Tacrolimus is a medication that belongs to a class of drugs known as calcineurin inhibitors. It is used primarily to prevent organ rejection in people who have received an organ transplant. Tacrolimus works by suppressing the immune system, thereby reducing the body's natural response to a transplanted organ.

It is commonly prescribed for individuals who have undergone liver, kidney, or heart transplantation. By inhibiting the immune response, tacrolimus helps prevent the body from attacking and rejecting the transplanted organ.

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

Tacrolimus Dose in Adults:

Note: Tacrolimus is a medicine used after organ transplants to stop the body from rejecting the new organ. It works by calming down the body's immune system. It comes in different forms: immediate-release and extended-release. But, the extended-release types, like Astagraf XL and Envarsus XR, can't be swapped with the immediate-release one, and they can't be swapped with each other either because they work differently in the body. It's important to take the right kind exactly as the doctor says to keep the new organ healthy.

Following a solid-organ transplant, immunosuppression:

• In the treatment of immunosuppression after solid-organ transplant, sublingual administration of tacrolimus (off-label route) involves placing the contents of immediate-release tacrolimus capsules under the tongue.
• The optimal dose hasn't been firmly established, but studies suggest a sublingual to oral dosing ratio of 1:2, meaning about half of the oral dose is used sublingually.
• However, dosing ratios have varied from 1:3 to 1:1 in different studies.
• It's important to monitor serum trough concentrations and adjust the dose accordingly.
• Lower doses might be needed when tacrolimus metabolism is inhibited by other drugs being taken concurrently.

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Prevention of organ rejection in transplant recipients:

• In the prevention of organ rejection in transplant recipients, tacrolimus dosing is typically initiated based on recommendations, but it's crucial to consider potential drug interactions.
• After the initial dose, adjustments are made to achieve target trough concentrations, which are levels of the drug in the blood.
• Early post-transplant, it's common to use other immunosuppressants alongside tacrolimus, like corticosteroids.
• Intravenous (IV) administration is only for patients unable to take oral medication, and it should be stopped once oral medication can be tolerated due to the risk of anaphylaxis with IV use.
• If switching from IV to oral, the oral dose should begin 8 to 12 hours after stopping the IV infusion.
• Sublingual administration might be an option for those who can't take oral medication.

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Tacrolimus dose in Liver transplant:

Immediate Release (Oral):

• Initial dose: 0.1 to 0.15 mg/kg/day in 2 doses every 12 hours, alongside corticosteroids. Adjust to reach target levels in the blood. For liver transplant recipients with graft problems, a lower dose might be considered.

Extended Release (Oral):

• Start within 12 to 18 hours of transplantation at a dose of 0.1 to 0.2 mg/kg once daily with corticosteroids. Adjust to reach target levels.
• Note: In the US, Astagraf XL isn't approved for liver transplants due to increased mortality in female recipients.

Conversion from Immediate to Extended Release:

• Patients stable on immediate release can switch to extended release in a 1:1 ratio based on their total daily dose. Administer once daily.

Intravenous (IV):

• Initial dose: 0.03 to 0.05 mg/kg/day given continuously via infusion.

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Tacrolimus dose in a Heart transplant:

Immediate Release (Oral):

• Start with 0.075 mg/kg/day divided into 2 doses every 12 hours. Adjust dosage to reach desired levels in the blood.

Intravenous (IV):

• Initial dose: 0.01 mg/kg/day administered continuously through infusion.

Combination Therapy:

• Typically used with an antimetabolite like azathioprine or mycophenolate mofetil. Alternatively, it can be combined with an mTOR kinase inhibitor such as everolimus or sirolimus.

Conversion from Oral to IV:

• According to ISHLT guidelines, when switching from oral to IV administration, administer one-fifth (1/5th) of the oral daily dose as a continuous infusion over 24 hours.

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Tacrolimus in Kidney transplant:

Immediate Release (Oral - Prograf):

• Initial dose: 0.2 mg/kg/day with azathioprine or 0.1 mg/kg/day with mycophenolate mofetil. Adjust to reach target trough concentrations. Administer in 2 doses every 12 hours.

Extended Release (Advagraf, Astagraf XL):

• With basiliximab induction: Start with 0.15 to 0.2 mg/kg once daily in combination with corticosteroids and mycophenolate. Adjust to target levels.
• Without basiliximab induction:
  • Preoperative dose: 0.1 mg/kg within 12 hours before reperfusion.
  • Postoperative dose: 0.2 mg/kg once daily, at least 4 hours after preoperative dose and within 12 hours of reperfusion. Adjust to reach target trough concentrations.

