Prograf Capsules

Update section 4.8:

Musculoskeletal and connective tissue disorders

common:              arthralgia, back pain, muscle spasms, pain in limb extremity

Description of selected adverse reactions

Pain in extremity has been described in a number of published case reports as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.

Section 4.4 & 4.5:

Addition of further information on the risk of interaction with herbal preparations including the Chinese herb Schisandra sphenanthera.

Section 4.8:

This section has been revised and now includes a section on “Investigations” which lists the side effects relating to investigations in a single section rather than throughout section 4.8.

The date of revision is updated to June 2015

 

2. Qualitative and quantitative composition, the following text has been added:

 

The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total printing ink composition).

 

4.4     Special warnings and precautions for use

Section reformatted & the following text added:

 

High potassium intake or potassium-sparing diuretics should be avoided (see section 4.5).

 

Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see section 4.5).

 

Vaccination

Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.

 

Gastrointestinal disorders

Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments should be considered immediately after suspected symptoms or signs occur.

 

Underlined text added:

Tacrolimus may prolong the QT interval and may cause Torsades de Pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see section 4.5).

 

The printing ink used to mark Prograf capsules 0.5mg contains soya lecithin. In patients who are hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the benefit of using Prograf

 

4.5       Interaction with other medicinal products and other forms of interaction

Underlined text added

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. It is therefore strongly recommended to closely monitor tacrolimus blood levels, as well as QT prolongation (with ECG),

 

Other interactions potentially leading to increased tacrolimus blood levels

Tacrolimus is extensively bound to plasma proteins. Possible interactions with other medicinal products known to have high affinity for plasma proteins should be considered (e.g., NSAIDs, oral anticoagulants, or oral antidiabetics).

Other potential interactions that may increase systemic exposure of tacrolimus include the prokinetic agent metoclopramide, cimetidine and magnesium-aluminium-hydroxide.

 

 

Section 4.8 is updated throughout with the following added;

very rare:          echocardiogram abnormal, electrocardiogram QT prolonged, Torsades de Pointes

The information on reporting suspected adverse drug reactions hás also been added

5.3     Preclinical safety data, the following text is added:

 

When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with Prograf in clinical transplantation.



2.       Qualitative and quantitative composition

 

Each capsule contains 0.5 mg of tacrolimus (as monohydrate).

Excipient with known effect: 62.85 mg of lactose monohydrate

 

For thea full list of excipients, see section 6.1.

 

4.3     Contraindications

 

Hypersensitivity to tacrolimus or other macrolides.

Hypersensitivity to any of the excipients listed in section 6.1.

 

4.4     Special warnings and precautions for use

 

When substances with a potential for interaction (see section 4.5) - particularly strong inhibitors of

CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) – are being

combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose

as appropriate in order to maintain similar tacrolimus exposure.

 

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Metabolic interactions

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. It is therefore strongly recommended to closely monitor tacrolimus blood levels, as well as renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism are used concomitantly and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4).

 

Inhibitors of metabolism

Clinically the following substances have been shown to increase tacrolimus blood levels:

Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin, or HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir) or HCV protease inhibitors (e.g. telaprevir, boceprevir). Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.

Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole and nefazodone.

 

 

4.6     Fertility, pPregnancy and lactation

 

In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3). Tacrolimus affected male fertility in rats (see section 5.3).

 

Lactation

Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Prograf.

 

Fertility

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).

 

 

 

4.8 Undesirable effects

 

Reporting of suspected adverse reactions

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions preferably through the online reporting option accessible from the IMB homepage. A

downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’. Alternatively, the traditional post-paid ‘yellow card’ option may also continue to be used.

 

 

FREEPOST

Pharmacovigilance Section

 

Irish Medicines Board

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

6.6     Special precautions for disposal and other handling

 

No special requirements.

 

 

 

 

 

 

 

 

 

Correction of spacing errors

4.6     Pregnancy and lactation

 

Human data show that tacrolimus is able to cross the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse effects on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported. To date, no other relevant epidemiological data are available. 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. In case of in utero exposure, monitoring of the newborn for the potential adverse effects of tacrolimus is recommended (in particular the effects on the kidneys). There is a risk for premature delivery (<37 week) as well as for hyperkalaemia in the newborn, which, however, normalizes spontaneously.

4.8     Undesirable effects

 

The adverse drug reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medications.

