Tacrolimus (Prograf) is an immunosuppressive drug that is used primarily in the treatment of patients who have undergone an organ transplant. It is used to prevent graft rejection.

Tacrolimus Uses:

• Organ rejection prophylaxis:
  • Astagraf XL:  It is used for the prevention of organ rejection in kidney transplant recipients in combination with other immunosuppressants.
  • Envarsus XR: It is indicated for the prevention of organ rejection in kidney transplant recipients in combination with other immunosuppressants.
  • Prograf: It is indicated for the Prevention of organ rejection in heart, kidney, and liver transplant recipients in combination with other immunosuppressants.

Off-label uses of Tacrolimus:

• Crohn disease (perianal/fistulizing disease);
• Graft-versus-host disease (prevention/treatment);
• Immunosuppression (maintenance) after lung transplant;
• Intestinal transplant;
• Myasthenia gravis;
• Rheumatoid arthritis (refractory);
• Uveitis

Tacrolimus dose in Adults

Note:

• Extended-release products (Astagraf XL and Envarsus XR) are not interchangeable or substitutable with immediate-release tacrolimus.
• In addition, the once a day formulations (Astagraf XL and Envarsus XR) are not interchangeable with each other due to significantly different pharmacokinetic properties.

Tacrolimus dose for Immunosuppression after solid-organ transplant, sublingual administration: Sublingual (off-label route):

• Immediate release:

  • If immediate release tacrolimus capsules being used sublingually, the sublingual to oral dosing ratio has ranged from 1:3 to 1:1
  • However, many studies suggest a dosing ratio of 1:2 (or 50% of the oral dose given sublingually), and most centers use this approach in practice
  • Monitor serum trough concentrations and titrate accordingly.
  • Give lower doses of sublingual tacrolimus along with drugs that inhibit tacrolimus metabolism

Tacrolimus Dose in the Prevention of organ rejection in transplant recipients:

Note:

• Initial dose recommendations exists
• For further doses monitor trough concentrations titrate dose accordingly
• Adjunctive therapy with other immunosuppressants recommended early after transplant.
• IV route is reserved for patients unable to take orally and shift to take oral tacrolimus once patient tolerate oral medications. Anaphylaxis may occur with oral medications
• If switching from IV to oral, start oral dose 8 - 12 hours after stopping the infusion.
• Sublingual administration may be considered in those unable to take oral.

Tacrolimus Dose in Liver transplant:

Oral:

• Immediate release:

  • Initial: 0.1 - 0.15 mg/kg/day every 12 hours along with corticosteroids
  • Monitor trough concentrations and titrate dose accordingly
  • Lower the dose in liver transplant recipients with graft dysfunction.

• Extended release:

  • 0.1 - 0.2 mg/kg once a day along with corticosteroids; initiate within 12 - 18 hours of transplantation;
  • Monitor trough concentrations and titrate dose accordingly

Note: In the US,  Astagraf XL is not approved for use in liver transplantation because it showed increased mortality in female liver transplant recipients receiving Astagraf XL.

• Conversion from immediate release to extended release (Advagraf [Canadian product]):

  • Extended-release treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of immediate-release product.
  • Administer once a day.
• IV: Initial: 0.03 - 0.05 mg/kg/day as a continuous infusion

Tacrolimu Dose in Heart transplant:

Use along with antimetabolite agent (eg, azathioprine or mycophenolate mofetil). Instead of an antimetabolite, can also be used along with mTOR kinase inhibitor

• Immediate release:

  • Oral: Initial: 0.075 mg/kg/day every 12 hours
  • Monitor trough concentration and titrate dose accordingly
  • IV: Initial: 0.01 mg/kg/day as a continuous infusion

  • Conversion from oral to continuous IV infusion:

    •  One-fifth (1/5th) of the oral daily dose as a continuous infusion over 24 hours should be given (According to the ISHLT guidelines for the care of heart transplant recipients)

Tacrolimus Dose in Kidney transplant:

Use along with azathioprine or mycophenolate mofetil. Note: African-American patients may require larger doses to attain trough concentration. Oral:

• Immediate release (Prograf):

  • Initial: 0.2 mg/kg/day along with azathioprine or 0.1 mg/kg/day along with mycophenolate mofetil
  • Monitor serum trough concentrations and titrate dose accordingly.
  • Administer every 12 hourly in two divided doses.

  • Conversion from immediate release oral to IV:

    • Administer one-third (1/3rd) of the oral dose as a continuous infusion over 24 hours.