Extended Release (Envarsus XR):

• Start with 0.14 mg/kg/day. Adjust to target trough concentrations.

Conversion from Oral to IV:

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

Conversion from IV to Extended Release:

• Start the first oral extended release dose 8 to 12 hours after stopping IV tacrolimus.

Conversion from Immediate Release to Extended Release:

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

IV (Intravenous):

• Initial dose: 0.03 to 0.05 mg/kg/day as a continuous infusion. Adjust as needed.

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Tacrolimus Crohn disease (off-label use):

Immediate Release (Oral):

• Start with an initial dose of 0.1 mg/kg twice daily. Adjust dosage to reach target concentrations.

Note:

• Tacrolimus therapy for Crohn's disease, particularly perianal/fistulizing disease, should only be used for the short term due to its potential toxicity.

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

Prevention:

• Oral Conversion from IV: Multiply the total daily IV dose by 4 and administer it in 2 divided oral doses per day, every 12 hours.
• IV Initial Dose: Start with 0.03 mg/kg/day (based on lean body weight) as a continuous infusion. Begin treatment at least 24 hours before stem cell infusion and continue until oral medication is tolerated.

Treatment:

• Oral Immediate Release: Take 0.06 mg/kg twice daily.
• IV Initial Dose: Begin with 0.03 mg/kg/day (based on lean body weight) as a continuous infusion. Adjust treatment according to response.

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Tacrolimus Lung transplant (off-label use):  

Oral/Nasogastric:

• Immediate Release: Start with 0.05 to 0.3 mg/kg/day divided into 2 doses every 12 hours. The usual dose is 0.05 mg/kg every 12 hours. Adjust to reach target trough concentrations. Sublingual administration at about 50% of the oral/nasogastric dose may also be considered.
• Note: In stable lung transplant recipients, conversion from twice-daily dosing to once-daily dosing using extended-release formulations like Astagraf XL (US) or Advagraf (Canada) may be done on a mg per mg basis. Conversion to extended-release Envarsus with a once-daily dose that is 70% to 80% of the total daily dose of immediate-release tacrolimus is also possible, although clinical trial data is lacking.

Intravenous (IV):

• Start with 0.01 to 0.05 mg/kg over 24 hours as a continuous IV infusion. Adjust to reach target trough concentrations.
• For patients receiving the initial dose intravenously, it can start immediately after transplantation or up to 2 days postoperatively based on renal function and hemodynamic stability. Switch to an oral maintenance regimen when the patient can take oral medication, typically after extubation.

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

Oral (Immediate Release):

• Initial Dose: 3 to 5 mg/day or 0.1 mg/kg/day, taken once or twice daily. Adjust dosage to achieve target trough concentrations after the initial dose.
• Note: Tacrolimus can be used alone or with glucocorticoids and/or pyridostigmine. It may take up to 6 to 12 months to see a clinical response.

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

Oral (Immediate Release):

• In Combination Therapy:
  • Start with 2 to 3 mg once daily alongside NSAID and/or oral corticosteroid therapy. Research suggests that 3 mg once daily yields better ACR response rates.
• With Methotrexate:
  • For patients not responding to methotrexate alone, add tacrolimus at a lower dose, typically 1.5 mg once daily, in combination with methotrexate.
• Monitoring:
  • Monitor serum creatinine levels closely during therapy to ensure safety and efficacy.

Tacrolimus Dose in Children:

Note:

• When switching between different forms of tacrolimus, like granules or capsules, keep an eye on tacrolimus concentrations because the granules might lead to higher levels in the blood.
• Extended-release versions, like Astagraf XL and Envarsus XR, can't be swapped with immediate-release ones, and the once-a-day types can't be switched between each other either because they work differently in the body.
• Younger kids usually need higher doses based on their weight compared to older kids or adults.
• Make sure to adjust the starting dose to reach the right tacrolimus level, and it's a good idea to follow specific hospital guidelines for this.

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

Continuous Infusion:

• Infants, Children, and Adolescents:
  • Start with 0.03 mg/kg/day as a continuous IV infusion, based on lean body weight.
  • Begin prior to pretransplant, with the specific day varying according to the protocol.
  • Monitor drug levels in the blood and adjust the dose as needed.
  • Switch to oral formulation when the patient can tolerate it.

