NEORAL® Soft Gelatin Capsules and NEORAL® Oral Solution (ciclosporin*, also known as ciclosporin A) - Immunosuppressive agent

*INN rec.

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

Neoral Soft Gelatin Capsules 10mg: Yellow-white, oval soft gelatin capsules marked 'NVR 10'.

Neoral Soft Gelatin Capsules 25mg: Blue-grey, oval soft gelatin capsules marked 'NVR 25mg'.

Neoral Soft Gelatin Capsule 50mg: Yellow-white, oblong soft gelatin capsules marked 'NVR 50mg'.

Neoral Soft Gelatin Capsules 100mg: Blue-grey, oblong soft gelatin capsules marked 'NVR 100mg'.

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are for oral administration.

NEORAL is an improved pharmaceutical form of the active ingredient ciclosporin. NEORAL is a pre-concentrate formulation of ciclosporin which undergoes a microemulsification process in the presence of water, either in the form of a beverage or in the form of the gastrointestinal fluid. NEORAL reduces the intra-patient variability of pharmacokinetic parameters, with a more consistent absorption profile and less influence of concomitant food intake and the presence of bile. In pharmacokinetic and clinical studies it has been demonstrated that the correlation between trough concentration (Cmin) and total exposure (AUC) is significantly stronger when ciclosporin is given as NEORAL than when it is given as SANDIMMUN. NEORAL therefore allows greater predictability and consistency of ciclosporin exposure.

Transplantation indications

Organ transplantation

Prevention of graft rejection following kidney, liver, heart, combined heart-lung, lung or pancreas transplants.

Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.

Bone marrow transplantation

Prevention of graft rejection following bone marrow transplantation and prophylaxis of graft-versus-host disease (GVHD).

Treatment of established graft-versus-host disease (GVHD).

Non-transplantation indications

Psoriasis

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated in patients with severe psoriasis in whom conventional therapy is ineffective or inappropriate.

Atopic dermatitis

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated for the short term treatment (8 weeks) of patients with severe atopic dermatitis in whom conventional therapy is ineffective or inappropriate.

Rheumatoid arthritis

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated for the treatment of severe, active rheumatoid arthritis in patients in whom classical, slow-acting antirheumatic agents are inappropriate or ineffective.

Nephrotic syndrome

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated for the treatment of steroid dependent or steroid resistant nephrotic syndrome (associated with adverse prognostic features) due to minimal change glomerulonephritis, focal segmental glomerulosclerosis or membranous glomerulonephritis in both adults and children.

Dosage

Following initiation of treatment with NEORAL, due to the different bioavailabilities of the different oral ciclosporin formulations, patients should not be transferred to any other oral formulation of ciclosporin without appropriate monitoring of ciclosporin blood concentrations, serum creatinine levels and blood pressure. This does not apply to the conversion between NEORAL Soft Gelatin Capsules and NEORAL Oral Solution as these two forms are bioequivalent.

Due to the differences in bioavailability between different oral formulations of ciclosporin, it is important that prescribers, pharmacists and patients be aware that substitution of NEORAL with any other oral formulation of ciclosporin is not recommended as this may lead to alterations in ciclosporin blood levels. For this reason it may be appropriate to prescribe by brand.

Transplantation indications

Organ transplantation

Treatment with NEORAL Soft Gelatin Capsules or NEORAL Oral Solution should be initiated within 12 hours before transplantation at a dose of 10 to 15mg/kg body weight given in two divided doses.

As a general rule, treatment should continue at a dose of 10 to 15mg/kg per day given in two divided doses for one to two weeks post-operatively. Dosage should then be gradually reduced until a maintenance dose of about 2 to 6mg/kg per day is reached. This total daily dose should be given in two divided doses. Dosage should be adjusted by monitoring ciclosporin trough levels and kidney function (see Section 4.2 and 4.4).

When NEORAL is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (e.g. 3 to 6mg/kg per day given orally in two divided doses) may be used for the initial treatment. For trough level monitoring, whole blood is preferred, measured by a specific analytical method. Target trough concentration ranges depend on organ type, time after transplantation and immunosuppressive regimen.

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.

If NEORAL Soft Gelatin Capsules or NEORAL Oral Solution are used to initiate therapy, the recommended dose is 12.5 to 15mg/kg per day, given in two divided doses, starting on the day before transplantation.

If GVHD develops after NEORAL is withdrawn it should respond to reinstitution of therapy. Low doses of NEORAL should be used for mild, chronic GVHD.