• Extended release (Advagraf [Canadian product], Astagraf XL):

  • With basiliximab induction (prior to reperfusion or within 48 hours of transplant completion):

    • 0.15 - 0.2 mg/kg once a day (along with corticosteroids and mycophenolate);
    • Monitor trough concentration and titrate dose accordingly

  • Without basiliximab induction:

    • Preoperative dose (administer within 12 hours prior to reperfusion):
      • 1 mg/kg (along with corticosteroids and mycophenolate)
    • Postoperative dose (administer at least 4 hours after preoperative dose and within 12 hours of reperfusion):
      • 2 mg/kg once a day (along with corticosteroids and mycophenolate)
      • Monitor serum trough concentrations and titrate dose accordingly

  • Conversion from IV to extended release (Astagraf XL):

    • Administer the first oral extended release dose 8 - 12 hours after discontinuation of IV tacrolimus.

  • Conversion from immediate release to extended release (Advagraf [Canadian product], Astagraf XL):

    • Start extended release treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of immediate release
    • Administer once a day.

• Extended-release (Envarsus XR):

  • 0.14 mg/kg/day
  • Monitor serum trough concentration and titrate dose accordingly

  • Conversion from IV to extended release (Envarsus XR):

    • Administer the first oral extended release dose 8 - 12 hours after discontinuation of IV tacrolimus

  • Conversion from immediate release to extended release (Envarsus XR):

    • Start ER treatment with a once a day dose that is 70% - 80% of the total daily dose of the immediate-release tacrolimus
• IV: Initial: 0.03 - 0.05 mg/kg/day as a continuous infusion

Tacrolimu Dose in the treatment of Crohn disease (perianal/fistulizing disease) (off-label): Oral:

• Immediate release:

  • Initial: 0.1 mg/kg twice a day
  • Monitor trough concentrations and titrate dose accordingly

Note: Tacrolimus therapy should for short term as it has serious toxicity potential

Tacrolimus Dose in Graft-versus-host disease (GVHD) (off-label):

• Prevention:

  • Oral:
    • Convert from IV to immediate release oral dose: 1:4 ratio: Multiply total daily IV dose times 4
    • Administer in 2 divided doses 12 hours apart
  • IV:
    • Initial: 0.03 mg/kg/day as continuous infusion.
    • Start treatment 24 hours before stem cell infusion and continue until oral medications tolerable

• Treatment:

  • Oral: Immediate release: 0.06 mg/kg twice a day
  • IV: Initial: 0.03 mg/kg/day as continuous infusion

Tacrolimus Dose in the treatment of Lung transplant (off-label):

Usually used along with regimen that contains a corticosteroid and either azathioprine or mycophenolate

• Oral, nasogastric:

  • Immediate release:
    • .05 - 0.3 mg/kg/day in 2 divided doses 12 hours apart (usual dose: 0.05 mg/kg every 12 hours)
    • Monitor trough concentrations and  titrate dose accordingly
    • Can also be given sublingually at ~50% of the oral/NG dose

Note: Dose can be converted from twice a day dosing to once a day dosing (on a mg per mg basis) using the ER formulation (Astagraf XL [US] or Advagraf [Canada]) in stable lung transplant recipients Dose can also be converted to extended-release Envarsus with a once a day dose that is 70% - 80% of the total daily dose of immediate-release tacrolimus

• IV:
  • .01 - 0.05 mg/kg over 24 hours as a continuous IV infusion
  • Monitor trough concentrations and titrate dose accordingly
  • IV tacrolimus can be given immediately after transplantation, or up to 2 days postoperatively depending on renal function and hemodynamic stability
  • When patient is able to take oral medication, may switch to an oral maintenance regimen

Tacrolimus Dose in the treatment of Myasthenia gravis (off-label):

• Patients who remain significantly symptomatic on pyridostigmine: Oral:

  • Immediate release:

    • Initial: 3 - 5 mg/day or 0.1 mg/kg/day, in one or two divided doses.
    • Monitor trough concentrations and titrate to dose accordingly
    • Can be given as monotherapy or along with glucocorticoids and/or pyridostigmine
    • Onset of clinical response to tacrolimus may take up to 6 - 12 months.

Tacrolimus Dose in the treatment of Rheumatoid arthritis (refractory) (off-label): Oral:

• Immediate release:

  • 2 - 3 mg once a day along with NSAID and/or oral corticosteroid therapy
  • 3 mg once a day resulted in better ACR response rates
  • For methotrexate non-responsive patients Tacrolimus can be given at a lower dose (ie, 1.5 mg once a day) along with methotrexate
  • Carefully monitor serum creatinine during therapy.