Intermittent Infusion:

• Children and Adolescents:
  • Administer 0.015 mg/kg/dose every 12 hours as a 2-hour infusion.
  • Start treatment on day -2 or day -3 before transplant and continue until the patient can tolerate oral medication.
  • This dosing regimen is based on a study involving 33 patients with a median age of 10 years, ranging from 1.2 to 17 years.
  • During the trial, no reactions to the infusion were reported, and there was no higher incidence of toxicity or adverse effects.

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

Children and Adolescents:

• Oral Immediate Release:
  • Initial Dose: Start with 0.1 mg/kg/day divided every 12 hours.
  • Adjustment: Modify the dose to achieve the desired serum concentration.
  • Reported Dose Range: Typically falls between 0.06 to 0.19 mg/kg/day in divided doses every 12 hours.
• Target Tacrolimus Concentration:
  • Variation: The goal concentration varies depending on the type of nephrotic syndrome and patient characteristics.
  • Common Goal: Most frequently, the aim is to achieve concentrations between 5 to 10 ng/mL, largely based on transplant data.
  • Alternative Goal: Some studies suggest targeting lower trough concentrations of 3 to 5 ng/mL.

Tacrolimus dose in heart Transplant; prevention of rejection:

Infants, Children, and Adolescents:

• Oral Immediate Release:
  • Initial Dose: Start with 0.1 to 0.3 mg/kg/day divided every 12 hours.
  • Adjustment: Titrate the dose to achieve the target trough concentration.
  • Note: A lower initial dose can be considered for patients who receive cell-depleting induction treatment.
• Limited Data for Intravenous (IV):
  • Administer 0.01 to 0.03 mg/kg/day as a continuous IV infusion.
  • Note: Reserve parenteral use for patients who cannot take oral formulations, and transition to oral medication as soon as possible.

Tacrolimus dose in kidney Transplant; prevention of rejection: Oral:

Immediate Release (Oral):

• Children and Adolescents:
  • Initial Dose: 0.2 to 0.3 mg/kg/day divided every 12 hours.
  • Adjustment: Titrate to reach target trough concentrations.

Extended Release (Astagraf XL):

• With Basiliximab Induction:
  • Children ≥4 years and Adolescents <16 years:
    • Initial Dose: 0.3 mg/kg once daily, within 24 hours of reperfusion.
  • Adolescents ≥16 years:
    • Initial Dose: 0.15 to 0.2 mg/kg once daily, prior to reperfusion or within 48 hours of transplant.
• Without Basiliximab Induction (Adolescents ≥16 years):
  • Preoperative Dose: 0.1 mg/kg once, within 12 hours prior to reperfusion.
  • Postoperative Dose: 0.2 mg/kg once daily, first dose at least 4 hours after preoperative dose and within 12 hours of reperfusion.
• Conversion:
  • IV to Extended Release: Administer the first oral extended-release dose 8 to 12 hours after discontinuing IV tacrolimus.
  • Immediate Release to Extended Release: Initiate extended-release treatment in a 1:1 ratio using previously established total daily dose of immediate release. Administer once daily.

Intravenous (IV) (Infants, Children, and Adolescents):

• Limited Data: 0.06 mg/kg/day as a continuous IV infusion.
• Note: Reserve parenteral use for patients unable to take oral formulations; switch to oral medication as soon as possible.

Tacrolimus Dose in Liver transplant:

Infants, Children, and Adolescents:

• Immediate Release (Oral):
  • Initial Dose: 0.15 to 0.2 mg/kg/day divided every 12 hours.
• Intravenous (IV):
  • Initial Dose: 0.03 to 0.05 mg/kg/day as a continuous IV infusion.
  • Note: Reserve IV use for patients unable to take oral medication; switch to oral form as soon as possible, usually initiated 8 to 12 hours after stopping the IV infusion.

Dose Conversion:

• IV Continuous Infusion to Immediate-Release Oral:
  • GVHD Prophylaxis: Convert from IV to oral dose at a 1:4 ratio; multiply total daily IV dose by 4 and administer in 2 divided oral doses every 12 hours. Adjust to reach goal trough concentration.
• Immediate-Release Oral to Sublingual:
  • Very Limited Data: To convert from oral to sublingual dose, use a 2:1 ratio; divide the oral dose by 2 for sublingual administration. Dosing based on experience in adult solid organ transplant recipients unable to take oral medication.

