Tacrolimus (Prograf) - Uses, Dose, Side effects, Brands, MOA

A calcineurin inhibitor called tacrolimus is given as a preventative measure to transplant recipients to lessen the risk of organ rejection. The extended-release and immediate-release formulations should not be used interchangeably. Neither should the extended-release formulations be used interchangeably because of the variable pharmacokinetic properties of Astagrad XL and Evarsus XR in combination with other immunosuppressants. These are employed in kidney transplant recipients to avoid rejection. Organ rejection is prevented in kidney, heart, and liver transplant recipients with Hecoria, Prograf, and other immunosuppressants. Tacrolimus is also utilized to manage graft vs. host disease, uveitis, Crohn's disease, myasthenia gravis, refractory rheumatoid arthritis, myasthenia gravis, intestine transplant, and as continuous therapy in patients who have had lung transplantation.

Tacrolimus Dose in Adults:

Note: It is not recommended to utilise the immediate-release and extended-release versions interchangeably.

Following a solid-organ transplant, immunosuppression:

Sublingual (off-label route): The primary-release tablets may be administered sublingually. However, the dose may be reduced from half to one-third of the oral dose. Serum trough concentrations should be monitored for dose adjustment.


Prevention of organ rejection in transplant recipients:

  • Tacrolimus dose should be titrated based on the target trough concentrations.
  • For the prevention of organ rejection, particularly in the early post-transplant period, tacrolimus should be taken in conjunction with or as an adjuvant to other immunosuppressants.
  • Only individuals who are unable to tolerate oral medication should get intravenous tacrolimus.
  • Eight to twelve hours following the end of the intravenous infusion, the oral dosage should be given.
  • Furthermore, the sublingual dose may be considered if oral therapy cannot be tolerated and the risks of anaphylaxis with intravenous administration are high.

Tacrolimus dose in Liver transplant:

Immediate release formulation:

  • In addition to corticosteroids, 0.1 to 0.15 mg/kg/day orally, divided into two doses, given once every 12 hours (titrate to the appropriate trough level).
  • Lower dosage recommendations should be made to patients with graft malfunction.

Extended-release oral formulation:

  • 0.1 to 0.2 mg/kg once a day when taking steroids
  • It should begin to titrate to the optimum trough concentrations 12 to 18 hours after the transplant.
  • In a 1:1 ratio, the extended-release formulation can be changed from the immediate-release formulation (mg: mg).

Intravenous dose: As a continuous infusion, 0.03 to 0.05 mg per kg per day


Tacrolimus dose in a Heart transplant:

  • Tacrolimus should be administered in conjunction with a mycophenolate mofetil or azathioprine-type antimetabolite agent.
  • mTOR kinase inhibitors like sirolimus and everolimus can also be used with it.

Immediate-release oral formulation: To achieve the appropriate trough concentrations, 0.075 mg/kg/day in two split doses is delivered every 12 hours. Continuous infusion of 0.01 mg/kg/day administered intravenously.

1/5th of the oral dose can be administered intravenously in cases where a switch from oral to intravenous form is necessary.


Tacrolimus in Kidney transplant:

Mycophenolate mofetil or azathioprine ought to be used with it.

Immediate-release oral formulation:

  • Give two split doses of 0.2 mg per kg per day, separated by 12 hours, when used in conjunction with azathioprine, or 0.1 mg per kg per day, separated by 12 hrs, when used in conjunction with mycophenolate mofetil, to titrate the dosage to a target trough concentration.
  • If the patient is changing from an oral, immediate-release formulation to an intravenous formulation, one-third (1/3) of the dose should be provided intravenously over the course of 24 hrs.

Extended-release Tacrolimus (Advagraf, Astagraf XL):

Without induction with basiliximab:

Postoperative dose (should be given no longer than 4 hours following the preoperative dosage and no later than 12 hours following reperfusion.):

  • once daily 0.2 mg/kg (in combination with corticosteroids and mycophenolate).
  • The dosage needs to be adjusted to get the desired trough concentration.
  • When moving from an intravenous to an oral formulation with an immediate release, you should start your oral medication 8 to 12 hours after stopping your intravenous dosage.
  • Once daily administration of a 1:1 (mg: mg) switch from the immediate-release to the extended-release version is advised.