Tacrolimus dose in Childrens

Note: Tacrolimus granules may have higher AUC compared to capsule formulation; if changing between products, monitor tacrolimus concentrations.

• ER products (Astagraf XL and Envarsus XR) are not interchangeable or substitutable with immediate-release tacrolimus (Prograf capsules and granules).
• In addition, the once-daily formulations (Astagraf XL and Envarsus XR) are not interchangeable with each other due to significantly different pharmacokinetic properties.
• Younger children generally require higher maintenance doses on a mg/kg basis than older children, adolescents, or adults
• Adjust initial dose to achieve desired target tacrolimus concentration

Tacrolimus Dose in the prevention of Graft-vs-host disease (GVHD): Limited data available; dosing regimens variable:

• Continuous infusion:

  • Infants, Children, and Adolescents:
  • IV:
    • Initial: 0.03 mg/kg/day as continuous IV infusion
    • Start pre-transplant
    • Monitor serum drug concentrations and adjust dose accordingly
    • Convert to oral formulation when tolerated

• Intermittent infusion:

  • Children and Adolescents:
  • IV:
    • 0.015 mg/kg/dose every 12 hours as a 2hour infusion
    • Start treatment on day 2-3 days before transplant and continued until oral medication tolerated

Tacrolimus Dose in the treatment of steroid-resistant or steroid-dependent Nephrotic syndrome: Limited data available:

• Children and Adolescents: Oral:

  • Immediate release:
    • Initial: 0.1 mg/kg/day divided every 12 hours
    • Monitor the serum concentration and titrate accordingly
    • The reported dose range (regardless of target serum concentration) is 0.06 - 0.19 mg/kg/day in divided doses 12 hours apart
    • Target serum concentrations depends on type of nephrotic syndrome and patient characteristics; most frequently reported target is 5 - 10 ng/mL
    • Some studies suggest targeting lower trough concentrations of 3 - 5 ng/mL

Tacrolimus Dose in heart Transplant for the prevention of rejection:

• Infants, Children, and Adolescents: Dose should be individualized and titrated to target trough concentration:

  • Immediate release:

    • Oral: Initial: 0.1 - 0.3 mg/kg/day divided 12 hours apart
    • Note: Lower initial dose can be used in patients who receive cell-depleting induction treatment.
    • Limited data available: IV: 0.01 - 0.03 mg/kg/day as a continuous IV infusion
    • Note: IV use should be limited and patients should be switched to oral formulation as early as possible.

Tacrolimus Dose in kidney Transplant for the prevention of rejection: Oral:

Dose should be individualized and titrated to target trough concentrations:

• Immediate release:

  • Children and Adolescents: Initial: 0.2 - 0.3 mg/kg/day divided, 12 hours apart

• Extended release: Astagraf XL: Use along with corticosteroids and mycophenolate:

  • With basiliximab induction:

    • Children ≥4 years and Adolescents <16 years: 
      • Initial: 0.3 mg/kg once a day
      • Administer first dose within 24 hours of reperfusion
      • Monitor the trough concentrations and titrate accordingly
    • Adolescents ≥16 years:
      • Initial: 0.15 - 0.2 mg/kg once a day
      • Administer first dose before reperfusion or within 48 hours of transplant.
      • Monitor trough concentrations and adjust dose acccordingly

  • Without basiliximab induction:

    • Adolescents ≥16 years:
      • Preoperative dose:
        • 1 mg/kg once; administer within 12 hours before reperfusion
      • Postoperative dose:
        • 2 mg/kg once a day
        • Administer first postoperative dose at least 4 hours after preoperative dose and within 12 hours of reperfusion.
        • Monitor trough concentrations and adjust dose accordingly

    • Conversion from IV to extended release (Astagraf XL):

      • Administer the first oral extended-release dose 8 - 12 hours after discontinuation of IV tacrolimus

    • Conversion from immediate release to extended release (Astagraf XL): Limited data available:

      • Initiate extended-release treatment in a 1:1 ratio (mg:mg) using previously established total daily dose of immediate release
      • Administer once a day.