Pregnancy Risk factor C

• Tacrolimus, used in organ transplant patients, can reach the baby during pregnancy, appearing in cord blood, amniotic fluid, and the newborn's blood.
• Sometimes, the levels in the placenta can be higher than in the mother's blood.
• Babies with lower birth weights might have more tacrolimus in their system.
• In utero exposure to tacrolimus has been linked to risks like miscarriage, preterm birth, low birth weight, and various birth defects.
• However, it's essential to note that these risks might also be influenced by other medications the mother is taking.
• During pregnancy, tacrolimus levels change; while overall levels in the blood decrease, the amount not bound to proteins increases.
• Monitoring unbound levels, especially in women with conditions like anemia or low albumin, may be preferred.
• Despite these risks, tacrolimus can still be used to manage immune reactions during pregnancy.
• Pregnant women who have had kidney transplants, in particular, might face increased risks of infections, high blood pressure, and pre-eclampsia.
• The Transplant Pregnancy Registry International tracks pregnancies in transplant recipients and encourages reporting for better understanding and management of risks.

Breast-Feeding Considerations

• Tacrolimus can be found in breast milk, but the levels are usually lower than in the mother's blood.
• The amount that reaches a breastfeeding baby might be further reduced because tacrolimus isn't very well absorbed when taken orally.
• In one study, the levels of tacrolimus in infants didn't differ whether they were breastfed or bottle-fed, but all infants had been exposed to tacrolimus during pregnancy.
• It's estimated that the amount of tacrolimus a breastfeeding baby is exposed to is less than 0.5% of the mother's dose adjusted for weight.
• The decision about breastfeeding while taking tacrolimus should consider the potential risk to the baby, the benefits of breastfeeding, and the benefits of treatment for the mother.

Dose in Renal Disease:

• Renal impairment doesn't usually impact how tacrolimus is eliminated or its levels in the blood, but it can lead to kidney problems, so the dose might need to be lowered.
• It's recommended to start with the lowest recommended dose for both IV and oral administration, and sometimes even lower doses might be necessary.

Hemodialysis/ peritoneal dialysis:

• Tacrolimus isn't removed by hemodialysis, so there's no need for an extra dose during dialysis.
• Similarly, significant removal of the drug during peritoneal dialysis is unlikely due to its characteristics.

Dose in Liver disease:

• In liver transplant recipients who develop hepatic impairment after surgery, using tacrolimus may raise the risk of kidney problems due to high levels of the drug in the blood.
• When liver function is severely affected (with high bilirubin levels or a Child-Pugh score of 10 or more), tacrolimus metabolism is affected.
• This means the drug stays in the body longer and its clearance is reduced after IV administration, while its availability increases after oral intake.
• Higher plasma concentrations, found through testing, in patients with severe liver issues are likely due to the buildup of less active metabolites.
• These patients need close monitoring, and adjustments to the dosage may be necessary, usually starting with lower doses.

Common Side Effects of Tacrolimus Include:

• 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 Include:

• Gastrointestinal:
  • Gastrointestinal Infection
• Infection:
  • Fungal Infection
  • Polyoma Virus Infection
• Respiratory:
  • Upper Respiratory Tract Infection

Contraindications to Tacrolimus:

• If someone is allergic or hypersensitive to tacrolimus, polyoxyl 60 hydrogenated castor oil (HCO-60), or any other ingredient in the medication, they should avoid using it.

Warnings and precautions:

Anaphylaxis: Injection:

• Tacrolimus injection can cause hypersensitivity reactions, including anaphylaxis.
• It contains polyoxyl 60 hydrogenated castor oil (HCO-60), similar to polyoxyethylated castor oil (also known as polyoxyl 35 castor oil or Cremophor EL), which is linked to hypersensitivity reactions.
• IV use of tacrolimus should be reserved for patients who can't take oral capsules.
• Patients receiving IV tacrolimus should be monitored closely for at least 30 minutes after starting the infusion and regularly afterward.
• If anaphylaxis occurs, the infusion should be stopped immediately.
• As soon as the patient can tolerate oral medication, they should switch from IV to oral tacrolimus.