Preoperative dose (administer within 12 hrs before the reperfusion):

    • 0.1 mg/kg (in conjunction with corticosteroids and mycophenolate) 

Prior to reperfusion or within two days after the completion of the transplant, when basiliximab is initiated:

    • a daily dose of 0.15 to 0.2 mg/kg (in combination with corticosteroids and mycophenolate).

Crohn disease (off-label use):

oral formulation for immediate release (limit to short-term use only because of potential toxicity)

  • Initial dose: twice daily, 0.1 mg/kg. (Adjust the dose to the desired trough levels).

Graft-versus-host disease (GVHD) with tacrolimus dosage (off-label use):

For the Prevention of GVHD:

  • 0.03 mg/kg/day as a continuous intravenous infusion (depending on lean body weight). Prior to the infusion of stem cells, treatment should start a day (24 hours) in advance and continue until the patient can tolerate taking medications orally. It is possible to change the intravenous dosage to an immediate-release medication in a 1:4 ratio and administer it twice daily.

For the Treatment of GVHD:

  • Immediate-release oral formulation: 0.06 mg/kg twice daily.
  • A continuous infusion of 0.03 mg/kg/day (based on lean body weight) is administered intravenously.

Lung transplant (off-label use):

Usually used in conjunction with either azathioprine or mycophenolate plus a corticosteroid.

Immediate-release oral formulation:

  • 0.05 to 0.3 mg/kg/day, split into two doses and administered every 12 hours (titrate the dose to the target trough concentrations)
  • Sublingual administration at half the oral dosage is also an option.
  • Patients with stable conditions may take the extended-release formulation.

Intravenous infusion: 0.01 to 0.05 mg/kg as a continuous IV infusion over 24 hours


Tacrolimus Dose in Myasthenia gravis (off-label use):

Patients who continue to experience substantial symptoms while taking pyridostigmine should be treated:

Immediate-release oral formulation:

  • 0.1 mg/kg/day, or 3 to 5 mg/day, given in one or two split doses (titrate the dose to the target trough concentrations). Up to 12 months may pass before there is a clinical response.

Tacrolimus Dose in Refractory Rheumatoid arthritis (off-label use):

Immediate-release oral formulation:

  • (May be used with NSAID/oral corticosteroid treatment) 2 to 3 mg once daily

  • May be used with methotrexate at a lower dosage (1.5 mg once daily).

  • Throughout the course of treatment, serum creatinine levels should be checked.

Dose in Children:

Dose in Liver transplant:

Immediate-release oral formulation:

  • 0.2 to 0.15 mg per kg per day in two evenly spaced doses (titrate to the target trough concentrations)

Intravenous dose:

  • As a continuous infusion, 0.03 to 0.05 mg/kg/day

Note: Tacrolimus should be administered for the first time six hours after a liver or heart transplant and within twenty-four hours following a kidney transplant. Early on after transplantation, corticosteroid adjunctive treatment is advised. Due to the dangers of anaphylaxis, intravenous treatment should only be used in individuals who cannot tolerate oral drugs. 8 to 12 hours following the end of the intravenous infusion, oral treatment may begin.

Dose in Renal Disease:

  • Patients with renal disease may require a reduction in the dose because of the risks of tacrolimus-induced nephrotoxicity.

Hemodialysis/ peritoneal dialysis:

  • Supplemental doses are not required in patients on hemodialysis as it is not removed via hemodialysis or peritoneal dialysis.

Dose in Liver disease:

  • Patients with moderate to severe hepatic impairment experience an extended tacrolimus half-life (serum bilirubin >2 mg/dL or Child-Pugh score ≥10) leading to high blood levels resulting in nephrotoxicity.
  • It can also cause liver toxicity (hepatocellular and cholestatic liver disease)
  • The dose should be modified based on the medication trough levels while patients are being regularly watched.
  • Initiating the patient on a lower dose may be required in such situations.