• Infants, Children, and Adolescents: Limited data available:

  • IV: 0.06 mg/kg/day as a continuous IV infusion
  • Note: IV formulation should be reserved for patients unable to take orally. Switch to oral dose once patient can take oral medications

Tacrolimus Dose in liver Transplant for the prevention of rejection:

• Infants, Children, and Adolescents:

  • Immediate release:

    • Oral: Initial: 0.15 - 0.2 mg/kg/day divided, 12 hours apart
    • IV: 0.03 - 0.05 mg/kg/day as a continuous IV infusion.
    • Note: IV formulation should be reserved for patients unable to take orally. Switch to oral dose once patient can take oral medications

  • Dose conversion of different routes of administration:

    • Conversion of IV continuous infusion to immediate-release oral:
      • GVHD prophylaxis: From IV to oral dose (1:4 ratio): Multiply total daily IV dose by 4 and administer in 2 divided oral doses, 12 hours apart
      • Monitor trough concentration and titrate accordingly
    • Conversion of immediate-release oral to sublingual (using immediate-release capsule):
      • To convert from oral to sublingual dose (2:1 ratio): Divide oral dose by 2 for sublingual administration. This dosing is on basis of experience in adult solid organ transplant recipients

Tacrolimus Pregnancy Category: N

• Tacrolimus crosses over the human placenta.
• It is measured in the cord blood and amniotic fluid as well as the newborn serum.
• Tacrolimus may be more concentrated in the placenta than in maternal blood, and less concentrated in infants born at lower birth weight than those born normal.
• There are possible adverse effects that may occur, including miscarriage and preterm delivery, low baby weight, birth defects (including cardiac and craniofacial, neurological, renal/urogenital, skeletal abnormalities, and renal dysfunction), fetal distress, transient neonatal hypokalemia, and renal dysfunction.
• The pharmacokinetics of Tacrolimus are affected by pregnancy.
• Unbound concentrations increase and whole blood concentrations decrease. 
• Measurement of unbound concentration is important. Unbound concentration measurements are not possible.
• Interpretation of whole blood concentrations should take into account RBC count as well as serum albumin concentration.
• During pregnancy, Tacrolimus may be used as an immunosuppressant.
• Patients undergoing kidney transplant have a higher risk of infection, hypertension and pre-eclampsia.
• Patients receiving tacrolimus may develop hypertension or diabetes during pregnancy.
• Transplant Pregnancy International (TPRI), a registry that tracks pregnancies in male transplant recipients and mothers of those recipients, is called Transplant Pregnancy Register International (TPRI).

Tacrolimus use during breastfeeding:

• Breast milk contains Tacrolimus, which excretes in lower concentrations than maternal serum.
• Some data show that the concentrations of tacrolimus serum in infants who were breastfed or bottle-fed did not differ.
• The maternal dose of Tacrolimus to breastfeeding infants is =0.5%.
• After considering the risks of infant exposure, the benefits of breastfeeding to the baby, and the benefits to the mother, the manufacturer recommends that tacrolimus be used in lactating mothers.

Tacrolimus Dose in Kidney Disease:

• Tarolimus elimination and serum concentrations are not affected by renal impairment Tacrolimus can cause nephrotoxicity.
• Therefore, it may be necessary to reduce the dose. Patients should be given the lowest doses within the IV and oral recommended dosing ranges.

Hemodialysis:

• Hemodialysis does not remove the need for supplemental dosing.

Peritoneal dialysis:

• It is not likely that significant drug removal will occur

Tacrolimus Dose in Liver disease:

• Tacrolimus may increase the risk of renal insufficiency in liver transplant recipients with post-transplant hepatic impairment.
• Moderate-to severe liver dysfunction (bilirubin >2mg/dL; Child Pugh score >=10) can affect the metabolism of tacrolimus.
• This may lead to a prolonged half-life and decreased clearance
• These patients should be closely monitored and adjusted dosages may be necessary.
• Patients with severe hepatic impairment might need to take lower starting doses.

Common Side Effects of Tacrolimus:

• Cardiovascular:

  • Acute Cardiorespiratory Failure
  • Angina Pectoris
  • Atrial Fibrillation
  • Atrial Flutter
  • Bradycardia
  • Cardiac Arrhythmia
  • Cardiac Failure
  • Cardiac Fibrillation
  • Chest Pain
  • Deep Vein Thrombophlebitis
  • Deep Vein Thrombosis
  • ECG Abnormality (Including Abnormal QRS Complex)
  • Edema
  • Flushing
  • Hemorrhagic Stroke
  • Hypertension
  • Hypotension
  • Orthostatic Hypotension
  • Peripheral Edema
  • Phlebitis
  • ST Segment Changes On ECG
  • Syncope
  • Tachycardia
  • Thrombosis
  • Vasodilatation

• Central Nervous System:

  • Abnormal Dreams
  • Abnormality In Thinking
  • Agitation
  • Amnesia
  • Anxiety
  • Ataxia
  • Chills
  • Confusion
  • Depression
  • Dizziness
  • Drowsiness
  • Emotional Lability
  • Encephalopathy
  • Falling
  • Fatigue
  • Flaccid Paralysis
  • Hallucination
  • Headache
  • Hypertonia
  • Hypoesthesia
  • Insomnia
  • Intolerance To Temperature
  • Mobility Disorder
  • Mood Elevation
  • Myoclonus
  • Nerve Compression
  • Nervousness
  • Neuralgia
  • Neuropathy
  • Neurotoxicity
  • Nightmares
  • Pain
  • Paralysis (Monoparesis, Quadriparesis, Quadriplegia)
  • Paresthesia
  • Peripheral Neuropathy
  • Psychomotor Disturbance
  • Psychosis
  • Seizure
  • Vertigo
  • Voice Disorder
  • Writing Difficulty

• Dermatologic:

  • Acne Vulgaris
  • Alopecia
  • Cellulitis
  • Condyloma Acuminatum
  • Dermal Ulcer
  • Dermatitis
  • Diaphoresis
  • Ecchymoses
  • Exfoliative Dermatitis
  • Fungal Dermatitis
  • Hyperhidrosis
  • Hypotrichosis
  • Pityriasis Versicolor
  • Pruritus
  • Skin Discoloration
  • Skin Photosensitivity
  • Skin Rash

• Endocrine & Metabolic:

  • Acidosis
  • Albuminuria
  • Alkalosis
  • Anasarca
  • Cushingoid Appearance
  • Cushing Syndrome
  • Decreased Serum Bicarbonate
  • Decreased Serum Iron
  • Dehydration
  • Diabetes Mellitus (Including New-Onset)
  • Gout
  • Hirsutism
  • Hypercalcemia
  • Hypercholesterolemia
  • Hyperkalemia
  • Hyperlipidemia
  • Hyperphosphatemia
  • Hypertriglyceridemia
  • Hyperuricemia
  • Hypervolemia
  • Hypocalcemia
  • Hypoglycemia
  • Hypokalemia
  • Hypomagnesemia
  • Hyponatremia
  • Hypophosphatemia
  • Increased Gammaglutamyl Transferase
  • Increased Lactate Dehydrogenase
  • Metabolic Acidosis
  • Weight Gain

• Gastrointestinal:

  • Abdominal Distention
  • Abdominal Pain
  • Anorexia
  • Aphthous Stomatitis
  • Biliary Tract Disease
  • Cholangitis
  • Cholestasis
  • Constipation
  • Diarrhea
  • Duodenitis
  • Dyspepsia
  • Dysphagia
  • Esophagitis
  • Flatulence
  • Gastritis
  • Gastroenteritis
  • Gastroesophageal Reflux Disease
  • Gastrointestinal Disease
  • Gastrointestinal Hemorrhage
  • Gastrointestinal Perforation
  • Hernia Of Abdominal Cavity
  • Hiccups
  • Increased Appetite
  • Intestinal Obstruction
  • Nausea
  • Oral Candidiasis
  • Pancreatic Pseudocyst
  • Peritonitis
  • Stomatitis
  • Ulcerative Esophagitis
  • Vomiting

• Genitourinary:

  • Anuria
  • Bladder Spasm
  • Cystitis
  • Dysuria
  • Hematuria
  • Nephrotoxicity
  • Nocturia
  • Oliguria
  • Proteinuria
  • Pyuria
  • Toxic Nephrosis
  • Urinary Frequency
  • Urinary Incontinence
  • Urinary Retention
  • Urinary Tract Infection
  • Urinary Urgency
  • Vaginitis

• Hematologic & Oncologic:

  • Anemia
  • Benign Skin Neoplasm
  • Decreased Platelet Count
  • Decreased White Blood Cell Count
  • Disorder Of Hemostatic Components Of Blood
  • Hemolytic Anemia
  • Hemorrhage
  • Hypochromic Anemia
  • Hypoproteinemia
  • Hypoprothrombinemia
  • Increased Hematocrit
  • Kaposi Sarcoma
  • Leukocytosis
  • Leukopenia
  • Neutropenia
  • Polycythemia
  • Thrombocytopenia
  • Thrombotic Microangiopathy

• Hepatic:

  • Abnormal Hepatic Function Tests
  • Ascites
  • Cholestatic Jaundice
  • Granulomatous Hepatitis
  • Hepatitis (Including Acute And Chronic)
  • Hepatotoxicity
  • Hyperbilirubinemia
  • Increased Liver Enzymes
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Aspartate Aminotransferase
  • Jaundice