 

Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use. Adverse drug reactions are listed below in descending order by frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

 

Cardiac disorders

common:         ischaemic coronary artery disorders, tachycardia

uncommon:     ventricular arrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, ECG investigations abnormal, heart rate and pulse investigations abnormal

rare:                             pericardial effusion

very rare:         echocardiogram abnormal

 

Blood and lymphatic system disorders

common:         anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal

uncommon:     coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia

rare:                             thrombotic thrombocytopenic purpura, hypoprothrombinaemia

not known:      pure red cell aplasia, agranulocytosis, haemolytic anaemia

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.

4.8     Undesirable effects

Blood and lymphatic system disorders

common:         anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal

uncommon:     coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia

rare:                             thrombotic thrombocytopenic purpura, hypoprothrombinaemia

not known:      pure red cell aplasia

August 2010

Change detail

 

Prograf 0.5mg

                                                  Changes in Red

 

 

4.5     Interaction with other medicinal products and other forms of interaction

Inhibitors of metabolism

Clinically the following substances have been shown to increase tacrolimus blood levels:

Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin or HIV protease inhibitors (e.g. ritonavir). Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.

Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.

In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided.

Lansoprazole and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.

 

 

6.5     Nature and contents of container

 

PVC/PVDC/Aluminium blisters or perforated unit-dose blisters. Ten capsules per blister. Two, three, five, six, nine or ten blisters with a desiccant in an aluminium wrapper.

 

Packs of 20, 30, 50, 60 and 100 hard capsules in blisters.

Packs of 20×1, 30×1, 50×1, 60×1 and 100×1 hard capsules in perforated unit-dose blisters.

 

 

Not all pack sizes may be marketed.

 

10.   Date of revision of the text

 

July 2010

 

 

 



 

Section 4.2      Posology and method of administration

Inserted

 

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 overimmunosuppression, 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.

 

 

Section 4.4      Special warnings and precautions for use

 

Inserted

 

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.

 

 

 

Section 4.8      Undesirable effects

 

Inserted

Infections and infestations

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.

 

 

Injury, poisoning and procedural complications

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. A number of associated cases of transplant rejection have been reported (frequency cannot be estimated from available data).

 

Section 5.1      Pharmacodynamic properties

 

Pharmacotherapeutic group: Macrolide immunosuppressant, ATC code: L04A A05

 

Changed to read:

Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02

 

 

7.             Date of revision of the text

 

February 2008 updated to April 2009

 

 

 

 

Prograf Capsules SPCs

Changes from April 2006 v April 2007

 

Reason for updates: Harmonisation of quality dossier in Europe.

 

2.       Qualitative and quantitative composition

New text added:

 0.5mg SPC:  “…(as monohydrate). Excipient: 62.85mg of lactose monohydrate.“

1mg SPC: “…(as monohydrate). Excipient: 61.35mg of lactose monohydrate.“

5mg SPC: “...(as monohydrate). Excipient: 123.60mg of lactose monohydrate.“

 

3.       Pharmaceutical form

 

New text added (shown here as underlined):

 

0.5mg SPC: “Capsule hard. Opaque light yellow, hard gelatin capsule imprinted in red with “0.5 mg” and “[F] 607” containing white powder.”

 

1mg SPC: “Capsule hard. Opaque white hard gelatin capsules imprinted in red with “1mg” and “[f] 617”, containing white powder.”

 

5mg SPC: “Capsule, hard. Opaque grayish red gelatin capsules imprinted in white with “5mg” and “[f] 657”, containing white powder.”

 

 

4.2     Posology and method of administration

Method of administration

New text added: “Patients should be advised not to swallow the desiccant.”

 

4.4     Special warnings and precautions for use

New text added: “As Prograf 0.5mg hard capsules contain lactose, special care should be taken in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.”

Note: “0.5mg” reads “1mg” or “5mg” as appropriate in each SPC.

 

5.1       Pharmacodynamic properties

Deleted text: “ATC code: LO4A A05.”

 

6.1         List of excipients

Excipients split into Capsule Content, Capsule Shell and Printing Ink.

 

“Ferric oxide red (E172)” rephrased to “red iron oxide (E172).”

 

0.5mg SPC only:

“Ferric oxide yellow E172” rephrased and E number corrected to “Yellow iron oxide (E173)”.

“Dimethicone” changed to “Simethicone”.

New excipient added: “hydroxypropylcellulose”.

 

6.2     Incompatibilities

Deleted text “not applicable” and replaced with new text: “Tacrolimus is not compatible with PVC. Tubing, syringes and other equipment used to prepare or administer a suspension of Prograf 0.5 mg hard capsule contents should not contain PVC.”