Contraindications to Tacrolimus:

Warnings and precautions:

  • Patients who are able to tolerate oral therapy should use it. There is a high risk of anaphylaxis from intravenous tacrolimus.
  • Anaphylaxis should be monitored in patients receiving intravenous tacrolimus. Patients should be able to take oral tablets once they are able.
  • Arrhythmias should be checked in patients, especially those who are taking antiarrhythmic drugs and amiodarone, as well as patients with electrolyte imbalances like hypokalemia and hypomagnesemia.
  • Reversible myocardial hypertrophy may also occur in patients. This can be treated with dose reductions or discontinuation.
  • Patients are at risk of developing diabetes (also known as post transplant diabetes mellitus), especially with tacrolimus use.
  • Patients who used tacrolimus experienced gastrointestinal perforation. However, most cases were due to complications of transplant surgery, infection or malignant neoplasm.
  • Tacrolimus should be administered to patients who are hyperkalemic. Avoid potassium-sparing diuretics, and any other drugs that can cause hyperkalemia.
  • Tacrolimus may cause hypertension. Avoid drugs that cause hyperkalemia. Do not use calcium channel blockers.
  • Infections (BOXED warning):
    • Hospitalization or death may result from serious bacterial, viral and protozoal infections. Reactivation of latent infections like JC (John Cunningham) virus associated with progressive multifocal leukoencephalopathy, the BK virus which is associated with the polyomavirus-associated nephropathy (PVAN) and the cytomegalovirus (CMV) infection.
  • Malignancies (Boxed warning):
    • Tacrolimus could be associated with skin malignancies and lymphoma. Patients should apply sunscreens and limit prolonged sun exposure
  • Nephrotoxicity: Patients who have been taking a higher dose of tacrolimus or are using concomitant drugs that can cause nephrotoxicity, such as those who have taken a longer-lasting regimen.
  • Neurotoxicity:
    • Patients who take high dosages of tacrolimus may have tremors, headaches, confusion, and seizures. An altered mental status, headaches, hypertension, seizures, and visual problems can all contribute to PRES (Posterior Reversible Encephalopathy Syndrome). When blood pressure is stabilised and the medicine dose is decreased or stopped, this normally gets better.
  • Pure red cell aplasia:
    • Patients who have taken mycophenolate or are at a high risk of contracting parvovirus b19 infections may experience pure red cell aplasia. Pure red cell aplasia has to be identified and treated right away.
  • Hepatic impairment 
  • Renal impairment
    • Tacrolimus shouldn't be administered if post-transplant oliguria develops. Patients with compromised renal function shouldn't exceed the advised dosage.

How to administer Tacrolimus?

  • Tacrolimus should only be used under the guidance of a skilled medical professional.
  • Intravenous tacrolimus should be given via a slow infusion over 24 hours. The solution should not be mixed with acyclovir or ganciclovir and PVC tubing should be avoided.

Oral Tacrolimus:

  • You can take an immediate-release formulation with or without meals.
  • It is best to take the once-daily dosage in the morning and the twice-daily dose 12 hours apart.
  • If there is a difference between the morning and evening dosages, the morning dose should be higher.

Everolimus in combination with treatment for liver transplantation: 

  • Tacrolimus and everolimus should be administered together.

Tacrolimus granules:

  • Granules shouldn't be sprinkled on meals.
  • Fill each packet's whole contents into a glass cup. Add 15 to 30 mL of room temperature drinking water, stir, and then dispense the full contents of the cup. Immediately after preparation, administer. The granules won't totally dissolve, so keep that in mind.

Extended-release formulation:

  • It is recommended to take the extended-release tacrolimus on an empty stomach at least one hour before or two hours after a meal. Do not chew, crush, or split the capsule; instead, swallow it whole.
  • Take one dose every day at a certain time in the morning.
  • If a dosage is missed, you have up to 14 hours (or 15 hours in the case of Envarsus XR) to make up for it. Resuming at the following scheduled time if more than 14 hours have passed (more than 15 hours for Envarsus XR). (A missing dosage shouldn't be made up by doubling the dose.)

