When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
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 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
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
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
4.6 Pregnancy and lactation
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
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.
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).
coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal
not known: pure red cell aplasia
09/2011
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/1/07/387/024
EU/1/07/387/025
EU/1/07/387/026
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 (AUC0-24) for Advagraf was approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) 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 1/5th 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 1/5th 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.
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:
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).
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.
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 4.4 Special warnings and precautions for use
wort inserted capital W Wort
The following paragraphs were inserted into the section:
Patients treated with immunosuppressants, including Advagraf are at increased risk for 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 the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
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 and seizure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
4.8 Section Undesirable effects
Inserted the following paragraph
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 Advagraf.
Vascular disorders
thrombembolic was changed to thromboembolic
August 2008
Changed to
10/2008
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.
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 {MM/YYYY}