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TACROLIMUS (PROGRAF/ADVAGRAF/ADOPORT)

 

Current indication

  • As the lead agent in standard triple therapy for all patients.


Dosage

  • Prograf 0.05mg/kg/day in 2 divided doses (normally between 2 mg and 5 mg bd).


Preparation

  • Tacrolimus is available as 0.5 mg (cream), 1 mg (white) and 5 mg (greyish red) capsules. The brand is Prograf although Adoport is being increasingly used by some centres. Note that Prograf and Adoport are clinically equivalent although they cannot be used interchangeably in the same patient.
  • In addition, the once a day preparation Advagraf is also available.
  • Prograf will be used in the initial post-operative period in most patients, although this may change soon.
  • Patients can be switched to Advagraf once stable levels have been achieved if this is felt to be clinically beneficial.


Administration

  • Oral route in most instances (well absorbed even in those with NG tubes).
  • It is administered at 10 am and 10 pm.
  • The capsules are taken on an empty stomach either 1 hour before or 2 - 3 hours after meals.
  • Contents of the capsule can be suspended in water for NG administration.
  • One fifth of the oral dose can be given as a continuous IV infusion in saline via non PVC bags/tubing if absolutely necessary.


Levels

  • Whole blood trough levels to be checked on Mondays, Wednesdays and Fridays.
  • The target levels may be found in the immunosuppression section.
  • In adult kidney transplant patients steady state may be reached 2-3 days after starting therapy or changing dose.


Pregnancy

  • Tacrolimus may be used during pregnancy. Quantities of tacrolimus in breast milk are negligible and not clinically relevant so women may safely breastfeed while taking tacrolimus.


Side Effects

The most frequent side effects seen with tacrolimus include:

  • abnormal kidney function (similar to Ciclosporin)
  • tremor
  • headache
  • paraesthesia

Less common side effects are:

  • diarrhoea
  • hypertension
  • hyperglycaemia
  • hyperkalaemia
  • hypomagnesaemia
  • visual and neurological disturbances (affected patients should not drive or operate machinery)
  • hypertrophic cardiomyopathy (in paediatric patients with trough levels >25 mg/ml).


Interactions

Potential interactions due to effects on hepatic microsomal enzymes.

Tacrolimus is extensively metabolised via the hepatic microsomal cytochrome P450 3A4 isoenzyme. Concomitant use of substances known to inhibit or induce cytochrome P450 3A4 (CYP3A4) may affect the metabolism of tacrolimus. Therefore:

  • Inhibitors of CYP3A4 may decrease metabolism of tacrolimus and thus increase tacrolimus blood levels, e.g.

clotrimazole

diltiazem

fluconazole*

nicardipine

ketoconazole*

danazol

itraconazole*

grapefruit juice (naringenin)

erthromycin*

ethinyl oestradiol

clarithromycin*

omeprazole

voriconazole

nifedipine

 

  • Inducers of CYP3A4 may increase metabolism of tacrolimus and thus decrease blood levels, e.g.  

rifampicin*

phenobarbitol

phenytoin*


    *Drugs marked with an asterisk will require a dose adjustment of tacrolimus in nearly all patients. Other listed drugs may require dose adjustment only in individual cases.

    • Tacrolimus itself has a powerful inhibitory effect on CYP3A4. Thus concomitant use of tacrolimus with drugs metabolised by CYP3A4 dependant pathways may affect the metabolism of such drugs. For this reason Ciclosporin A should not be co-prescribed with tacrolimus. Patients switched from ciclosporin to tacrolimus should receive the first tacrolimus dose at least 24 hours after the last ciclosporin dose.


    Interactions due to cumulative toxicity/synergistic effects:

    • Concurrent use of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the degree of toxicity. Enhanced nephrotoxicity has been observed with co-administration of:

    Ciclosporin A

    Amphotericin B

    Ibuprofen

    Sirolimus (Rapamune)

     

    • As tacrolimus may cause hyperkalaemia, high potassium intake or potassium sparing diuretics should be avoided.

    Interactions due to plasma protein binding of tacrolimus:

    Tacrolimus is extensively bound (>98%) to plasma proteins so competition with other highly protein bound drugs may result in displacement of either drug. This displacement may not be reflected in the blood levels of tacrolimus or other drugs. Therefore, dosage adjustment may not be needed unless clinical signs and symptoms suggest otherwise.
     

    Other interactions:

    • Vaccinations may be less effective and the use of live attenuated vaccines should be avoided.
    • Administration of tacrolimus with a meal of moderate fat content reduces the oral bioavailability of the drug.
    • Complimentary medicines may cause a variety of interactions (See page 45).

    This is not a comprehensive list of potential interactions with tacrolimus. For further information please ask a member of staff or consult the transplant unit pharmacist.

    ......


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    This page last modified 05.03.2018 10:25 by Emma Farrell. edren and edrep are produced by the Renal Unit at the Royal Infirmary of Edinburgh and the University of Edinburgh. CAUTIONS and Contact us.