Nasogastric tube:

  • The contents of the capsules may be combined with water and pumped through a nasogastric tube if the patient is unable to swallow them. After administration, keep the nasogastric tube clamped for 30 to 60 minutes.

Sublingual:

  • The medication can be given sublingually (at a lower dose) if the patient is unable to swallow the capsules. To do this, open the immediate-release capsules, place the contents beneath the tongue, and let them completely dissolve.

Hazardous Drugs Handling Considerations

Use appropriate precautions like wearing gloves (single) for receiving, handling, administration, and disposal. Wearing double gloves, goggles, face mask, and a protective gown is recommended if the capsules or tablets are manipulated or crushed.

Similar to this, closed system transfer devices (CSTDs), ventilated engineering controls, double gloves, and protective gowns are advised for IV preparation.

Pregnancy Risk factor C

  • Infants of transplant patients have been documented to have a premature delivery, miscarriage, low birthweight, preterm birth, birth deformities (including craniofacial and renal/urogenital anomalies), renal dysfunction, transitory newborn hypokalemia, and cardiac illness.
  • Tacrolimus traverses the placenta and its levels may be higher in the placenta than in the maternal serum.
  • As pregnancy progresses, Tacrolimus whole-blood concentrations decrease, but concentrations of unbound form rise.
  • It may be preferable to measure unbound concentrations, particularly in females with hypoalbuminemia or anemia.
  • Pregnant females who have had a transplant of the kidney may have a higher risk of developing infection, hypertension, or pre-eclampsia if they are using an immunosuppressant during pregnancy.
  • Both liver transplant recipients of tacrolimus have experienced diabetes and hypertension during pregnancy.

Breast-Feeding Considerations

  • Breast milk contains varying amounts of Tacrolimus. 
  • It is important to consider the risks of infant exposure and the benefits to infants of breastfeeding.

Common side effects of Tacrolimus (alphabetical order):

  • A:
    • Acne, alopecia, anemia, anorexia, anxiety, arthralgia, ascites,
  • B:
    • bile-duct abnormalities, bloating, blood disorders,
  • C:
    • cholestasis, confusion, constipation,
  • D:
    • depression, diarrhea, dizziness, dyspepsia, dyspnoea,
  • E:
  • electrolyte disturbances, edema
  • F:
    • flatulence,
  • G:
    • gastrointestinal inflammation, gastrointestinal perforation, gastrointestinal ulceration,
  • H:
    • hemorrhage, headache, hepatic dysfunction, hyperglycaemia, hyperkalaemia, hypertension, hyperuricaemia, hypokalaemia,
  • I:
    • impaired hearing, ischaemic events,
  • J:
    • jaundice,
  • L:
  • leucopenia,
  • M:
  • mood changes, muscle cramp,
  • N:
  • nausea,
  • P:
  • pancytopenia, paraesthesia, parenchymal lung disorders, peripheral neuropathy,  photophobia, pleural effusion, psychosis,
  • R:
    • renal failure, renal impairment, renal tubular necrosis,
  • S:
    • seizures, sleep disturbances, sweating,
  • T:
    • tachycardia, thrombocytopenia, thromboembolic events, tinnitus, tremor,
  • U:
    • urinary abnormalities,
  • V:
    • visual disturbances, vomiting, and
  • W:
    • weight changes.

Uncommon Side effects (alphabetical order):

Amnesia, arrhythmia, cardiac arrest, cardiomyopathy, cataract, cerebrovascular accident, coagulation problems, coma, dermatitis, dysmenorrhea, encephalopathy, gastrointestinal reflux disease, heart failure, hypertonia, hypoglycemia, flu-like symptoms, palpitation, pancreatitis, paralysis, paralytic ileus, peritonitis, photosensitivity, respiratory failure, and speech disorder are some of the symptoms that


Rare side effects:

Myasthenia, Stevens-Johnson syndrome, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, hemorrhagic cystitis, dehydration, hirsutism, pericardial effusion, posterior reversible encephalopathy syndrome, respiratory distress syndrome, agranulocytosis, hemolytic anaemia, and pure red cell aplasia. For the first several weeks, take measurements three times per week of the following parameters, and then progressively cut back on the frequency:

  • serum electrolytes like magnesium, phosphorus, potassium,
  • blood pressure,
  • Renal function,
  • Liver function,
  • glucose, and

When given via the intravenous route:

  • Monitor for anaphylaxis.
  • In patients who exhibit signs of ventricular dysfunction, renal failure, and electrolyte abnormalities, watch for QT prolongation and take an echocardiographic examination into consideration.

