This document discusses different types of tacrolimus medications, including Adoport capsules and Advagraf extended release capsules. Adoport contains tacrolimus monohydrate and various excipients in the capsule and gelatin shell. It is indicated for preventing transplant rejection and treating resistant rejection. Advagraf is an extended release formulation intended for kidney and liver transplant patients. It is dosed once daily compared to Adoport which is dosed twice daily. Both aim to maintain whole blood trough concentrations of 5-15 ng/mL for maintenance therapy. The document provides details on dosing, administration, conversion between formulations, and overdose treatment for the different tacrolimus medications.

1. Different types of Tacrolimus
Review
The different types of tacrolimus in the market and different between them.
Prepared by:
CL.Ph: Joseph Talat William

2. Adoport
Hard Capsules
(Tacrolimus monohydrate)
List of excipients:
Capsule contents:
1- Hypromellose (E 464)
2- Lactose monohydrate
3- Croscarmellose Sodium (E468)
4- Magnesium stearate (E 572)
Hard gelatin capsule:
1- Gelatin
2- Titanium dioxide (E 171)
3- Sodium laurilsulfate
4- Sorbitan laureate
5- Yellow iron oxide (E 172)
6-Red iron oxide (E 172)
7- Black iron oxide (E 172)
Special precautions for storage:
1- Do not store above 30°C.
2- Store in the original package in order to protect from moisture.

3. Therapeutic indications:
1- Prophylaxis of transplant rejection in liver, kidney or heart allograft
recipients.
2- Treatment of allograft rejection resistant to treatment with other
immunosuppressive medicinal products.
Method of administration:
It is recommended that the oral daily dose be administered in two
divided doses (e.g. morning and evening).
Capsules should be taken immediately following removal from the
blister. Patients should be advised not to swallow the desiccant.
The capsules should be swallowed with fluid (preferably water).
Capsules should generally be administered on an empty stomach or at
least 1 hour before or 2 to 3 hours after a meal, to achieve maximal
absorption.
Dosage recommendations - Kidney transplantation:
Prophylaxis of transplant rejection – adults:
Oral tacrolimus therapy should commence at 0.20-0.30 mg/kg/day
administered as two divided doses (e.g. morning and evening).
Administration should commence within 24-hours after the completion
of surgery.
Prophylaxis of transplant rejection – children:
An initial oral dose of 0.30 mg/kg/day should be administered in two
divided doses (e.g. morning and evening).

4. Conversion from ciclosporin:
Care should be taken when converting patients from ciclosporin-based
to tacrolimus-based therapy (see sections 4.4 and 4.5). Tacrolimus
therapy should be initiated after considering ciclosporin blood
concentrations and the clinical condition of the patient. Dosing should
be delayed in the presence of elevated ciclosporin blood levels. In
practice, tacrolimus therapy has been initiated 12-24 hours after
discontinuation of ciclosporin. Monitoring of ciclosporin blood levels
should be continued following conversion as the clearance of
ciclosporin might be affected.
Target whole blood trough concentration recommendations:
In clinical practice, whole blood trough levels have generally been in the
range 5-20 ng/ml in liver transplant recipients and 10-20 ng/ml in
kidney and heart transplant patients in the early post-transplant period.
Subsequently, during maintenance therapy, blood concentrations have
generally been in the range of 5-15 ng/ml in liver, kidney and heart
transplant recipients.
Overdose:
Experience with overdosage is limited. Several cases of accidental
overdosage have been reported; symptoms have included tremor,
headache, nausea and vomiting, infections, urticaria, lethargy,
increased blood urea nitrogen and elevated serum creatinine
concentrations, and increase in alanine aminotransferase levels.
No specific antidote to tacrolimus therapy is available. If overdosage
occurs, general supportive measures and symptomatic treatment
should be conducted.

5. Based on its high molecular weight, poor aqueous solubility, and
extensive erythrocyte and plasma protein binding, it is anticipated that
tacrolimus will not be dialyzable. In isolated patients with very high
plasma levels, hemofiltration or diafiltration have been effective in
reducing toxic concentrations. In cases of oral intoxication, gastric
lavage and/or the use of adsorbents (such as activated charcoal) may
be helpful, if used shortly after intake.

