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

Risk Factor C (Monitor therapy)
Angiotensin II Receptor Blockers	May enhance the hyperkalemic effect of Tacrolimus (Systemic).
Angiotensin-Converting Enzyme Inhibitors	May enhance the hyperkalemic effect of Tacrolimus (Systemic).
Antidiabetic Agents	Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Asunaprevir	May increase the serum concentration of Tacrolimus (Systemic). Specifically, this increase in tacrolimus concentrations may occur during the first week of combined therapy. Asunaprevir may decrease the serum concentration of Tacrolimus (Systemic). Specifically, this decrease in tacrolimus concentrations may occur with continued prolonged combination therapy.
Azithromycin (Systemic)	May increase the serum concentration of Tacrolimus (Systemic).
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Calcium Channel Blockers (Dihydropyridine)	May increase the serum concentration of Tacrolimus (Systemic). Exceptions: Clevidipine.
Calcium Channel Blockers (Nondihydropyridine)	May decrease the metabolism of Tacrolimus (Systemic). Exceptions: Bepridil.
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
Cinacalcet	May decrease the serum concentration of Tacrolimus (Systemic).
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Clotrimazole (Oral)	May increase the serum concentration of Tacrolimus (Systemic).
Clotrimazole (Topical)	May increase the serum concentration of Tacrolimus (Systemic).
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
Colchicine	Tacrolimus (Systemic) may increase the serum concentration of Colchicine.
Corticosteroids (Systemic)	May decrease the serum concentration of Tacrolimus (Systemic). Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Daclatasvir	May decrease the serum concentration of Tacrolimus (Systemic). Specifically, this decrease in tacrolimus concentrations may occur with continued prolonged combination therapy. Daclatasvir may increase the serum concentration of Tacrolimus (Systemic). Specifically, this increase in tacrolimus concentrations may occur during the first week of combined therapy.
Danazol	May increase the serum concentration of Tacrolimus (Systemic).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Efonidipine	May increase the serum concentration of Tacrolimus (Systemic).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Ertapenem	May increase the serum concentration of Tacrolimus (Systemic).
Erythromycin (Systemic)	May increase the serum concentration of Tacrolimus (Systemic).
Fenofibrate and Derivatives	Tacrolimus (Systemic) may enhance the nephrotoxic effect of Fenofibrate and Derivatives.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosphenytoin	May decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Fosphenytoin.
Glecaprevir and Pibrentasvir	May increase the serum concentration of Tacrolimus (Systemic).
Grazoprevir	May decrease the serum concentration of Tacrolimus (Systemic). Grazoprevir may increase the serum concentration of Tacrolimus (Systemic).
Haloperidol	QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTcprolonging effect of Haloperidol.
Isavuconazonium Sulfate	May increase the serum concentration of Tacrolimus (Systemic).
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ledipasvir	May decrease the serum concentration of Tacrolimus (Systemic).
Letermovir	May increase the serum concentration of Tacrolimus (Systemic).
LevoFLOXacin (Systemic)	May enhance the QTc-prolonging effect of Tacrolimus (Systemic). LevoFLOXacin (Systemic) may increase the serum concentration of Tacrolimus (Systemic).
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Metoclopramide	May increase the serum concentration of Tacrolimus (Systemic). Specifically, treatment of gastroparesis may increase tacrolimus concentrations.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Nonsteroidal Anti-Inflammatory Agents	May enhance the nephrotoxic effect of Tacrolimus (Systemic).
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
Phenytoin	May decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Phenytoin.
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Potassium-Sparing Diuretics	May enhance the hyperkalemic effect of Tacrolimus (Systemic).
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
QT-prolonging Agents (Highest Risk)	QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Ranolazine	May increase the serum concentration of Tacrolimus (Systemic).
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Schisandra	May increase the serum concentration of Tacrolimus (Systemic).
Sevelamer	May decrease the serum concentration of Tacrolimus (Systemic).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Sofosbuvir	May decrease the serum concentration of Tacrolimus (Systemic).
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Tofisopam	May increase the serum concentration of Tacrolimus (Systemic).
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Afatinib	Tacrolimus (Systemic) may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10 mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer tacrolimus simultaneously with or after the dose of afatinib.
Alcohol (Ethyl)	May increase the absorption of Tacrolimus (Systemic). More specifically, the initial absorption rate may be increased, as alcohol may speed the release of tacrolimus from extended-release tablets. Management: Advise patients receiving extended-release tacrolimus (Astagraf XL or Envarsus XR brands) not to take the medication with alcoholic beverages.
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
Chloramphenicol (Systemic)	May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose reductions will likely be required with initiation of concurrent chloramphenicol. Monitor tacrolimus concentrations and response closely following initiation and/or discontinuation of chloramphenicol.