Non-transplantation indications

Psoriasis

(Refer also to Section 4.4 Additional precautions in psoriasis and atopic dermatitis section)

Due to the variability of this condition, treatment must be individualised. To induce remission, the recommended initial dose of NEORAL is 2.5mg/kg a day given orally in two divided doses. If there is no improvement after 1 month, the daily dose may be gradually increased, but should not exceed 5mg/kg. Treatment should be discontinued if sufficient response is not achieved within 6 weeks on a daily basis of 5mg/kg per day, or if the effective dose is not compatible with the safety guidelines given below (see Section 4.4). Initial doses of 5mg/kg per day of NEORAL are justified in patients whose condition requires rapid improvement.

For maintenance treatment, NEORAL dosage must be individually titrated to the lowest effective level, and the dosage should not exceed 5mg/kg per day, given orally in two divided doses.

Some clinical data are available which provide evidence that once satisfactory response is achieved, NEORAL may be discontinued and subsequent relapse managed with re-introduction of NEORAL at the previous effective dose. In some patients continuous maintenance therapy may be necessary.

Atopic dermatitis

(Refer also to Section 4.4 Additional precautions in atopic dermatitis section)

The recommended dose range for NEORAL is 2.5-5mg/kg per day given orally in two divided doses for a maximum of 8 weeks. If a starting dose of 2.5mg/kg/day does not achieve a good initial response within 2 weeks the dose may be rapidly increased to a maximum of 5mg/kg per day. In very severe cases rapid and adequate control of disease is more likely with a starting dose of 5mg/kg per day, given orally in two divided doses.

Rheumatoid arthritis

(Refer also to Section 4.4 Additional precautions in rheumatoid arthritis section)

It is recommended that initiation of NEORAL therapy should take place over a period of 12 weeks. For the first 6 weeks of treatment, the recommended dose is 2.5mg/kg per day, given orally in two divided doses. If the clinical effect is considered insufficient, the daily dose may be increased gradually as tolerability permits, but should not exceed 4mg/kg per day.

If, after 3 months of treatment at the maximum permitted or tolerable dose the response is considered inadequate, treatment should be discontinued.

For maintenance treatment the dose has to be titrated individually according to tolerability.

NEORAL can be given in combination with low-dose corticosteroids. Pharmacodynamic interactions can occur between ciclosporin and NSAIDs and therefore this combination should be used with care (see Section 4.4 Additional precautions in rheumatoid arthritis section and Section 4.5).

Long-term data on the use of ciclosporin in the treatment of rheumatoid arthritis are still limited. Therefore, it is recommended that patients are re-evaluated after 6 months of maintenance treatment and therapy only continued if the benefits of treatment outweigh the risks.

Nephrotic syndrome

(Refer also to Section 4.4 Additional precautions in nephrotic syndrome section)

To induce remission, the recommended dose is 5mg/kg per day given orally in two divided doses for adults and 6mg/kg per day given orally in two divided doses for children if, with the exception of proteinuria, renal function is normal. In patients with impaired renal function, the initial dose should not exceed 2.5mg/kg per day orally.

In focal segmental glomerulosclerosis, the combination of NEORAL and low dose corticosteroids may be of benefit.

In the absence of efficacy after 3 months treatment for minimal change glomerulonephritis and focal segmental glomerulosclerosis or 6 months treatment for membranous glomerulonephritis, NEORAL therapy should be discontinued.

For maintenance treatment the maximum recommended dose is 5mg/kg per day orally in adults or 6mg/kg per day orally in children. The doses need to be slowly reduced individually according to efficacy (proteinuria) and safety (primarily serum creatinine), to the lowest effective level.

Long-term data of ciclosporin in the treatment of nephrotic syndrome are limited. However, in clinical trials patients have received treatment for 1 to 2 years. Long-term treatment may be considered if there has been a significant reduction in proteinuria with preservation of creatinine clearance and provided adequate precautions are taken (see Section 4.4 Additional precautions in nephrotic syndrome section).

Conversion of transplant patients from SANDIMMUN Soft Gelatin Capsules or Oral Solution to NEORAL

Ciclosporin absorption from SANDIMMUN oral formulations is highly variable and the relationship between SANDIMMUN dose and ciclosporin exposure (AUC) is non-linear. In contrast with NEORAL the absorption of ciclosporin is less variable and the correlation between ciclosporin trough concentrations and exposure is much stronger than with SANDIMMUN.

For converting patients from SANDIMMUN to NEORAL an initial mg for mg conversion from SANDIMMUN to NEORAL is recommended with subsequent dose titration if required. Available data confirm that following this initial mg for mg conversion, comparable trough concentrations of ciclosporin in whole blood are achieved, maintaining adequate immunosuppression. In many patients, higher peak concentrations (Cmax) and an increased exposure to the drug (AUC) may occur. In a small proportion of patients headache and paraesthesia may occur during transfer from SANDIMMUN to NEORAL, presumably related to higher exposure to ciclosporin.No additional adverse events, including renal dysfunction, however, were observed due to these changes in pharmacokinetic parameters during long-term treatment. In a small percentage of patients, these changes may be more marked and of clinical significance. Their magnitude depends largely on the individual ability to absorb ciclosporin from the originally used SANDIMMUN. In these patients, dose reduction should be undertaken to achieve the appropriate trough concentration range.

