Novartis Pharmaceuticals UK Ltd

Section 4.4

Changed from:

Ciclosporin predisposes patients to infection with a variety of pathogens including bacteria, parasites, viruses and other opportunistic pathogens.  This appears to be related to the degree and duration of immunosuppression rather than to the specific use of ciclosporin.  As this can lead to a fatal outcome, effective pre-emptive and therapeutic strategies should be employed particularly in patients on multiple long-term immunosuppressive therapy.

To:

Ciclosporin predisposes patients to infection with a variety of pathogens including bacteria, parasites, viruses and other opportunistic pathogens.  This appears to be related to the degree and duration of immunosuppression rather than to the specific use of ciclosporin.  Activation of latent Polyomavirus infections that may lead to Polyomavirus associated nephropathy (PVAN), especially to BK virus nephropathy (BKVN), or to JC virus associated progressive multifocal leukoencephalopathy (PML) have been observed in patients receiving ciclosporin. These conditions are often related to a high total immunosuppressive burden and should be considered in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. Effective pre-emptive and therapeutic strategies should be employed particularly in patients on multiple long-term immunosuppressive therapy.

Section 4.8

Changed from:

Infections and infestations:

Patients receiving ciclosporin and ciclosporin-containing regimens as well as other immunosuppressive regimens are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Section 4.4). Both generalised and localised infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. The most important infections observed during long-term post-marketing surveillance of solid-organ transplant patients were:

Very common:            Lower respiratory tract infection including cases of bronchiolitis, urinary tract infection, cytomegalovirus infection, upper respiratory tract infection.

Common:        Sepsis, herpes infections, candidal infection.

To:

Infections and infestations:

Patients receiving ciclosporin and ciclosporin-containing regimens as well as other immunosuppressive regimens are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Section 4.4). Both generalised and localised infections can occur. Pre-existing infections may also be aggravated and reactivation of Polyomavirus infections may lead to Polyomavirus associated nephropathy (PVAN) or to JC virus associated progressive multifocal leukoencephalopathy (PML). Serious and/or fatal outcomes have been reported. The most important infections observed during long-term post-marketing surveillance of solid-organ transplant patients were:

Very common:            Lower respiratory tract infection including cases of bronchiolitis, urinary tract infection, cytomegalovirus infection, upper respiratory tract infection.

Common:        Sepsis, herpes infections, candidal infection.

Changes to the Neoral SmPC 

Section 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Changed from:

NEORAL Soft Gelatin Capsules containing 10, 25, 50, or 100mg ciclosporin.

NEORAL Oral Solution containing 100mg ciclosporin/mL

To:

NEORAL Soft Gelatin Capsules containing 10, 25, 50, or 100mg ciclosporin.

For a full list of excipients see section 6.1 List of excipients.

NEORAL Oral Solution containing 100mg ciclosporin/mL

From Section 4.2 Posology and method of administration

Changed from:

           The use of SANDIMMUN Concentrate for Intravenous Infusion is recommended only in organ transplant patients who are unable to take SANDIMMUN/NEORAL orally (e.g. shortly after surgery) or in whom the absorption of the oral forms might be impaired such as during episodes of gastrointestinal disturbances.  It is recommended, however, that patients be transferred to NEORAL therapy as soon as the given circumstances allow (please refer to SANDIMMUN data sheet/SmPC for prescribing information on SANDIMMUN Concentrate for I.V. Infusion).

            Bone marrow transplantation/prevention and treatment of graft-versus-host-disease (GVHD)

            SANDIMMUN Concentrate for Intravenous Infusion is usually preferred for initiation of therapy, although NEORAL Soft Gelatin Capsules or NEORAL Oral Solution may be used (please refer to SANDIMMUN data sheet/SmPC for prescribing information on SANDIMMUN Concentrate for I.V. Infusion).

            Maintenance treatment should continue using NEORAL Soft Gelatin Capsules or NEORAL Oral Solution at a dosage of 12.5mg/kg per day, given in two divided doses, for at least three and preferably six months before tailing off to zero.  In some cases it may not be possible to withdraw NEORAL until a year after bone marrow transplantation.  Higher doses of NEORAL or the use of SANDIMMUN Concentrate for Intravenous Infusion may be necessary in the presence of gastro-intestinal disturbances which might decrease absorption.

To:

The use of SANDIMMUN Concentrate for Solution for Infusion is recommended only in organ transplant patients who are unable to take SANDIMMUN/NEORAL orally (e.g. shortly after surgery) or in whom the absorption of the oral forms might be impaired such as during episodes of gastrointestinal disturbances.  It is recommended, however, that patients be transferred to NEORAL therapy as soon as the given circumstances allow (please refer to SANDIMMUN data sheet/SmPC for prescribing information on SANDIMMUN Concentrate for Solution for Infusion).

