Astellas Pharma Ltd

4.4 Special warnings and Precautions for use:

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA.

4.7 Undesirable effects

Pure red cell aplasia has been added to the frequency sub-category ‘not known’

Section 10 Date Of Revision Of Text

Updated to 21^st July 2011

In section 7 the address of the MAH, Astellas Pharma Ltd., has been updated following a move to new premises.  This entails the address changing from Lovett House, Lovett Road, Staines, TW18 3AZ, United Kingdom to 3rd Floor, Future House, The Glanty, Egham, Surrey, TW20 9AH, United Kingdom.

In section 10 the last revision date of the text has been revised to correspond with this move to new premises as detailed in Section 7.  This date is updated to 13th December 2010.

Prograf Infusion and Prograf Capsules:

Section 4.5 - Interaction with other medicinal products and other forms of interaction

The sentence below has been added:

4.2       Posology and method of administration

The following paragraph has been added:

Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including under- or over immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

4.4       Special warnings and precautions for use

The following three paragraphs have been added:

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse events, including graft rejection, or other side effects which could be a consequence of either under- or over-exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.2 and 4.8).

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.

Patients treated with immunosuppressants, including Prograf are at increased risk of opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in patients with deteriorating renal function or neurological symptoms.

4.8       Undesirable effects

Infections and infestations

The following paragraph has been added:

Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Prograf.

The following changes have been made to the SPC

• Re-arrangement/rewording of the text in accordance with the latest QRD template
• Replacement of British Approved Names/USP names by INNs

6.1               List of Excipients

Prograf 0.5mg hard capsules

Prograf 1mg hard capsules

In the list of

Printing ink of capsules shell, hydroxypropyl cellulose has been added and the name has been changed from dimeticon to simeticon.

Prograf 5mg hard capsules

The name has been changed from dimeticon to simeticon.

2.         Qualitative and Quantitative composition

The quantity of lactose monohydrate has been added.

3.         Pharmaceutical form

This section has been reworded but contains no new information.

4.2       Method of Administration

The following sentence has been added –

Patients should be advised not to swallow the desiccant.

4.4       Special warnings and precautions for use

The following sentence has been added –

As Prograf contains lactose, special care should be taken in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

6.1       List of excipients

This section has been reorganised but contains no new information.

6.2       Incompatibilities. 

The following sentence has been added –

Tubing, syringes and other equipment used to prepare or administer a suspension of Prograf capsule contents should not contain PVC.

6.4       Special precautions for storage

Changed to –

This medicinal product does not require any special temperature storage conditions.  Store in the original package in order to protect from moisture.

Hard capsules should be taken immediately following removal from the blister.

6.5       Nature and contents of container

This section has been reorganised and pack sizes are now included.

6.6.      Special precautions for disposal

This now states –

No special requirements.

1.        Prograf 5mg/ml concentrate for infusion removed from sections

1.        Name of the Medicinal Product

2.        Qualitative and Quantitative composition

3.        Pharmaceutical Form

           Description of capsules expanded

                        6.1          List of excipients

                        6.2     Incompatibilities

                        6.3     Shelf-Life

                        6.4    Special precautions for storage

              6.5    Nature and contents of container

              6.6    Special precautions for disposal

              8.       Marketing Authorisation Number(s)

              9.       Date of first authorisation / renewal of the authorisation

       There is now a separate SPC for the concentrate for Infusion.    

4.1    The therapeutic indications are now:

Prophylaxis of transplant rejection in liver, kidney or heart allograft recipients. Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products.

4.2    The following text has been inserted:

Prograf therapy requires careful monitoring by adequately qualified and equipped personnel. The medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.

Duration of dosing

To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given.

The following text has been changed:

Dosage recommendations – Liver transplantation

The recommended time of commencement of administration of Prograf has changed from 6 hours to 12 hours after the completion of surgery.

Dosage recommendations - Kidney transplantation

Prophylaxis of transplant rejection - adults

The recommended oral starting dose has changed from 0.15 - 0.30mg/kg per day to 0.20 - 0.30mg/kg per day.

Prophylaxis of transplant rejection - children

If the clinical condition of the patient prevents oral dosing, the initial intravenous dose has changed from 0.1mg/kg/day to 0.075 –0.100 mg/kg/day, should be administered as a continuous 24-hour infusion.

Dosage recommendations - Heart transplantation

Dosage recommendations for heart transplantation have been added.

Dosage recommendations - Rejection therapy, other allografts

Dose recommendations for lung, pancreas and intestinal transplantation based on limited prospective clinical trial data have been added. 

Dosage adjustments in specific patient populations

The following text has been added:

Paediatric patients

In general, paediatric patients require doses 1½ - 2 times higher than the adult doses to achieve similar blood levels.

Target whole blood trough concentration recommendations

Target levels for heart transplant patients have been inserted.

4.3     Contraindications

Pregnancy is no longer a contraindication. (see section 4.6)

4.4     Special warnings and precautions for use

The following text has been inserted:

Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.

4.5       Interaction with other medicinal products and other forms of interaction

The information on drug interactions has been re-categorised under the following headings:

Metabolic interactions

Inhibitors of metabolism

Inducers of metabolism

Effect of tacrolimus on the metabolism of other medicinal products

Other interactions which have led to clinically detrimental effects

Protein binding considerations

The nature of the interaction of tacrolimus with corticosteroids has been clarified.

The following advice on statins has been added:

Limited knowledge of interactions between tacrolimus and statins is available. Available data suggests that the pharmacokinetics of statins are largely unaltered by the co-administration of tacrolimus.

4.6       Pregnancy and lactation

New data from organ transplant recipients on the course and outcome of pregnancy under tacolimus treatment has been added. 

The following text has been inserted:

Due to the need of treatment, tacrolimus can be considered in pregnant women when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus.

Tacrolimus affected male fertility in rats (see section 5.3).

4.8     Undesirable effects

The side effects have been reclassified according to disease category.  Updated terms have been used and the most appropriate terms used based on the current safety data available for Prograf.

5.1     Pharmacodynamic properties

Results from published data in other primary organ transplantation

The results from studies in pancreas, lung and intestinal transplantation have been added.

5.2     Pharmacokinetic properties

Absorption

The following text has been added:

In healthy subjects, Prograf 0.5 mg, Prograf 1 mg and Prograf 5 mg Capsules, hard have been shown to be bioequivalent, when administered as equivalent dose.

Also the effect of food on the rate and extent of absorption of tacrolimus  has been more fully explained. 

Distribution and elimination

Data for heart transplant patients has been added.

Metabolism and biotransformation

Further information on the metabolites of tacrolimus has been added.

5.3     Preclinical safety data

Details of the toxicity studies in animals have been more fully explained.

10.    Date of revision of the text

1 October 2005 changed to April 2006.