• Hypersensitivity:

  • Hypersensitivity Reaction

• Immunologic:

  • CMV Viremia
  • Graft Complications

• Infection:

  • Abscess
  • Bacterial Infection (May Be Serious)
  • BK Virus (Including Nephropathy)
  • Candidiasis
  • Cytomegalovirus Disease
  • Epstein-Barr Infection
  • Herpes Simplex Infection
  • Herpes Zoster Infection
  • Infection
  • Opportunistic Infection
  • Sepsis (Children & Adolescents)
  • Serious Infection

• Neuromuscular & Skeletal:

  • Arthralgia
  • Asthenia
  • Back Pain
  • Lower Limb Cramp
  • Muscle Cramps
  • Muscle Spasm
  • Myalgia
  • Myasthenia
  • Osteoporosis
  • Tremor

• Ophthalmic:

  • Amblyopia
  • Blurred Vision
  • Conjunctivitis
  • Visual Disturbance

• Otic:

  • Otalgia
  • Otitis Media
  • Tinnitus

• Renal:

  • Acute Renal Failure
  • Hydronephrosis
  • Increased Blood Urea Nitrogen
  • Increased Serum Creatinine
  • Renal Insufficiency
  • Renal Failure Syndrome
  • Renal Tubular Necrosis

• Respiratory:

  • Acute Respiratory Distress Syndrome
  • Asthma
  • Atelectasis
  • Bronchitis
  • Decreased Lung Function
  • Dyspnea
  • Emphysema
  • Flu-Like Symptoms
  • Increased Cough
  • Nasopharyngitis
  • Pharyngitis
  • Pleural Effusion
  • Pneumonia
  • Pneumothorax
  • Productive Cough
  • Pulmonary Edema
  • Respiratory Tract Infection
  • Rhinitis
  • Sinusitis

• Miscellaneous:

  • Abnormal Healing
  • Accidental Injury
  • Crying
  • Fever
  • Postoperative Pain
  • Postoperative Wound Complication
  • Ulcer
  • Wound Healing Impairment

Less Common Side Effects Of Tacrolimus:

• Gastrointestinal:

  • Gastrointestinal Infection

• Infection:

  • Fungal Infection
  • Polyoma Virus Infection

• Respiratory:

  • Upper Respiratory Tract Infection

Contraindications to Tacrolimus Use:

• Hypersensitivity to tacrolimus or any other component of this formulation

Warnings and Precautions

• Anaphylaxis: Injection:

  • Tacrolimus injection has been linked to hypersensitivity reactions including anaphylaxis.
  • Tacrolimus injection is a castor-oil derivative that contains polyoxyl 60 hydrogenated casting oil (HCO-60).
  • HCO-60 is a similar solubilizer to polyoxyethylated casting oil (also known by Cremophor EEL or polyoxyl 35), but it is also associated with hypersensitivity reactions.
  • Patients who are unable to swallow oral capsules should not be allowed to use Tacrolimus intravenous IV (IV).
  • Monitor patient for at least 30 minutes following infusion. Continue monitoring the patient at regular intervals. If anaphylaxis develops, discontinue infusion immediately.
  • As soon as possible, patients should be able to tolerate oral tacrolimus.

• Cardiovascular:

  • There have been reports of myocardial hypertrophy. This can be reversed by reducing or stopping the dose.
  • Patients with congenital long QT syndrome may experience prolonged QT/QTc or torsade des pointes.
  • Patients with congestive heart disease, bradyarrhythmias, antiarrhythmic medication or other medicines that prolong QT should have electrocardiograms performed periodically. Also, be aware of electrolyte disturbances like hypocalcemia, hypocalcemia or hypomagnesemia.

• Diabetes mellitus (post-transplant):

  • Tacrolimus use after transplantation increases the risk of developing diabetes mellitus and insulin-dependent posttransplant diabetes mellitus (IDPDM). This includes patients with no diabetes mellitus history.
  • Insulin dependence can be reversed.
  • Keep an eye on your blood glucose levels.
  • Patients undergoing kidney transplants from African Americans and Hispanics are at greater risk.

• Gastrointestinal perforation:

  • It is possible for gastrointestinal perforation to occur. All reported cases were deemed to be complications of transplant surgery, or accompanied with infection, diverticulum or malignant neplasm.

• Hyperkalemia:

  • It is possible to experience mild-to-severe hypokalemia. Monitor your serum potassium levels and stay away from potassium-sparing diuretics.