Bone marrow transplantation/prevention and treatment of graft-versus-host-disease (GVHD)

SANDIMMUN Concentrate for Solution for Infusion is usually preferred for initiation of therapy, although NEORAL Soft Gelatin Capsules or NEORAL Oral Solution may be used (please refer to SANDIMMUN data sheet/SmPC for prescribing information on SANDIMMUN Concentrate for Solution for Infusion).

Maintenance treatment should continue using NEORAL Soft Gelatin Capsules or NEORAL Oral Solution at a dosage of 12.5mg/kg per day, given in two divided doses, for at least three and preferably six months before tailing off to zero.  In some cases it may not be possible to withdraw NEORAL until a year after bone marrow transplantation.  Higher doses of NEORAL or the use of SANDIMMUN Concentrate for Solution for Infusion may be necessary in the presence of gastro-intestinal disturbances which might decrease absorption.

There have also been minor changes to the template of the SmPC text in line with EU requirements.

Update to section 4.2 of the SmPC with additional information on use in the elderly

Changed from:

Use In The Elderly

There is currently no experience with NEORAL in the elderly. However, no particular problems have been reported following the use of ciclosporin at the recommended dose.  However, factors sometimes associated with ageing, in particular impaired renal function, make careful supervision essential and may necessitate dosage adjustment.

To:

Use in the Elderly

Experience with NEORAL in the elderly is limited.  However, no particular problems have been reported following the use of ciclosporin at the recommended dose.  Factors sometimes associated with ageing, in particular impaired renal function, make careful supervision essential and may necessitate dosage adjustment.

In rheumatoid arthritis clinical trials with ciclosporin, 17.5% of patients were aged 65 or older.  These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥ 50% above the baseline after 3‑4 months of therapy.

Clinical studies of NEORAL in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

SECTION 4.4

Paragraph 6 in Precautions section:

….. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the specific use if ciclosporin. Hence a treatment regimen containing immunosuppressants should be used with caution as this could lead to lymphoproliferative disorders and solid organ tumours, some with reported fatalities.

changed to:

….. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents. Hence a treatment regimen containing multiple immunosuppressants (including ciclosporin) should be used with caution as this could lead to lymphoproliferative disorders and solid organ tumours, some with reported fatalities.

SECTION 4.5

Paragraph entitled Drug interactions:

Second paragraph:

            P450

replaced with:

            CYP3A4

The following has also been added:

Ciclosporin is also an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase plasma levels of comedications that are substrates of this enzyme and/or transporter.

Paragraph entitled Other relevant drug interactions:

Etoposide has been added to the 6^th paragraph, to read:

Ciclosporin may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and etoposide.

The following sentence has also been added at the end of this section:

Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.

SECTION 4.8

·         Including cysts and polyps has been added to the following title:

                    Neoplasms benign, malignant and unspecified including cysts and polyps

·         Incidences changed from percentages to ≥ 1/100 etc and formatting changed so that side effects are now tabulated instead of just being listed.

SECTION 5.1

Changed from:

Pharmacotherapeutic group: Selective immunosuppressive agents, calcineurin inhibitors (ATC code L04A).

to:

Pharmacotherapeutic group: Immunosuppressive agents, calcineurin inhibitors (ATC code L04A D01).

SECTION 10

Date of revision changed from 14 April 2008 to 11 August 2008

• Paragraph on infections and infestations added:

            Infections and infestations:

Patients receiving ciclosporin and ciclosporin- containing regimens as well as other immunosuppressive regimens are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Section 4.4). Both generalised and localised infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. The most important infections observed during long-term post-marketing surveillance of solid-organ transplant patients were:

 
Very common: Lower respiratory tract infection including cases of bronchiolitis, urinary tract infection, cytomegalovirus infection, upper respiratory tract infection.

Common: Sepsis, herpes infections, candidal infection.

Section 3: new capsule markings included

Section 4.4:

"in elderly patients, renal function should be monitored with particular care" added

Statement on excess ultraviolet light exposure moved to this section

Statement on vaccination moved from section 4.5 to 4.4

Inclusion of statment on lercandipine

Section4.5:

Interactions added: oxcarbazepine, sulfinpyrazone, terbinafine, bosentan, voriconazole, imatinib, methotrexate, tacrolimus, lercandipine, everolimus, sirolimus, fibric acid derivatives (e.g.bezafibrate,  fenofibrate)

colchicine added to drugs which  increase ciclosporin levels

digoxin: additional information  on digitalis toxicity 

potassium sparing drugs: additional information included