Monitor trough levels 30 minutes prior to the next scheduled oral dose. Whole blood should be used to monitor trough levels. The frequency of monitoring of trough levels depends on the type of transplant and clinical situation.


Reference Ranges for Tacrolimus levels in the blood.

Heart transplant:

Typical whole blood trough concentrations (goals levels may vary and have not been adequately determined):

  • Months 3 - 6: 8 to 12 ng per mL
  • Days 0 - 60: 10 to 15 ng per mL
  • More than 6 months: 5 to 10 ng per mL

Kidney transplant:

Whole blood trough concentrations: Immediate release (in combination with azathioprine):

  • Months 1 - 3: 7 to 20 ng/mL
  • Months 4 - 12: 5 to 15 ng/mL

When used with an IL-2 receptor antagonist (such as basiliximab) and mycophenolate mofetil:

  • 4 - 11 ng/mL

In combination with mTOR inhibitor (everolimus):

  • 4 - 8 ng/mL for the first 2 months after transplant followed by 3 - 5 ng/mL thereafter

Without basiliximab induction:

  • Month 1: 10 - 15 ng/mL
  • Months 2 - 6: 5 - 15 ng/mL
  • More than 6 months: 5 - 10 ng/mL

Extended-release (Astagraf XL): Adult: With basiliximab induction:

  • Month 1: 7 - 15 ng/mL
  • More than 6 months: 5 - 10 ng per mL
  • Months 2 - 6: 5 - 15 ng/mL

Reference ranges in Pediatric age groups:

Extended-release (Envarsus XR):

  • Month 1: 6 - 11 ng/mL
  • More than 1 month: 4 - 11 ng/mL

With basiliximab induction:

  • More than one month: 5 - 15 ng/mL
  • Month 1: 10 - 20 ng/mL

Liver transplant:

When administered in combination with everolimus for liver transplant:

  • By 3 weeks after the first everolimus dose and through month 12 post-transplant: 3 to 5 ng per mL

Whole blood trough concentrations:

  • Months 1 - 12: 5 - 20 ng per mL

Intestinal transplant (off-label use):

  • Months 1 - 3: 10 - 20 ng/mL followed by a gradual dose reduction

Crohn's disease (fistulizing disease; off-label use):

  • Whole blood concentration target range: 10 - 20 ng/mL

Lung transplant (off-label use):

  • Whole blood trough concentrations: 5 - 15 ng/mL

Myasthenia gravis (off-label use):

  • Whole blood trough concentrations: 8 - 9 ng/mL

Prevention of graft-versus-host disease (off-label use):

  • Whole blood trough concentrations: 10 - 20 ng/mL

Mechanism of Action of Tacrolimus:

It suppresses cellular immunity by inhibiting T lymphocyte activation and Interleukin 2 production.

Absorption:

  • Orally, absorption can be variable due to food containing high fat.
  • Mucositis, an inflammatory condition of the stomach, can also affect oral absorption. Patients who have had their stomas resected will absorb more.
  • Additionally, clamping the T-tube in patients with liver transplants had no effect on the trough levels or AUC, unlike cyclosporine.
  • It is distributed to the erythrocytes and kidneys, liver, spleen and heart.
  • 99% of proteins are linked to the medication, mostly albumin and alpha-1-acid glycoprotein.
  • The liver metabolizes it extensively via CYP3A4.

