Tacrolimus preparations - Prograf, Modigraf, Advagraf

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Tacrolimus preparations - Prograf, Modigraf, Advagraf

Original article by: Alexandra Denby

Source: London New Drugs Group

Keywords: tacrolimus

Date published: 09/03/2010 09:04

Summary

by: Alexandra Denby

Tacrolimus is a calcineurin inhibitor and a highly potent immunosuppressant. There are three formulations currently available in the UK: Prograf, which is an immediate-release preparation taken twice a day, Advagraf, a modified-release preparation taken once a day and Modigraf, a granule formulation made into an immediate-release oral suspension.
Advagraf (modified release) is not directly interchangeable with either Prograf or Modigraf (both immediate release).
The MHRA/CSM have highlighted the need for care when prescribing and dispensing the tacrolimus preparations to avoid any more serious medication errors that have already occurred from incorrect prescribing, dispensing and administration of Prograf and Advagraf.
No studies evaluating the switch from Modigraf to Prograf were submitted for the licence application. Small studies, some of which are uncontrolled show that tacrolimus granules is an appropriate formulation for immunosuppression after kidney and liver transplant in adults and children.
The clinical development programme studied efficacy and safety of Prograf and Advagraf used as maintenance treatment after solid organ transplant as well as conversion between the preparations. No studies were found using Advagraf to treat transplant rejection.
The main pivotal study was an open label study that was not designed to compare Prograf and Advagraf with each other, but instead was designed to compare them to ciclosporin. No statistical significance was given to the differences seen in patient and graft survival and the number and treatment of biopsy confirmed acute rejection episodes between the two tacrolimus groups.
The evidence does not suggest significant differences in the pharmacokinetics or the outcomes seen with these two preparations.
No trial has been designed to compare long term follow up with Advagraf vs. Prograf.
Some investigators claim that the use of once-daily Advagraf may improve compliance but we are unable to identify any evidence that directly supports that claim. It should be noted that a) the trials were not designed to monitor compliance with medication and the majority were supported by Astellas Pharma and b) that the reasons behind non-compliance are complex and may not necessarily be solved by a simple shift from twice-daily to once-daily drug administration.
Many patients taking tacrolimus will also be having mycophenolate treatment. As mycophenolate is taken twice daily there may be little advantage of using once-daily tacrolimus.
Processes should be put into place which makes the prescribing and dispensing of all tacrolimus preparations safer.
Ensure the GP, pharmacist and patient knows which formulation the patient should be taking and its correct dosing regimen as the formulations are not interchangeable.
Ensure that records are kept up to date.
Do not switch established patients from their current formulation unless there is a valid clinical reason to do so; and if there is, switching of formulation should be under direct supervision of a transplant specialist.
The least expensive tacrolimus product should be prescribed for new patients.
Shared Care Protocols state that tacrolimus should be prescribed by brand name and should not be changed unless on the advice of a transplant specialist.
There should be consistency of prescribing a product that the patient is known to be stable on and tolerates. If changing to another product, the patient should be closely monitored [e.g. alternate days for in-patients, two-three times a week for out-patients, for the first week]. Switching between preparations should only be done under the supervision of a transplant specialist.
The possible consequences of incorrect prescribing and dispensing may be graft rejection (worse case scenario). Patients must be maintained on a particular formulation of tacrolimus to avoid this.