Cardiovascular:

• Tacrolimus use has been associated with myocardial hypertrophy, which may improve with dose adjustment or stopping the medication.
• It can also lead to QT/QTc prolongation and potentially dangerous heart rhythms like torsade de pointes, especially in patients with congenital long QT syndrome.
• Electrocardiograms and electrolyte levels (magnesium, potassium, calcium) should be monitored regularly during treatment, particularly in patients with congestive heart failure, bradyarrhythmias, or taking medications that affect heart rhythm.
• It's essential to avoid tacrolimus in patients with congenital long QT syndrome and to exercise caution in those with electrolyte imbalances like hypokalemia, hypocalcemia, or hypomagnesemia.

Diabetes mellitus (post-transplant):

• Tacrolimus use after transplantation raises the risk of new-onset diabetes, including insulin-dependent post-transplant diabetes mellitus (PTDM), even in patients without a history of diabetes before the transplant.
• Insulin dependence might be reversible.
• It's crucial to monitor blood glucose levels regularly, especially in African-American and Hispanic kidney transplant patients, as they face an increased risk.

Gastrointestinal perforation:

• Gastrointestinal perforation is a possible complication that may occur after transplant surgery or be associated with infection, diverticulum, or malignant neoplasm.
• All reported cases of gastrointestinal perforation were deemed to be related to these underlying factors.

Hyperkalemia:

• Tacrolimus use can lead to mild to severe hyperkalemia (high potassium levels).
• It's important to monitor serum potassium levels regularly and avoid using potassium-sparing diuretics to prevent further elevation of potassium levels.

Hypertension:

• Hypertension is a common occurrence with tacrolimus use, often requiring treatment with antihypertensive medications.
• However, potassium-sparing diuretics should be avoided because they can increase the risk of hyperkalemia (high potassium levels).
• If calcium channel blockers are used concurrently with tacrolimus, dosage adjustments may be necessary to manage blood pressure effectively.

Infections: [US Boxed Warning]:

• Tacrolimus and other immunosuppressant drugs raise the risk of infections, which can be severe and even life-threatening.
• These infections can include bacterial, viral (such as CMV), fungal, and protozoal infections, including opportunistic ones.
• Latent viral infections like BK virus (linked to polyoma virus-associated nephropathy [PVAN]) and JC virus (associated with progressive multifocal leukoencephalopathy [PML]) can become active and cause serious complications.
• Immunosuppression also heightens the chances of CMV viremia and/or CMV disease, especially for patients who were CMV-negative before the transplant and receive an organ from a CMV-positive donor.
• Regular monitoring for signs of infection is crucial, and if PVAN, PML, CMV viremia, or CMV disease develops, reducing immunosuppression might be necessary.

Malignancies (Boxed warning):

• Tacrolimus and other immunosuppressant drugs can increase the risk of developing malignancies, including lymphoma and predominantly skin malignancies, which could lead to severe outcomes.
• The risk of malignancies is linked to the intensity and duration of therapy.
• It's important to minimize sun and ultraviolet light exposure and use proper sun protection measures to reduce the risk further.
• Post-transplant lymphoproliferative disorder related to Epstein-Barr virus (EBV) infection has been reported in immunosuppressed organ transplant patients, with the highest risk observed in EBV-seronegative patients, including many young children.
• Therefore, the use of combination immunosuppressant therapy should be approached with caution.

Nephrotoxicity:

• Tacrolimus can cause nephrotoxicity, both acute and chronic, particularly when used in high doses, in patients with kidney impairment, or when taken alongside other nephrotoxic medications like sirolimus or cyclosporine.
• Additionally, concurrent use with CYP3A inhibitors can lead to increased tacrolimus levels, exacerbating nephrotoxicity risk.
• It's crucial to monitor renal function regularly and contemplate reducing the dosage if signs of nephrotoxicity appear.

Neurotoxicity:

• Tacrolimus use, especially in high doses, can lead to neurotoxicity, manifesting as symptoms like tremors, headaches, coma, and delirium, which correlate with serum concentrations.
• Seizures are also possible.
• Posterior reversible encephalopathy syndrome (PRES) has been reported, characterized by symptoms such as altered mental status, headache, hypertension, seizures, and visual disturbances.
• These symptoms can be reversed by reducing or discontinuing tacrolimus therapy, stabilizing blood pressure, and adjusting the dosage when PRES is suspected or diagnosed.

