Tacrolimus

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Contents

[edit] BRAND NAMES

[edit] STRUCTURE

Tacrolimus.jpg

[edit] MECHANISM OF ACTION

Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

[edit] INDICATIONS

Approved Indications

  • Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants
  • Use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF)

Limitations of Use:

  • Do not use simultaneously with cyclosporine
  • Intravenous use reserved for patients who can not tolerate capsules orally
  • Use with sirolimus is not recommended in liver and heart transplant; use with sirolimus in kidney transplant has not been established

[edit] DOSAGE

Patient Population
Recommended Initial 
Oral Dosage (two 
divided doses every 12 
hours)
Observed Whole Blood 
Trough Concentrations
Adult Kidney transplant
In combination with 
azathioprine 

0.2 mg/kg/day

month 1-3: 7-20 ng/mL

month 4-12: 5-15 ng/mL

 In combination with 
 MMF/IL-2 receptor 
 antagonist
0.1 mg/kg/day 
month 1-12: 4-11 ng/mL 
Liver transplant Adult 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL
Pediatric 0.15-0.20 mg/kg/day
month 1-12: 5-20 ng/mL 
Adult Heart transplant 
0.075 mg/kg/day 

month 1-3: 10-20 ng/mL

month ≥4: 5-15 ng/mL 
  • Careful and frequent monitoring of tacrolimus trough concentrations is recommended; Black patients may require higher doses in order to achieve comparable trough concentrations
  • Hepatic/Renal impaired patients should receive doses at the lowest value of the recommended initial oral dosing range
  • Administer capsules consistently with or without food; do not drink grapefruit juice


[edit] PHARMACOKINETICS

  • Oral bioavailability is about 25%

[edit] DOSAGE FORMS AND STRENGTHS

  • Capsules: 0.5 mg, 1 mg and 5 mg
  • Injection: 5 mg/mL

[edit] CONTRAINDICATIONS

Hypersensitivity to tacrolimus

[edit] WARNINGS AND PRECAUTIONS

  • Lymphoma and Other Malignancies: Risk of lymphomas, including post transplant lymphoproliferative disorder (PLTD); appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight
  • Serious infections: Increased risk of bacterial, viral, fungal and protozoal infections, including opportunistic infections: combination immunosuppression should be used with caution
  • Polyoma Virus Infections: Serious, sometimes fatal outcomes, including polyoma virus-associated nephropathy (PVAN), mostly due to BK virus, and JC virus-associated progressive multifocal leukoencephalopathy (PML); consider reducing immunosuppression
  • Cytomegalovirus (CMV) Infections: Increased risk of CMV viremia and disease; consider reducing immunosuppression
  • New Onset Diabetes After Transplant: Monitor blood glucose
  • Nephrotoxicity: Acute and/or chronic; reduce the dose; use caution with other nephrotoxic drugs
  • Neurotoxicity: Risk of Posterior Reversible Encephalopathy Syndrome, monitor for neurologic abnormalities; reduce or discontinue Tacrolimus and other immunosuppressants
  • Hyperkalemia: Monitor serum potassium levels. Careful consideration should be given prior to use of other agents also associated with hyperkalemia
  • Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions
  • Anaphylactic Reactions with IV formulation: Observe patients receiving Tacrolimus injection for signs and symptoms of anaphylaxis
  • Use with Sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions
  • Myocardial Hypertrophy: Consider dosage reduction or discontinuation
  • Immunizations: Use of live vaccines should be avoided
  • Pure Red Cell Aplasia: Discontinuation should be considered
  • Hepatic/Renal impaired patients: Administer at the lower end of the recommended starting dose. Monitor renal function in patients with impaired renal function.

[edit] INTERACTIONS

  • Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to Prograf; monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed
  • Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use
  • CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use
  • CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use

[edit] PREGNANCY AND LACTATION

  • Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk.
  • Nursing Mothers: Discontinue nursing taking into consideration importance of drug to mother.

[edit] SIDE EFFECTS

Nephrotoxicity is the major side effect.

Neurotoxicity and posttransplant diabetes are more common than with cyclosporine.


  • Kidney Transplant: The most common adverse reactions ( ≥ 30%) were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, anemia
  • Liver Transplant: The most common adverse reactions (≥ 40%) were tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia
  • Heart Transplant: The most common adverse reactions ( ≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection and hyperlipemia

[edit] RELATED LINKS

[edit] BIBLIOGRAPHY

https://www.astellas.us/docs/prograf.pdf

[edit] REFERENCES