6. Advagraf®
(Extended release capsules)
INDICATIONS AND CLINICAL USE:
Advagraf® (tacrolimus extended release capsules) is indicated for
prophylaxis of organ rejection in adult patients receiving allogeneic
kidney and liver transplants.Advagraf is to be used concomitantly with
adrenal corticosteroids and mycophenolate mofetil (MMF) in de novo
renal transplant recipients. Antibody induction therapy should also be
used in kidney transplant recipients.
Blood Concentration Monitoring:
Advagraf kidney study indicate that trough concentrations of tacrolimus
in whole bloodwere most variable during the first week of dosing. By
month 2, 76% of the patients had trough concentrations between 7 –
16 ng/mL, and greater than 78% maintained concentrations between 5
– 15 ng/mL, from month 4 through 1 year.
Recommended Dose and Dosage Adjustment:
The recommended starting oral dose of Advagraf for kidney transplant
patients is 0.15 to 0.2 mg/kg. The initial dose of Advagraf should be
administered within 24 hours of kidney transplantation. Dosing should
be titrated to maintain the whole blood trough concentration levels
noted above.

7. Conversion from Prograf (immediate release
formulation) to Advagraf (extended release
formulation):
Stable kidney and liver transplant recipients can be converted from
Prograf (immediate release formulation) twice daily to once-daily
Advagraf (extended release formulations). Patients converting from
Prograf (immediate release formulation) to Advagraf (extended release
formulation) should be administered a single daily morning dose of
Advagraf (extended release formulation) equivalent to the patient’s
previous stable total daily dose of Prograf (immediate release
formulation). The same target trough range and whole blood trough
concentration monitoring should be used as with Prograf (immediate
release formulation) in order to maintain whole blood trough
concentrations of tacrolimus similar to those prior to conversion.
In patients unable to take oral Advagraf (extended release) capsules,
therapy may be initiated with Prograf injection and the patient
subsequently converted to oral Advagraf.
Conversion from Cyclosporine to Advagraf:
Tacrolimus should not be used simultaneously with cyclosporine.
Patients converted from cyclosporine to Advagraf should receive the
first Advagraf dose no sooner than 24 hours after the last cyclosporine
dose. Dosing may be further delayed in the presence of elevated
cyclosporine levels.

8. Conversion from A dvagraf to Cyclosporine:
Patients converted from Advagraf to cyclosporine should receive the
first cyclosporine dose no sooner than 24 hours after the last Advagraf
dose. Dosing may be further delayed in the presence of elevated
tacrolimus levels.
Missed Dose:
If a dose of Advagraf is missed, the dose may be taken up to 14 hours
after the scheduled time without risk of overexposure (i.e., for a missed
8:00 am dose, take by 10:00 pm). Beyond the 14-hour time frame, the
patient should wait until the usual scheduled time the following
morning to take the next regular daily dose.
Administration:
Advagraf can be administered with or without food; however, doses
should be administered in a consistent manner.
Limited over dosage experience with tacrolimus is available. An over
dosage of 5 times the intended dose has been reported with Advagraf,
followed by an adverse event of hypomagnesaemia that was
successfully treated with medication. Acute over dosages of up to 30
times the intended dose have been reported with Prograf (immediate
release formulation). Almost all cases have been asymptomatic and all
patients recovered with no sequelae. Occasionally, acute over dosage
has been followed by adverse reactions consistent with those listed in
theadverse reactions section except in one case where transient
urticaria and lethargy were observed. Based on the poor aqueous
solubility and extensive erythrocyte and plasma protein binding, it is

9. anticipated that tacrolimus is not dialyzable to any significant extent;
there is no experience with charcoal hemoperfusion. The oral use of
activated charcoal has been reported in treating acute overdoses, but
experience has not been sufficient to warrant recommending its use.
General supportive measures and treatment of specific symptoms
should be followed in all cases of over dosage.