Note: “0.5mg” reads “1mg” or “5mg” as appropriate in each SPC.

 

6.3     Shelf life

Unopened shelf life extended from 2 to 3 years.

 

6.4     Special precautions for storage

Deleted text: “Do not store above 30°C.”

New text added (underlined here): “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

Additional packs of  2, 3, 6 or 9 blisters.

0.5mg SPC: Additional pack sizes of 20, 30 and 60 capsules.

1mg SPC: Additional pack sizes of 20, 30, 60 and 90 capsules.

5mg SPC: Additional pack sizes of 30, 60 and 100 capsules.

 

9.       Date of first authorisation/RENEWAL OF THE AUTHORISATION

Updated to: “15^th February 2011”

 

10.       Date of revision of the text

Updated to: “April 2007”

CHANGES TO PROGRAF 0.5MG CAPSULES SPC

 

Introduction

The licenses and SPCs for Prograf have now been harmonised across Europe. The general wording of the SPCs has changed throughout. The main changes to the SPC are listed below.

 

In addition, this is a new individual SPC for Prograf 0.5mg Capsules. It was previously included in a combined SPC. There are now separate SPCs for the concentrate for Infusion and 1mg and 5mg Capsules.

 

New individual SPC

All references to Prograf 5mg/ml concentrate for infusion plus Prograf Capsules 1mg and 5mg have been removed from the following sections:

1.       Name of the Medicinal Product

2.       Qualitative and Quantitative composition

3.       Pharmaceutical Form

4.2     Posology and method of administration

                       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

 

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 (was previously in section 4.4):

“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.”

 
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.

 

Text on Prophylaxis of transplant rejection – children has been added:

“An initial oral dose of 0.30 mg/kg/day should be administered in two divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of 0.05 mg/kg/day should be administered as a continuous 24-hour infusion.”

 

Dosage recommendations - Kidney transplantation

Prophylaxis of transplant rejection - adults

The recommended oral starting dose has changed from 0.15 - 0.40mg/kg per day to 0.20 - 0.30mg/kg per day.

 

Text on Prophylaxis of transplant rejection - children has been added:

“An initial oral dose of 0.30 mg/kg/day should be administered in two divided doses (e.g. morning and evening). 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.”

 

The following text has been expanded and moved to Dosage adjustments in Specific Patient Populations:
“Conversion from cyslosporin

Care should be taken when converting patients from ciclosporin-based to Prograf -based therapy (see sections 4.4 and 4.5). Prograf 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, Prograf 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

Target levels have been reduced from 25ng/ml to 20ng/ml and target ranges for liver, kidney and heart transplant patients have been inserted.

 

4.4     Special warnings and precautions for use

 

The following text has been deleted:

“Several types of neurological and CNS disorders have been reported in association with Prograf therapy.  For this reason, patients exhibiting such adverse events should be controlled carefully.  Occurrence of severe CNS symptoms should prompt immediate dose review.  It has been reported that in some cases severe tremor and/or motoric (expressive) aphasia may be indicators for severe CNS disorders.”

 

The following text has been inserted:

“…Herbal preparations containing St. John’s wort (Hypericum perforatum) or other herbal preparations should be avoided when taking Prograf due to the risk of interactions that lead to decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus (see section 4.5 Interactions with other medicinal products and other forms of interactions).

 

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

 

The combined administration of ciclosporin and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.5).

 

….Tacrolimus may prolong the QT interval but at this time lacks substantial evidence for causing Torsades de Pointes. Caution should be exercised in patients with diagnosed or suspected Congenital Long QT Syndrome.

 

… Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

 

…As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown (see section 4.8).”

 

 

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

This section has been re-worded as follows:

 “Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if Prograf is administered in association with alcohol.”

 

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

ATC code has been added: LO4A A05

 

Results from published data in other primary organ transplantation

The results from studies in lung, pancreas, 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.

 

6.5     Nature and contents of container

Inclusion of “Not all pack sizes may be marketed.”

 

7. Marketing Authorisation Holder

Changed from Fujisawa Ireland Ltd, Co. Kerry to Astellas Pharma Co. Ltd., Dublin 22.

 

8. Marketing Authorisation Number(s)

Changed to PA 1241/14/1

 

9.       Date of first authorisation / renewal of the authorisation

16^th February 2001 changed to 16^th February 2006

 

10.    Date of revision of the text

10 May 2001 changed to April 2006.