Pfizer Limited

TIn rare cases, the concomitant administration of sirolimus and ACE inhibitors has resulted in angioneurotic oedema-type reactions.

In clinical trials, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates was well tolerated. During Rapamune therapy with or without CsA, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate, should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the respective Summary of Product Characteristics of these agents.

The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of sirolimus. Currently in clinical practice, sirolimus whole blood concentration are being measured by both chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. When using a proprietary immunoassay system, always refer to the manufacturer’s information to correlate values to a reference chromatographic assay.  All sirolimus concentrations reported in this Summary of Product Characteristics were either measured using chromatographic methods or have been converted to chromatographic method equivalents. Adjustments to the targeted range should be made according to the assay being utilised to determine the sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustment to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.

Physicians should therefore remain continuously informed by responsible representatives for their local laboratory on the performance of the locally used method for concentration determination of sirolimus.
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Two additional ADRs added –

Diabetes mellitus

(Metabollism and Nutrition Disorders)

Ascites

(Gastrointestinal disorders)

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Additional sentence:

There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults) in patients receiving Rapamune.

Additional sentence at end of section:

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In a retrospective review of hepatic veno-occlusive disease (VOD) in patients who underwent myeloablative stem cell transplantation using cyclosphophamide and total body irradiation, an increased incidence of hepatic VOD was observed in patients treated with Rapamune, especially with concomitant use of methotrexate.

A clinical study in liver transplant patients randomised to conversion from a CNI-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen 6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at 12 months (-4.45 mL/min and -3.07 mL/min, respectively). The study also failed to demonstrate non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus conversion group compared to the CNI continuation group. The rate of death in the sirolimus conversion group was higher than the CNI continuation group, although the rates were not significantly different. The rates of premature study discontinuation, adverse events overall (and infections, specifically), and biopsy‑proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group.

Sirolimus tablets contain sucrose and lactose. In those patients with a history of sucrase insufficiency, isomaltase insufficiency, fructose intolerance, glucose malabsorption, galactose intolerance (e.g. galactosemia), or Lapp lactase deficiency, a careful risk/benefit assessment should be performed prior to prescribing sirolimus tablets.

4.4  Special warnings and precautions for use - inserted - 'Based on information from subsequent clinical trials, the use of Rapamune, mycophenolate mofetil, and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo renal transplant setting (see section 5.1).'

Inserted - 'Periodic quantitative monitoring of urinary protein excretion is recommended.  In a study evaluating conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to Rapamune (see section 5.1).  New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study (see section 4.8).  The safety and efficacy of conversion from calcieurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.'

4.8  Undesirable effects - Inserted into table under Uncommon ( >1/1000 to <1/100) column and in 'Renal and urinary disorders' line - 'Nepthrotic syndrome (see section 4.4).'

5.1  Pharmacodynamic properties - Inserted 'phase 3' and changed 'sirolimus' to 'Rapamune (twice)' in third paragraph.

In the last half of this section - Inserted - 'At 12, 24 and 36 months, graft and patient survival were similar for both groups.  At 48 months, there was a statistically significant difference in graft survival in favour of the Rapamune following ciclosporin elimination group compared to the Rapamune with ciclosporin therapy group (including and excluding loss to follow-up).  There was a significantly higher rate of first biopsy-proven rejection in the ciclosporin elimination group compared to the ciclosporin maintenance group during the period post‑randomisation to 12 months (9.8% vs. 4.2%, respectively). Thereafter, the difference between the two groups was not significant.

The mean calculated glomerular filtration rate (GFR) at 12, 24, 36, 48 and 60 months was significantly higher for patients receiving Rapamune following ciclosporin elimination than for those in the Rapamune with ciclosporin therapy group.  Based upon the analysis of data from 36 months and beyond, which showed a growing difference in graft survival and renal function, as well as significantly lower blood pressure in the ciclosporin elimination group, it was decided to discontinue subjects from the Rapamune with ciclosporin group. By 60 months, the incidence of non-skin malignancies was significantly higher in the cohort who continued ciclosporin as compared with the cohort who had ciclosporin withdrawn (8.4% vs. 3.8%, respectively). For skin carcinoma, the median time to first occurrence was significantly delayed.

The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients (6-120 months after transplantation) was assessed in a randomised, multicentre, controlled trial, stratified by calculated GFR at baseline (20-40 mL/min vs > 40 mL/min). Concomitant immunosuppressive agents included mycophenolate mofetil, azathioprine, and corticosteroids.  Enrollment in the patient stratum with baseline calculated GFR < 40 mL/min was discontinued due to an imbalance in safety events (see section 4.8).

In the patient stratum with baseline calculated GFR > 40 mL/min, renal function was not improved overall.  The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment emergent adverse events occurred more frequently during the first 6 months after Rapamune conversion.  In the stratum with baseline calculated GFR > 40 mL/min, the mean and median urinary protein to creatinine ratios were significantly higher in the Rapamune conversion group as compared to those of the calcineurin inhibitors continuation group at 24 months (see section 4.4).  New onset nephrosis (nephrotic syndrome) was also reported (see section 4.8).

At 2 years, the rate of non-melanoma skin malignancies was significantly lower in the Rapamune conversion group as compared to the calcineurin inhibitors continuation group (1.8% and 6.9%).  In a subset of the study patients with a baseline GFR > 40 mL/min and normal urinary protein excretion, calculated GFR was higher at 1 and 2 years in patients converted to Rapamune than for the corresponding subset of calcineurin inhibitor continuation patients.  The rates of acute rejection, graft loss, and death were similar, but urinary protein excretion was increased in the Rapamune treatment arm of this subset.

In two multi-centre clinical studies, de novo renal transplant patients treated with Rapamune, mycophenolate mofetil (MMF), corticosteroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with a calcineurin inhibitor, MMF, corticosteroids, and an IL-2 receptor antagonist (see section 4.4).  Renal function was not better in the treatment arms with de novo Rapamune without a calcineurin inhibitor. An abbreviated dosing schedule of daclizumab was used in one of the studies.

6.3 Shelf life - inserted - 'and other handling'.

9.  Date of first authorisation/renewal of the authorisation - changed 'first' to 'latest'.

10.  Date of revision of the text - changed '07 September 2006' to '29 March 2007’.