Pure red cell aplasia:

• Tacrolimus use has been associated with pure red cell aplasia (PRCA) in some patients.
• It's important to exercise caution when using tacrolimus in patients with risk factors for PRCA, such as parvovirus B19 infection, underlying diseases, or concurrent medications linked to PRCA, like mycophenolate.
• If PRCA is diagnosed, discontinuing tacrolimus therapy should be considered.

Hepatic impairment 

• Tacrolimus should be used cautiously in individuals with hepatic impairment.
• It's advisable to start with the lowest recommended dose, whether administered intravenously or orally, and further dose reductions may be needed.
• In cases of severe hepatic impairment, with a Child-Pugh score of 10 or higher, a decreased dose may be necessary.

Renal impairment

• In patients with renal impairment, it's crucial to use tacrolimus cautiously to avoid worsening nephrotoxicity. Start with the lowest recommended dose, whether given intravenously or orally, and consider additional dose reductions if needed. If kidney transplant patients experience postoperative oliguria (reduced urine output), it's advisable to delay the initiation of tacrolimus therapy.

Monitoring Parameters:

Renal Function:

• Check kidney function regularly, especially in patients with kidney issues.
• Start with frequent measurements (3 times per week) during the initial weeks post-transplant.
• Gradually decrease frequency as the patient stabilizes.

Hepatic Function:

• Monitor liver function regularly, particularly in patients with liver problems.
• Consider additional dose reductions in severe hepatic impairment.

Serum Electrolytes:

• Keep an eye on electrolyte levels (magnesium, phosphorus, potassium).
• Monitor regularly, especially during the early post-transplant period.

Glucose and Blood Pressure:

• Measure blood sugar and blood pressure regularly.
• Initial monitoring should be frequent (3 times per week) and can be adjusted as the patient stabilizes.

Specific Monitoring Considerations

Anaphylactic Reactions:

• Watch out for signs of anaphylactic reactions during IV infusion.
• Monitor patients closely during the first 30 minutes of the infusion and afterward.

Hypersensitivity:

• Monitor patients for hypersensitivity reactions, particularly during the first 30 minutes of infusion and then at regular intervals.

QT Prolongation:

• Check for QT prolongation, especially in patients with renal failure, electrolyte imbalances, or signs of ventricular dysfunction.
• Consider echocardiographic evaluation if necessary.

Tacrolimus Concentration Monitoring

• Use whole blood concentrations for monitoring tacrolimus levels.
• Typically, measure trough levels before the next oral dose, usually within 30 minutes.
• Frequency of monitoring varies based on factors like transplant type, time since transplantation, and clinical status.

Note:

• Tacrolimus serum levels may appear falsely elevated in liver transplant patients with infections due to interference from beta-galactosidase antibodies.

How to administer Tacrolimus?

Intravenous (IV) Administration:

• Administer via continuous infusion over 24 hours if IV administration is necessary.
• Avoid PVC tubing for diluted solutions.
• Do not mix with solutions having a pH ≥9.
• Use different ports in multilumen lines if co-administered with incompatible medications.
• Do not adjust dose with concurrent T-tube clamping.
• Adsorption to PVC tubing may be significant at low concentrations.

Oral Administration:

• Immediate Release:
  • Administer with or without food; maintain consistency in timing and composition of meals if GI intolerance occurs.
  • If once-daily dosing, administer in the morning; if twice-daily dosing, space doses 12 hours apart.
  • If morning and evening doses differ, give the larger dose in the morning.
  • For thrice-daily dosing, separate doses by 8 hours.
• Granules for Oral Suspension:
  • Calculate dose based on patient weight.
  • Do not use PVC-containing equipment; use non-PVC oral syringe if needed.
  • Do not sprinkle granules on food; administer immediately after mixing with water.
• Extended Release:
  • Administer on an empty stomach at a consistent time each day.
  • Swallow whole, without chewing or crushing.
  • Missed doses may be taken up to 14 hours (15 hours for Envarsus XR) after scheduled time.

Special Administration Methods:

• Nasogastric Tube:
  • Mix contents of immediate-release capsules with water and flush through the tube.
  • Clamp the tube for 30 to 60 minutes after administration.
• Sublingual:
  • Open immediate-release capsules and place contents under the tongue.
  • Avoid swallowing for 5 to 15 minutes and oral intake for 15 to 30 minutes afterward.
  • Avoid mechanical suctioning for at least 30 minutes after administration.

