4.4     Special warnings and precautions for use

New headers:

Opportunistic infections

Posterior reversible encephalopathy syndrome (PRES)

4.8       Undesirable effects

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 section on adverse event reporting has been revised to reflect the updated HPRA contact details.

The date of revision is updated to June 2015

 

4.2         Posology and method of administration

 

Elderly Older peoplepatients

There is no evidence currently available to indicate that dosing should be adjusted in elderly older peoplepatients.

 

 

4.4     Special warnings and precautions for use

 

 

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.

 

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

 

Cardiac disorders

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed in Prograf treated patients on rare occasions and may also occur with Advagraf. Most cases have been reversible, occurring with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at 3 months and then at 9 -12 months). If abnormalities develop, dose reduction of Advagraf, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may but at this time lacks substantial evidence for causeing 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).  

 

4.5     Interaction with other medicinal products and other forms of interaction

 

It is strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with ECG),  renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels 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).

 

 

 

 

 

4.8         Undesirable effects

 Cardiac disorders

common:              ischaemic coronary artery disorders, tachycardia

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

rare:                      pericardial effusion

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

 

 

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 via the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

 

FREEPOST

Pharmacovigilance Section

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

 

5.3       Preclinical safety data

 

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.

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 Advagraf in clinical transplantation.

Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic doses and the offspring showed reduced birth weights, viability and growth.

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

Correct date format

 

 

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

 

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of substances known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.

It is 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 or otherwise influence tacrolimus blood levels 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).

 

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).

 

 

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

Amiodarone is a known inhibitor of CYP3A4 and so interaction with tacrolimus is likely to occur, associated with increased levels of tacrolimus.

 

Other interactions potentially leading to increased tacrolimus blood levels

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

 

 

7.       MARKETING AUTHORISATION HOLDER

 

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

Netherlands

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 23 April/04/ 2007

Date of latest renewal: 13 April 2012

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Excipients with known effect:

Each capsule contains 51.09 mg lactose.

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

 

For the full list of excipients, see section 6.1.

 

 

4.       Clinical particulars

 

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 adverse reactions, including under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus.

 

In de novo kidney and liver transplant patients AUC_0-24 of tacrolimus for Advagraf on Day 1 was 30% and 50% lower respectively, when compared with that for the immediate release capsules (Prograf) at equivalent doses.

 

Special populations

Hepatic impairment

 

Paediatric patients

The safety and efficacy of Advagraf in children under 18 years of age have not yet been established. Limited data are available but no recommendation on a posology can be made.

 

4.3     Contraindications

 

Hypersensitivity to tacrolimus, or to any of the excipients listed in section 6.1

 

4.4     Special warnings and precautions for use

 

This has led to serious adverse reactions, including graft rejection, or other adverse reactions which could be a consequence of either under- or over-exposure to tacrolimus.

 

Lymphoproliferative disorders and malignancies

Patients treated with tacrolimus have been reported to develop Epstein-Barr-Virus (EBV)-associated lymphoproliferative disorders (see section 4.8).

 

Excipients

Advagraf capsules contain lactose.

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse reactions on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products.

 

Breast-feeding

Human data demonstrate that tacrolimus is excreted in breast milk.

 

4.7     Effects on ability to drive and use machines

 

This effect may be enhanced if tacrolimus is administered in association with alcohol.

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02

 

 

6.       PHARMACEUTICAL PARTICULARS

 

6.5         Nature and contents of container

 

Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium wrapper with a desiccant containing 10 capsules per blister

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 23/04/2007

Date of latest renewal:

 

 

10.     DATE OF REVISION OF THE TEXT

 

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

 

 

 

 

4.6     Pregnancy and lactation

Pregnancy

Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse events 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.

4.8       Undesirable effects

Blood and lymphatic system disorders

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

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

rare:                     thrombotic thrombocytopenic purpura, hypoprothrombinaemia

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

 

 

10.     DATE OF REVISION OF THE TEXT


Nov 2011

 

 

4.4     Special warnings and precautions for use

 

 

Pure Red Cell Aplasia

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.

 

 

4.5     Interaction with other medicinal products and other forms of interaction

CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels

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).

 

4.8     Undesirable effects

Blood and lymphatic system disorders
common:	anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis
uncommon:	coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal
rare:	thrombotic thrombocytopenic purpura, hypoprothrombinaemia
not known:           pure red cell aplasia

10.       DATE OF REVISION OF THE TEXT

09/2011

please look at the symbolds on page 12-
(such as interleukins-2, -3 and γ interferon)

and on page 15 α-1-acid glycoprotein. the alpha is not the shown correctly



Section 6.5 Nature and contents of container

 

Unit-dose perforated blister

 

Packs sizes: 30x1, 50x1 and 100x1 prolonged-release hard capsule in unit-dose perforated blisters.