• Hypertension:

  • Hypertension can occur frequently; antihypertensive therapy may be required. Avoid potassium-sparing diuretics as they could lead to hyperkalemia.
  • Tacrolimus dosage adjustment may be required if you are using calcium channel blockers in conjunction.

• Infections [US Boxed Warning]

  • Tacrolimus, an immunosuppressant agent, increases the chance of infection, which can lead to death or hospitalization.
  • There are several latent viral infections that could be activated. These include BK virus (associated polyoma virus-associated nephropathy [PVAN]), and JC virus [associated progressive multifocal encephalopathy [PML]). This can lead to serious adverse effects.
  • CMV viremia is a risk factor for immunosuppression. Patients who have received a transplant from a CMV positive donor and are CMV-negative prior to transplant will be at greater risk.
  • If infection develops, monitor for it and reduce immunosuppression.

• Malignancy: [US Boxed Warning]

  • Tacrolimus, an immunosuppressant agent, can be linked to the development of malignancies, which may result in hospitalization or even death.
  • Malignancies are linked to the intensity and duration of therapy.
  • Avoid sunburns and UV light; take appropriate sun protection.
  • EBV infection can cause post-transplant lymphoproliferative disorders in patients with immunosuppressed organ transplants. This risk is highest in EBV seronegative patients.

• Nephrotoxicity:

  • High doses of nephrotoxic drugs can cause acute or chronic nephrotoxicity in patients with impaired kidney function.
  • If you notice nephrotoxicity, monitor your renal function and reduce the dosage.

• Neurotoxicity:

  • High doses of neurotoxicity can cause neurotoxicity. Tremor, headache, coma and delirium are all possible and may be associated with serum concentrations.
  • Seizures can also happen.
  • There has been a report of posterior reversible cerebrosis syndrome (PRES). These symptoms include altered mental status, headaches, hypertension, seizures and visual disturbances. Doses can be reduced or stopped.

• Pure red cell aplasia

  • Patients who received tacrolimus have been known to suffer from PRCA.
  • Patients at high risk for PRCA, such as parvovirus B19 infection, underlying diseases, or the use of concomitant PRCA medications (eg mycophenolate) should be used with caution.
  • PRCA diagnosis should include the possibility of discontinuing therapy.

• Hepatic impairment

  • Be cautious; use the lowest possible IV or oral dose. Additional dose reductions may also be required for severe hepatic impairment (Child Pugh score >=10).

• Renal impairment

  • You should use the lowest possible IV or oral dose to avoid further nephrotoxicity. Additional dose reductions may also be required.
  • If postoperative oliguria is present, delay initiating therapy for kidney transplant patients.

Tacrolimus (systemic): Drug Interaction

Monitoring parameters:

• Renal function
• Function of the liver
• Serum electrolytes (magnesium, phosphorus, potassium)
• Blood sugar level
• For the first few weeks, take blood pressure 3 times per week. Then, gradually reduce frequency until patient stabilizes.
• Anaphylactic reactions to IV infusions: Signs and symptoms
• Hypersensitivity in the first 30 minutes and often thereafter.
• Monitor for prolongation of QT
• Patients with electrolyte abnormalities or renal failure should have an echocardiogram.
• Concentrations of serum trough:
  • Oral therapy is usually taken within 30 minutes of the next dose.
  • The frequency of transplants varies according to the type and time since transplantation as well as clinical circumstances.
  • Infected liver transplant patients may have serum levels of Tacrolimus that are falsely high due to interference by beta-galactosidase antibody.

How to administer Tacrolimus?

IV:

• Continuous infusions are best (generally, for 24 hours).
• When administering diluted solutions, do not use PVC tubing.
• Mixing with solutions with a pH greater than 9 (e.g., acyclovir and ganciclovir), will cause chemical degradation of tacrolimus.
• Concurrent T-tube clamping should not be used to alter the dose.
• Low concentrations of drug may cause clinically significant adsorption to PVC tubing.

Oral: Release immediately:

• Can be taken with or sans food
• If GI intolerance is present and food administration becomes necessary, be consistent in the timing and composition of your meals.
• Take it in the morning if you are taking it once per day
• Dosage: Take it two times a day.
• The morning dose should always be the higher dose, as differences between morning and evening doses are rarely greater than 0.5 to 1 mg

Combination therapy with everolimus to treat liver transplantation: Give tacrolimus in the same dose as everolimus.