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Mechanism of Action of Tacrolimus:

• Tacrolimus works by stopping certain cells in the body, called T-lymphocytes, from becoming active.
• It does this by attaching to a protein inside the cells, called FKBP-12, and forming a complex with other proteins that depend on calcineurin.
• This complex stops calcineurin from working properly, which in turn prevents the activation of T-lymphocytes, reducing the body's immune response.

Absorption:

• Oral absorption varies widely (5% to 67%), with better absorption observed in patients with a closed stoma post-resection.
• Unlike cyclosporine, clamping of the T-tube in liver transplant patients does not affect trough concentrations or area under the curve (AUC).
• Food, particularly a high-fat meal, decreases the rate and extent of absorption by 27%.
• Mucositis in stem cell transplant patients can lead to variable oral absorption due to the conditioning regimen.

Distribution:

• Tacrolimus is distributed extensively to various organs including erythrocytes, lung, kidneys, pancreas, liver, heart, and spleen.
• The volume of distribution (V) varies, with mean values of 2.6 L/kg in infants and children undergoing liver transplant and 0.85 to 1.41 L/kg in adults undergoing liver and renal transplant.

Protein Binding:

• Approximately 99% of tacrolimus binds to plasma proteins, primarily albumin and alpha-1 acid glycoprotein.

Metabolism:

• Tacrolimus undergoes extensive hepatic metabolism via CYP3A4 to produce eight possible metabolites, with the major metabolite, 31-demethyl tacrolimus, exhibiting similar activity as tacrolimus in vitro.

Bioavailability:

• Oral bioavailability varies and is incomplete and variable.
• Immediate-release tacrolimus shows bioavailability of 19% ± 14% in children undergoing kidney transplant and 31% ± 24% in those undergoing liver transplant.

Half-life Elimination:

• Half-life elimination varies, with children undergoing kidney transplant showing a half-life of 10.2 ± 5 hours, while infants and children undergoing liver transplant show a half-life of 11.5 ± 3.8 hours.
• In adults, immediate-release tacrolimus has a variable half-life ranging from 23 to 46 hours in healthy volunteers and 2.1 to 36 hours in transplant patients. Extended-release tacrolimus has a half-life of 38 ± 3 hours.

Time to Peak:

• The time to peak concentration after oral administration ranges from 0.5 to 6 hours.

Excretion:

• Tacrolimus is primarily excreted via feces (approximately 93%) and urine (less than 1% as unchanged drug).

Clearance:

• Clearance varies widely, ranging from 7 to 103 mL/minute/kg, with an average of 30 mL/minute/kg. Clearance tends to be higher in children.

International Brands of Tacrolimus:

Pricing: United States

Capsule ER 24 Hour Therapy Pack (Astagraf XL Oral)

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

Capsules (Prograf Oral)

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

Capsules (Tacrolimus Oral)

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

Solution (Prograf Intravenous)

• 5 mg/mL (per mL): $249.49

Tablet, 24-hour (Envarsus XR Oral)

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

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Tacrolimus Brand Names: Canada

• Advagraf
• Prograf

Tacrolimus Brand Names: US

• Envarsus XR
• Prograf
• Astagraf XL

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Tacrolimus Brand Names: International

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

Tacrolimus Brands in Pakistan:

Tacrolimus [Oint 0.1 %W/W]
Crolimus	Valor Pharmaceuticals
Edtac	Amarant Pharmaceuticals (Pvt)
Tacrus	Shrooq Pharmaceuticals

 

Tacrolimus [Oint 0.01 %W/W]
Aimus	Aims Traders
Eczemus	Brookes Pharmaceutical Laboratories (Pak.) Ltd.

 

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

 

Tacrolimus [Cream 0.1 %W/W]
Tacro	Wise Pharmaceuticals (Pvt) Ltd
Tacro	Wise Pharmaceuticals (Pvt) Ltd

 

Tacrolimus [Cream 0.03 %W/W]
Tagora	Rogen Pharmaceuticals

 

Tacrolimus [Tabs 1 Mg]
Imunol	Saffron Pharmaceutical Company

 

Tacrolimus [Caps 1 Mg]
Inograf	Platinum Pharmaceuticals (Pvt.) Ltd.
Tacgraf	Consolidated Chemical Laboratories (Pvt) Ltd.
Tacogen	Allmed Labs

 

Tacrolimus [Caps 5 Mg]
Inograf	Platinum Pharmaceuticals (Pvt.) Ltd.

 

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