CYP3A4 Inducers (Strong)	May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Tacrolimus (Systemic). Management: Monitor clinical tacrolimus response closely and frequently monitor tacrolimus serum concentrations with concurrent use of any strong CYP3A4 inhibitor. Tacrolimus dose reductions and/or prolongation of the dosing interval will likely be required.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Dronedarone	Tacrolimus (Systemic) may enhance the QTc-prolonging effect of Dronedarone. Dronedarone may increase the serum concentration of Tacrolimus (Systemic). Management: Monitor for increased serum tacrolimus concentrations, tacrolimus toxicity, and QTc interval prolongation if combined with dronedarone. Tacrolimus dose adjustments may be needed.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Efavirenz	May decrease the serum concentration of Tacrolimus (Systemic). Management: Closely monitor tacrolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of tacrolimus may be required.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Fluconazole	May increase the serum concentration of Tacrolimus (Systemic). Management: Monitor tacrolimus concentrations closely and adjust oral tacrolimus dose as necessary when concomitantly administered with fluconazole. Reduced doses of tacrolimus will likely be required.
Itraconazole	May increase the serum concentration of Tacrolimus (Systemic). Management: Monitor tacrolimus concentrations closely and adjust dose as necessary when concomitantly administered with itraconazole. Tacrolimus dose reductions will likely be required. The magnitude of this interaction may be greater in older patients.
Ketoconazole (Systemic)	May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose adjustment may be required when taken with ketoconazole due to elevated plasma concentrations of tacrolimus. Monitor tacrolimus concentrations and clinical response closely.
Leflunomide	Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Mitotane	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Pitolisant	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
Posaconazole	May increase the serum concentration of Tacrolimus (Systemic). Management: Reduce tacrolimus dose to approximately one-third of original dose when starting posaconazole. Tacrolimus blood concentrations should be monitored closely during and at discontinuation of posaconazole.
Protease Inhibitors	May decrease the metabolism of Tacrolimus (Systemic).
Proton Pump Inhibitors	May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose adjustment may be required. Rabeprazole, pantoprazole, or selected H2-receptor antagonists (i.e., ranitidine or famotidine) may be less likely to interact. Genetic testing may predict patients at highest risk. Exceptions: Pantoprazole.
Rifamycin Derivatives	May decrease the serum concentration of Tacrolimus (Systemic). Management: Consider alternatives when possible. If these combination are used, monitor for reduced tacrolimus concentrations/effects following rifamycin initiation/dose increase, or increased concentrations/effects following rifamycin discontinuation/dose decrease.
Ritonavir	May increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose reductions may be needed with concurrent ritonavir. Monitor tacrolimus concentrations closely to determine dose; doses of tacrolimus 0.5 mg to 1 mg every week may be adequate.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Serotonin Reuptake Inhibitor/Antagonists	May decrease the metabolism of Tacrolimus (Systemic). Exceptions: TraZODone.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.
St John's Wort	May decrease the serum concentration of Tacrolimus (Systemic).
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Voriconazole	May increase the serum concentration of Tacrolimus (Systemic). Management: When starting voriconazole in patients already receiving tacrolimus, reduce tacrolimus dose to one-third of the original dose. Monitor tacrolimus blood levels closely.
Risk Factor X (Avoid combination)
BCG (Intravesical	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Crizotinib	May increase the serum concentration of Tacrolimus (Systemic).
CycloSPORINE (Systemic)	May enhance the nephrotoxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Tacrolimus (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Systemic).
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Enzalutamide	May decrease the serum concentration of Tacrolimus (Systemic).
Eplerenone	May enhance the hyperkalemic effect of Tacrolimus (Systemic).
Foscarnet	May enhance the nephrotoxic effect of Tacrolimus (Systemic).
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Grapefruit Juice	May decrease the metabolism of Tacrolimus (Systemic).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Mifamurtide	Tacrolimus (Systemic) may diminish the therapeutic effect of Mifamurtide.
MiFEPRIStone	May enhance the QTc-prolonging effect of Tacrolimus (Systemic). MiFEPRIStone may increase the serum concentration of Tacrolimus (Systemic). Management: Avoid tacrolimus during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically.
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Nelfinavir	May increase the serum concentration of Tacrolimus (Systemic).
Ombitasvir, Paritaprevir, and Ritonavir	May increase the serum concentration of Tacrolimus (Systemic).
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir	May increase the serum concentration of Tacrolimus (Systemic).
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Saquinavir	May increase the serum concentration of Tacrolimus (Systemic).
Sirolimus	May enhance the adverse/toxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may enhance the adverse/toxic effect of Sirolimus. Sirolimus may decrease the serum concentration of Tacrolimus (Systemic).
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
Temsirolimus	Tacrolimus (Systemic) may enhance the adverse/toxic effect of Temsirolimus. Temsirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Temsirolimus may decrease the serum concentration of Tacrolimus (Systemic).
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.