Half-life elimination

  • Children undergoing kidney transplantation take between 5 and 15 hours.
  • In infants and children with liver transplantation, it takes 7.5 to 14.5 hours
  • Variable in adults, when immediate-release formulations are taken
    • Healthy volunteers spend 23 to 46 hours on average
    • Transplant patients spend between 2.1 and 36 hours.
  • Extended-release formulation: 35-41 hours (prolonged for patients with severe hepatic impairment).
  • The time it takes to reach peak plasma levels is between 0.5 and 6 hours
  • Feces are the main route of excretion

International Brands of Tacrolimus:

Pricing: United States

Capsule ER 24 Hour Therapy Pack (Astagraf XL Oral)

  • 0.5 mg (per each): $2.83
  • 1 mg (per each): $5.65
  • 5 mg (per each): $28.26

Capsules (Prograf Oral)

  • 0.5 mg (per each): $3.62
  • 1 mg (per each): $7.24
  • 5 mg (per each): $36.19

Capsules (Tacrolimus Oral)

  • 0.5 mg (per each): $1.56 - $2.23
  • 1 mg (per each): $2.78 - $4.46
  • 5 mg (per each): $12.20 - $22.30

Solution (Prograf Intravenous)

  • 5 mg/mL (per mL): $249.49

Tablet, 24-hour (Envarsus XR Oral)

  • 0.75 mg (per each): $4.55
  • 1 mg (per each): $6.07
  • 4 mg (per each): $24.28

Brand Names: Canada

  • Advagraf
  • Prograf

Brand Names: US

  • Envarsus XR
  • Prograf
  • Astagraf XL

Brand Names: International

  • Adoport
  • Adport
  • Advagraf
  • Advagraf XL
  • Advahraf
  • Capexion
  • Cidimus
  • Envarsus
  • Graceptor
  • Modigraf
  • Pangraf
  • Panraf
  • Prograf
  • Prograf XL
  • Prograft
  • Prohraf
  • Regraf
  • Rolitac
  • T-Inmun
  • Taccin
  • Tacgraf
  • Tacrobell
  • Tacrocel
  • Tacrotec
  • Tacroz Forte
  • Tagraf
  • Tarimus
  • Treczimus
  • Vingraf
  • Vivadex

Tacrolimus Brands in Pakistan:

Tacrolimus [Oint 0.1 %W/W]

Crolimus Valor Pharmaceuticals
Edtac Amarant Pharmaceuticals (Pvt)
Tacrus Shrooq Pharmaceuticals

 

Tacrolimus [Oint 0.01 %W/W]

Aimus Aims Traders
Eczemus Brookes Pharmaceutical Laboratories (Pak.) Ltd.

 

Tacrolimus [Oint 0.03 %W/W]

Aimus Aims Traders
Crolimus Valor Pharmaceuticals
Eczemus Brookes Pharmaceutical Laboratories (Pak.) Ltd.
Limus Nabiqasim Industries (Pvt) Ltd.
Limus-J Ambrosia Pharmaceuticals
Tacroderm Sante (Pvt) Limited
Tacrogen Biogen Pharma
Tacrol Acme Laboratories Pakistan (Pvt) Ltd.
Taczam Laderly Bio-Tech Pharma

 

Tacrolimus [Cream 0.1 %W/W]

Tacro Wise Pharmaceuticals (Pvt) Ltd
Tacro Wise Pharmaceuticals (Pvt) Ltd

 

Tacrolimus [Cream 0.03 %W/W]

Tagora Rogen Pharmaceuticals

 

Tacrolimus [Tabs 1 Mg]

Imunol Saffron Pharmaceutical Company

 

Tacrolimus [Caps 1 Mg]

Inograf Platinum Pharmaceuticals (Pvt.) Ltd.
Tacgraf Consolidated Chemical Laboratories (Pvt) Ltd.
Tacogen Allmed Labs

 

Tacrolimus [Caps 5 Mg]

Inograf Platinum Pharmaceuticals (Pvt.) Ltd.

 

Tacrolimus [Caps 0.5 Mg]

Inograf Platinum Pharmaceuticals (Pvt.) Ltd.
Tacgraf Consolidated Chemical Laboratories (Pvt) Ltd.