 

8. Marketing Authorisation Number

 

EU/1/07/387/014

EU/1/07/387/015

EU/1/07/387/016

 

10. Date of Revision of the Text

 

08/2010

 

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each prolonged-release capsule contains 0.5 mg of tacrolimus, changed to read:

 

Each prolonged-release hard capsule contains 0.5 mg tacrolimus (as monohydrate).

 

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

 

 

3.       PHARMACEUTICAL form

 

Reference to yellow orange removed.

 

 

4.2          Posology and method of administration

 

All titles were updated

 

Insertion of:

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.

 

(see below under Target whole blood trough concentration recommendations) changed to (see below under Therapeutic drug monitoring).

 

 

The following paragraf was moved to Conversion of Prograf-treated patients to Advagraf: In stable patients converted from Prograf (twice daily) to Advagraf (once daily) on a 1:1 (mg:mg) total daily dose basis the systemic exposure to tacrolimus (AUC_0-24) for Advagraf was approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C₂₄) and systemic exposure (AUC_0-24) for Advagraf is similar to that of Prograf. When converting from Prograf capsules to Advagraf tacrolimus trough levels should be measured prior to conversion and within two weeks after conversion. Dose adjustments should be made to ensure that similar systemic exposure is maintained.

 

 

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

 

 

 

 

 

Removal of

 

In patients unable to take oral medicinal products during the immediate post-transplant period, tacrolimus therapy can be initiated intravenously (Prograf 5 mg/ml Concentrate for Infusion) at a dose approximately 1/5^th of the recommended oral dose for that indication.

 

 

Method of administration

It is recommended that the oral daily dose of Advagraf be administered once daily in the morning. Advagraf prolonged-release 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).

Advagraf 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 (see section 5.2). A forgotten morning dose should be taken as soon as possible on the same day. A double dose should not be taken on the next morning.

 

Duration of dosing

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

 

 

Dose recommendations - Kidney transplantation title removed

 

Removal of the title: Dose adjustment during post-transplant period

 

Dose recommendations - Liver transplantation title removed

 

Removed Following conversion, tacrolimus trough levels should be monitored and if necessary dose adjustments made to maintain similar systemic exposure.

 

Insertion of: Method of administration

Advagraf is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Advagraf be administered once daily in the morning. Advagraf prolonged-release hard capsules should be taken immediately following removal from the blister. Patients should be advised not to swallow the desiccant. The capsules should be swallowed whole with fluid (preferably water). Advagraf 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 (see section 5.2). A forgotten morning dose should be taken as soon as possible on the same day. A double dose should not be taken on the next morning.

 

In patients unable to take oral medicinal products during the immediate post-transplant period, tacrolimus therapy can be initiated intravenously (see Summary of Product Characteristics for Prograf 5 mg/ml concentrate for solution for infusion) at a dose approximately 1/5^th of the recommended oral dose for the corresponding indication.

 

 

4.3     Contraindications

 

Hypersensitivity to tacrolimus or other macrolides or to any of the excipients.

 Updated to read:

 

Hypersensitivity to tacrolimus, or to any of the excipients (see section 6.1)

Hypersensitivity to other macrolides

 

 

 

 

 

 

 

 

4.4     Special warnings and precautions for use

 

Insertion of

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).

 

Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or efficacy.

 

For prophylaxis of transplant rejection in adult heart allograft recipients and for paediatric allograft recipients clinical data are not yet available for the prolonged-release formulation Advagraf. Updated to read: For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available for Advagraf.

 

 

Insertion of:

 

When substances with a potential for interaction (see section 4.5) - particularly strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, 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.

 

 

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).

 

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.

 

Dose reduction may be necessary in patients with sever liver impairment (see section 4.2)

 

 

As Advagraf prolonged-release 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.

Updated to read

Advagraf capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

The printing ink used to mark Advagraf capsules 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 Advagraf.

 

 

 

 

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Other potential interactions that may increase systemic exposure of tacrolimus

Prokinetic agents such as metoclopramide and cisapride.

Cimetidine.

Magnesium-aluminum-hydroxide.

 

And

 

Protein binding considerations

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).

 

Combined  to read

Other interactions potentially leading to increased tacrolimus blood levels

Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances 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 prokinetic agents (such as metoclopramide and cisapride), cimetidine and magnesium-aluminium-hydroxide.

 

 

Addition of:

Protein binding considerations

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).

 

 

4.8          Undesirable effects

 

Addition of: The most commonly reported adverse drug reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.

 

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions are listed below in descending order by frequency of occurrence: very common (  1/10); common (  1/100 to < 1/10); uncommon (  1/1,000 to < 1/100); rare (  1/10,000 to < 1/1,000); very rare ( < 1/10,000), not known (cannot be estimated from the available data).

 

Updated to read

 

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

 

 

 

Injury, poisoning and procedural complications: Insertion of

 

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).