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:

Tacrolimus Ointment 0.1 %W/W in Pakistan
Crolimus	Valor Pharmaceuticals
Crolimus	Valor Pharmaceuticals
Edtac	Amarant Pharmaceuticals (Pvt)
Tacrus	Shrooq Pharmaceuticals

Tacrolimus Ointment 0.01 %W/W in Pakistan
Aimus	Aims Traders
Aimus	Aims Traders
Eczemus	Brookes Pharmaceutical Laboratories (Pak.) Ltd.

Tacrolimus Ointment 0.03 %W/W in Pakistan
Aimus	Aims Traders
Aimus	Aims Traders
Crolimus	Valor Pharmaceuticals
Eczemus	Brookes Pharmaceutical Laboratories (Pak.) Ltd.
Limus	Nabiqasim Industries (Pvt) Ltd.
Limus-J	Ambrosia Pharmaceuticals
Limus-J	Ambrosia Pharmaceuticals
Tacroderm	Sante (Pvt) Limited
Tacrogen	Biogen Pharma
Tacrogen	Biogen Pharma
Tacrol	Acme Laboratories Pakistan (Pvt) Ltd.
Taczam	Laderly Bio-Tech Pharma

Tacrolimus Cream 0.1 %W/W in Pakistan
Tacro	Wise Pharmaceuticals (Pvt) Ltd

Tacrolimus Cream 0.03 %W/W in Pakistan
Tagora	Rogen Pharmaceuticals

Tacrolimus Tabs 1 Mg in Pakistan
Imunol	Saffron Pharmaceutical Company

Tacrolimus Capsules 1 Mg in Pakistan
Inograf	Platinum Pharmaceuticals (Pvt.) Ltd.
Tacgraf	Consolidated Chemical Laboratories (Pvt) Ltd.
Tacogen	Allmed Labs

Tacrolimus Capsules 5 Mg in Pakistan
Inograf	Platinum Pharmaceuticals (Pvt.) Ltd.

Tacrolimus Caps 0.5 Mg in Pakistan
Inograf	Platinum Pharmaceuticals (Pvt.) Ltd.
Tacgraf	Consolidated Chemical Laboratories (Pvt) Ltd.