at the same time each day helps to keep the amount of medicine in your body at a steady level.
• If you take too many tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away.
• Do not open or crush tacrolimus capsules.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form: As Capsules: 0.5 mg, 1 mg and 5 mg

Prograf:

• Capsules: 0.5 mg, 1 mg and 5 mg
• Injection: 5 mg/mL
• For oral suspension: 0.2 mg, 1 mg unit-dose packets containing granules

Envarsus xr:

• Extended-release tablets: 0.75 mg, 1 mg, 4 mg

This medicine is available in fallowing brand namesː

• Prograf; Envarsus xr

What side effects can this medication cause?

The most common side effects of tacrolimus capsules in people who have received a kidney, liver, or heart transplant are:

• infections in general, including cytomegalovirus (cmv) infection
• tremors (shaking of the body)
• constipation
• diarrhea
• headache
• stomach pain
• trouble sleeping
• nausea
• high blood sugar (diabetes)
• low levels of magnesium in your blood
• low levels of phosphate in your blood
• swelling of the hands, legs, ankles, or feet
• weakness
• pain
• high levels of fat in your blood
• high levels of potassium in your blood
• low red blood cell count (anemia)
• low white blood cell count
• fever
• numbness or tingling in your hands and feet
• inflammation of your airway (bronchitis)
• fluid around your heart

Tacrolimus capsules may cause serious side effects, including:

• Increased risk of cancer
• Increased risk of infection
• problems from medicine errors
• diabetes]
• kidney problems
• nervous system problems
• high levels of potassium in your blood
• high blood pressure
• QT prolongation
• myocardial hypertrophy
• anemia

What special precautions should I follow?

• Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. Tacrolimus capsules are not interchangeable or substitutable for tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients or caregivers to recognize the appearance of tacrolimus capsules.
• Tacrolimus was shown to cause new onset diabetes mellitus. Monitor blood glucose.
• Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity. Reduce the dose; use caution with other nephrotoxic drugs.
• Tacrolimus may cause a spectrum of neurotoxicities. Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus capsules.
• Hyperkalemia has been reported with tacrolimus use. Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia.
• Hypertension is a common adverse effect of tacrolimus therapy. May require antihypertensive therapy. Monitor relevant drug-drug interactions.
• Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus injection. Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis.
• Tacrolimus is not recommended for use with sirolimus. Not recommended in liver and heart transplant due to increased risk of serious adverse reactions.
• When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended.
• Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus. Consider dose reduction/discontinuation.
• The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
• Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. Consider discontinuation of tacrolimus.

What to do in case of emergency/overdose?

Symptoms of overdosage may include:

• tremors
• abnormal renal function
• hypertension
• peripheral edema
• urticaria
• lethargy

Management of overdosage:

• General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
• The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use.

Can this medicine be used in pregnancy?

• Tacrolimus can cause fetal harm when administered to a pregnant woman.
• Advise pregnant women of the potential risk to the fetus.

Can this medicine be used in children?

• Safety and effectiveness have been established in pediatric liver transplant patients.

What are the active and inactive ingredients in this medicine?

• Active ingredient: tacrolimus
• Inactive ingredients:
• Tacrolimus capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.
• The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.
• In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

Who manufactures and distributes this medicine?

Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. PROGRAF Granules manufactured by: Astellas Pharma Tech Co., Ltd. Toyama, Japan

ENVARSUS XR:

• Manufactured by: Rottendorf Pharma GmbH, 59320 Ennigerloh, North Rhine-Westphalia, Germany
• Manufactured for: Veloxis Pharmaceuticals, Inc., Cary, North Carolina 27518, United States

What should I know about storage and disposal of this medication?

• Store tacrolimus capsules at room temperature between 20° to 25°C (68° to 77°F).

The following drugs used to prevent transplant rejection.

Immunosuppressants

• Cyclosporine
• Everolimus
• Mycophenolate
• Sirolimus
• Tacrolimus

Monoclonal Antibodies

• Alemtuzumab
• Basiliximab
• Daclizumab
• Muromonab

Antithymocyte Globulin

• Dailymed label info on Tacrolimus
• FDA Tacrolimus

Tacrolimus Resources
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