 

 

(incl cysts and polyps) removed

 

 

Hepatobiliary disorders

 

Updated from

common:               hepatic enzymes and function abnormalities, cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis

rare:                      hepatitic artery thrombosis, venoocclusive liver disease

very rare:               hepatic failure, bile duct stenosis

 

to read

very common:        liver function tests abnormal

common:               bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice

rare:                      venoocclusive liver disease, hepatitic artery thrombosis

very rare:               hepatic failure

 

 

5.1     Pharmacodynamic properties

 

The below paragraph was removed.

Results from published data of tacrolimus administered twice daily as Prograf capsules in other primary organ transplantation.

Prograf has evolved into an accepted treatment as primary immunosuppressive medicinal product following pancreas, lung and intestinal transplantation. In prospective published studies oral Prograf was investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of oral Prograf in these published studies appeared to be similar to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.

 

The below paragraphs were added

 

Results from clinical trials performed with once-daily tacrolimus Advagraf

Liver transplantation

The efficacy and safety of Advagraf and Prograf, both in combination with corticosteroids, was compared in 471 de novo liver transplant recipients. The event rate of biopsy confirmed acute rejection within the first 24 weeks after transplantation was 32.6% in the Advagraf group (N=237) and 29.3% in the Prograf group (N=234). The treatment difference (Advagraf Prograf) was 3.3% (95% confidence interval [-5.7%, 12.3%]).The 12‑month patient survival rates were 89.2% for Advagraf and 90.8% for Prograf; in the Advagraf arm 25 patients died (14 female, 11 male) and in the Prograf arm 24 patients died (5 female, 19 male). 12-month graft survival was 85.3% for Advagraf and 85.6% for Prograf.

 

Kidney transplantation

The efficacy and safety of Advagraf and Prograf, both in combination with mycophenolate mofetil (MMF) and corticosteroids, was compared in 667 de novo kidney transplant recipients. The event rate for biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the Advagraf group (N=331) and 14.9% in the Prograf group (N=336). The treatment difference (Advagraf-Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12‑month patient survival rates were 96.9% for Advagraf and 97.5% for Prograf; in the Advagraf arm 10 patients died (3 female, 7 male) and in the Prograf arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for Advagraf and 92.8% for Prograf.

 

The efficacy and safety of Prograf, ciclosporin and Advagraf, all in combination with basiliximab antibody induction, MMF and corticosteroids, was compared in 638 de novo kidney transplant recipients. The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute rejection, or lost to follow-up) was 14.0% in the Advagraf group (N=214), 15.1% in the Prograf group (N=212) and 17.0% in the ciclosporin group (N=212). The treatment difference was -3.0% (Advagraf-ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for Advagraf vs. ciclosporin and -1.9% (Prograf-ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for Prograf vs. ciclosporin. The 12-month patient survival rates were 98.6% for Advagraf, 95.7% for Prograf and 97.6% for ciclosporin; in the Advagraf arm 3 patients died (all male), in the Prograf arm 10 patients died (3 female, 7 male) and in the ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for Advagraf, 92.9% for Prograf and 95.7% for ciclosporin.

 

Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation

In prospective studies oral Prograf was investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of oral Prograf in these published studies appeared to be similar to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.

 

4.6     Pregnancy and lactation

 

Insertion of;

(incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the newborns had normal birth weight for their gestational age).

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).

 

No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have been performed.

 

 

 

 

5.2     Pharmacokinetic properties

Distribution and elimination

 

The following was omitted from the distribution and elmination paragraf and included under the Excretion paragraf.

 

Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism are considered to be responsible for the higher clearance rates observed following transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours.

 

 

Metabolism and biotransformation  heading changed to Metabolism

 

 

 

6.2          Incompatibilities

 

Inserted (polyvinylchloride)

 

 

6.5          Nature and contents of container

 

Ten changed to read 10

 

Section 10.       DATE OF REVISION OF THE TEXT

 

10/2008 {MM/YYYY} Changed to 04/2009

 

Section 4.8 Undesirable Effects

 

Neoplasms benign, malignant and unspecified, included (incl cysts and polyps) in the heading.

 

 

Section 5.1   Pharmacodynamic properties

 

Changed from: Pharmacotherapeutic group: Macrolide immunosuppressant, ATC code: L04A A05

To read

 Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02

 

Section 6.1   List of excipients

 

Printing ink (Opacode S-1-15013) changed to (Opacode S-1-15083)

 

Dimethicone change to Simethicone

 

Hydroxyl Cellulose added.

 

 

Section 10.    DATE OF REVISION OF THE TEXT

 

01/2008

{MM/YYYY}

 

Changed to  August 2008

 

 

Section 7.        MARKETING AUTHORISATION HOLDER updated to:

 

Astellas Pharma Europe B.V.

Elisabethhof 19

2353 EW Leiderdorp

Netherlands

 

 

Section 10.      Date of revision of the text updated to 01/2008