Granules for oral suspension

• Calculate the dose based upon patient weight
• For the morning or evening dose, only use the minimum number of packets.
• To make sure that the morning and evening doses are covered, you can add one packet of 0.2 mg to increase the dosage.
• To prepare or administer tacrolimus products, do not use PVC-containing tubing or syringes or cups.
• However, younger patients may be able to use a non-PVC oral Syringe (dispensed by prescription).
• Sprinkle granules not on food
• Place the contents of all packets into a glass cup.
• Mix 15-30 mL of room-temperature drinking water with the mixture
• Mix the contents of the cup and then take it to your mouth. Granules won't completely dissolve.
• After preparation, immediately administer.
• The suspension can also be made via an oral syringe that is non-PVC (dispensed with a prescription). 
• To ensure that all medication is taken, add 15-30 mL more water to rinse the cup/syringe.

Extended release

• Take all US-prepared foods on an empty stomach at least one hour before or two hours after eating.
• The Advagraf [Canadian Product] labeling indicates that the capsule can be taken with or without food, but should be used consistently.
• Take it whole.
• Each day, take one hour in the morning.
• Missed doses can be taken up until 14 hours (or Envarsus XR for 15 hours) after the scheduled time.
• If >14 hours (or Envarsus XR for more than 15 hours), you should resume your regular schedule at the next scheduled time. Do not double a dose in order to make up for a missed dose.

Nasogastric tube

• If you are giving the dose with a Nasogastric tube (or any other device), immediate release capsules may be combined with water and flushed through an nasogastric tub.
• After administration, clamp the nasogastric tubes for between 30 and 60 minutes
• Not all immediate release capsules can be used in the same way as Envarsus XR. 
• Consider converting from Envarsus XR into immediate release capsules for nasogastric administration by administering a 20% – 30% greater daily dose of immediate-release tacrolimus.

Sublingual:

• Tacrolimus may be given sublingually to those who are unable to swallow capsules.
• To do this, open the immediate-release capsules. Place the contents under your tongue and allow the contents to dissolve completely.
• Avoid swallowing for between 5 and 15 minutes, and avoid oral intake for between 15 to 30 minutes.
• After administration, avoid mechanical suctioning for at most 30 minutes

Notice: The sublingual route did not allow for the absorption of one dose of tacrolimus suspension.

Mechanism of action of Tacrolimus:

It suppresses cellular immunity by inhibiting T-lymphocyte activation, by binding to an intracellular protein, FKBP-12, and complexes with calcineurin-dependent proteins to inhibit calcineurin phosphatase activity

Absorption:

• The clamping of the T tube in patients undergoing liver transplant does not affect trough concentrations and AUC. However, cyclosporin concentrations can be altered.
• Oral:
  • Incomplete and variable (5% to 67%)
  • Food (especially high-fat meals) decreases absorption by 27 percent
  • Due to the conditioning regimen, oral absorption can be variable in stem-cell transplant patients with mucositis.
• Single dose capsules had an AUC of 16%, while single dose granules were 16% more.

Distribution:

• Distribution to erythrocytes and lung, kidneys. liver. heart.
• V: Means: Infants and children: 2.6 L/kg for liver transplant patients Adults: 0.85-1.41 L/kg for liver and kidney transplant patients

Protein binding:

• 99% primarily due to albumin and alpha-1- acid glycoprotein

Metabolism:

• Hepatic activity is extensive via CYP3A4 and up to eight possible metabolites. (major metabolite 31demethyl tacrolimus shows the same activity as tacrolimus when in vitro).

Bioavailability: Oral:

• Incomplete, variable:
  • Immediate Release Infants and children: Kidney transplant: 19% +-14%, liver transplant 31% +-24%
  • Adults: Kidney Transplant: 17% +-10%, Liver Transplant: 22% +- 66%, Heart Transplant: 23% +- 99%

Half-life elimination:

• Children: Kidney transplant for children: 10.2 +-5 hours.
• Infants and children: Liver transplant for 11.5 +-3.8 hours
• Adults Instant release: Variable, 23-46 hours for healthy volunteers; 2.1-36 hours for transplant patients; extended in patients with severe impairment Extended-release: 38 +-3 hours; extended-release for patients with severe hepatic impairment

Time to reach peak concentrations when administered Orally: 0.5 to 6 hours

Excretion:

• Feces (~93%)
• Urine (1% for an unchanged drug)

Clearance: 7-103 mL/minute/kg (average 30 mL/minute/kg); clearance is higher for children

International Brand Names of Tacrolimus:

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

Tacrolimus Brand Names in Pakistan: