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:

4.4       Special warnings and precautions for use

The following two paragraphs have been added:

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.

5.1       Pharmacodynamic properties

The ATC code has changed to:

ATC Code: L04AD02

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

2.         Qualitative and Quantitative composition

This section has been changed to –

1 ml concentrate for solution for infusion contains 5 mg of tacrolimus.

Excipients: 200 mg of polyoxyethylene hydrogenated castor oil and 638 mg of dehydrated alcohol.

4.2       Method of Administration

The following sentence has been added –

The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 – 500 ml.

The diluted solution should not be given as a bolus (see section 6.6).

6.2       Incompatibilities

This has been changed to –

When diluting, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Tacrolimus is absorbed by PVC plastics. Tubing, syringes and any other equipment used to prepare and administer Prograf 5 mg/ml concentrate for solution for infusion should not contain PVC.

Tacrolimus is unstable under alkaline conditions. Combination of the reconstituted Prograf 5 mg/ml concentrate for solution for infusion with other pharmaceutical products that produce a marked alkaline solution (e.g. aciclovir and ganciclovir) should be avoided.

6.3       Shelf life

This section states the same shelf life but with added information as follows -

2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.

6.4       Special precautions for storage

This section has added information and now states –

Store ampoule in the original package in order to protect from light.

Do not store above 25 °C.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5       Nature and contents of container

This section has added information and now states –

1 ml concentrate for solution for infusion in 2 ml, type I Ph. Eur. clear colourless glass ampoules.

Each carton contains 10 ampoules.

6.6       Special precautions for disposal

This section has been redrafted and now states –

Prograf 5 mg/ml concentrate for solution for infusion must not be injected undiluted.

Prograf 5 mg/ml concentrate for solution for infusion should be diluted in 5 % w/v glucose solution or physiological saline solution in polyethylene, polypropylene or glass bottles, but not in PVC containers (see section 6.2). Only transparent and colourless solutions should be used.

The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 – 500 ml.

The diluted solution should not be given as a bolus.

Unused concentrate in an opened ampoule or unused reconstituted solution should be disposed of immediately to avoid contamination.

2.         Qualitative and Quantitative composition

This section has been changed to –

1 ml concentrate for solution for infusion contains 5 mg of tacrolimus.

Excipients: 200 mg of polyoxyethylene hydrogenated castor oil and 638 mg of dehydrated alcohol.

4.2       Method of Administration

The following sentence has been added –

The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 – 500 ml.

The diluted solution should not be given as a bolus (see section 6.6).

6.2       Incompatibilities

This has been changed to –

When diluting, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Tacrolimus is absorbed by PVC plastics. Tubing, syringes and any other equipment used to prepare and administer Prograf 5 mg/ml concentrate for solution for infusion should not contain PVC.

Tacrolimus is unstable under alkaline conditions. Combination of the reconstituted Prograf 5 mg/ml concentrate for solution for infusion with other pharmaceutical products that produce a marked alkaline solution (e.g. aciclovir and ganciclovir) should be avoided.

6.3       Shelf life

This section states the same shelf life but with added information as follows -

2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.

6.4       Special precautions for storage

This section has added information and now states –

Store ampoule in the original package in order to protect from light.

Do not store above 25 °C.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5       Nature and contents of container

This section has added information and now states –

1 ml concentrate for solution for infusion in 2 ml, type I Ph. Eur. clear colourless glass ampoules.

Each carton contains 10 ampoules.

6.6       Special precautions for disposal

This section has been redrafted and now states –

Prograf 5 mg/ml concentrate for solution for infusion must not be injected undiluted.

Prograf 5 mg/ml concentrate for solution for infusion should be diluted in 5 % w/v glucose solution or physiological saline solution in polyethylene, polypropylene or glass bottles, but not in PVC containers (see section 6.2). Only transparent and colourless solutions should be used.

The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 – 500 ml.

The diluted solution should not be given as a bolus.

Unused concentrate in an opened ampoule or unused reconstituted solution should be disposed of immediately to avoid contamination.

2.         Qualitative and Quantitative composition

This section has been changed to –

1 ml concentrate for solution for infusion contains 5 mg of tacrolimus.

Excipients: 200 mg of polyoxyethylene hydrogenated castor oil and 638 mg of dehydrated alcohol.

4.2       Method of Administration

The following sentence has been added –

The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 – 500 ml.

The diluted solution should not be given as a bolus (see section 6.6).

6.2       Incompatibilities

This has been changed to –

When diluting, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Tacrolimus is absorbed by PVC plastics. Tubing, syringes and any other equipment used to prepare and administer Prograf 5 mg/ml concentrate for solution for infusion should not contain PVC.

Tacrolimus is unstable under alkaline conditions. Combination of the reconstituted Prograf 5 mg/ml concentrate for solution for infusion with other pharmaceutical products that produce a marked alkaline solution (e.g. aciclovir and ganciclovir) should be avoided.

6.3       Shelf life

This section states the same shelf life but with added information as follows -

2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.

6.4       Special precautions for storage

This section has added information and now states –

Store ampoule in the original package in order to protect from light.

Do not store above 25 °C.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5       Nature and contents of container

This section has added information and now states –

1 ml concentrate for solution for infusion in 2 ml, type I Ph. Eur. clear colourless glass ampoules.

Each carton contains 10 ampoules.

6.6       Special precautions for disposal

This section has been redrafted and now states –

Prograf 5 mg/ml concentrate for solution for infusion must not be injected undiluted.

Prograf 5 mg/ml concentrate for solution for infusion should be diluted in 5 % w/v glucose solution or physiological saline solution in polyethylene, polypropylene or glass bottles, but not in PVC containers (see section 6.2). Only transparent and colourless solutions should be used.

The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 – 500 ml.

The diluted solution should not be given as a bolus.

Unused concentrate in an opened ampoule or unused reconstituted solution should be disposed of immediately to avoid contamination.

1.        Prograf 0.5mg, 1mg 5mg removed from section:

1.        Name of the Medicinal Product

2.        Qualitative and Quantitative composition

3.        Pharmaceutical Form

           Description of Solution 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 Hard Capsules.     

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.

The risk of anaphylaxis may be reduced by slow infusion of reconstituted Prograf 5mg/ml Concentrate for Solution for Infusion or by the prior administration of an antihistamine.

The ethanol content (638mg per ml) of Prograf 5mg/ml Concentrate for Solution for Infusion should be taken into account.

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).

4.7       Effects on ability to drive and use machines

The text has been replaced with:

Not relevant.

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.