Long-term clinical data in renal transplant patients have demonstrated that a large proportion of patients previously on SANDIMMUN therapy can be maintained at the same dose of NEORAL as with SANDIMMUN.

All patients should be monitored according to the following recommendations:

a) Preconversion (i.e. on SANDIMMUN): Measure ciclosporin trough concentration, serum creatinine and blood pressure.

b) Day 1: Convert the patient to the same daily dose of NEORAL as was previously used with oral SANDIMMUN (i.e. on a mg to mg basis).

c) Day 4-7 post conversion: Follow-up visit to measure ciclosporin trough concentration, serum creatinine and blood pressure.

d) Subsequent follow-up: Depending on the findings on review at day 4-7, subsequent follow-up visits may need to be arranged (e.g. week 2 and week 4) in the first 12 week period after conversion to NEORAL. During these visits, ciclosporin trough concentrations, serum creatinine and blood pressure should be measured and dependent on these measurements the dose of NEORAL adjusted accordingly.

Further information on conversion can be obtained via the NEORAL Helpline (01276 698494)

Conversion of non-transplant (i.e. psoriasis, atopic dermatitis, rheumatoid arthritis, nephrotic syndrome) patients from SANDIMMUN Soft Gelatin Capsules or Oral Solution to NEORAL

Ciclosporin absorption from SANDIMMUN oral formulations is highly variable and the relationship between SANDIMMUN dose and ciclosporin exposure (AUC) is non-linear. In contrast with NEORAL the absorption of ciclosporin is less variable.

With equivalent doses following conversion from SANDIMMUN to NEORAL, higher peak concentrations (Cmax) and an increased exposure to the drug (AUC) may occur. In a small percentage of patients, these changes may be more marked and of clinical significance. Their magnitude depends largely on the individual ability to absorb ciclosporin from the originally used SANDIMMUN. Therefore, the clinical status of each patient should be assessed prior to initiating NEORAL therapy.

It is recommended that where any potential loss of efficacy results in considerable risk to the patients (e.g. rheumatoid arthritis), conversion from SANDIMMUN to NEORAL is on a mg for mg basis. In other patients, the lowest recommended starting dose of NEORAL is recommended initially with appropriate dose titration according to clinical response, serum creatinine and blood pressure levels.

All patients converting on a mg for mg basis should be monitored according to the following recommendations:-

a) Preconversion (i.e. on SANDIMMUN): Measure serum creatinine and blood pressure.

b) Day 1: Start the patient with the same daily dose of NEORAL as was previously used with oral SANDIMMUN (i.e. on a mg for mg basis).

c) Week 2: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

d) Week 4: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

e) Week 8: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

f) Week 12: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

If, on more than one measurement, the serum creatinine increases more than 30% above the pre-SANDIMMUN baseline, the dose of NEORAL should be decreased (see Section 4.4 Additional precautions for psoriasis, atopic dermatitis, rheumatoid arthritis and nephrotic syndrome sections).

Administration

The total daily dosage of NEORAL Soft Gelatin Capsules or NEORAL Oral Solution should always be given in two divided doses. NEORAL Soft Gelatin Capsules should be taken with a mouthful of water and should then be swallowed whole.

NEORAL Oral Solution should be diluted immediately before being taken. For improved taste the solution can be diluted with orange juice or squash or apple juice. However, it may also be taken with water if preferred. It should be stirred well.

NEORAL Oral Solution has a characteristic taste which is distinct to that of SANDIMMUN Oral Solution.

The measuring device should not come into contact with the diluent. The measuring device should not be rinsed with water, alcohol or any other liquid. If it is necessary to clean the measuring device, the outside should be wiped with a dry tissue.

Owing to its possible interference with the P450-dependent enzyme system, grapefruit or grapefruit juice should not be ingested for 1 hour prior to dose administration, and grapefruit juice should not be used as a diluent for the Oral Solution.

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 34 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.

Use in Children

There is currently no experience with NEORAL in young children. However, transplant recipients from three months of age have received ciclosporin at the recommended dosage with no particular problems although at dosages above the upper end of the recommended range children seem to be more susceptible to fluid retention, convulsions and hypertension. This responds to dosage reduction.

Known hypersensitivity to ciclosporin. NEORAL is contraindicated in psoriatic and atopic dermatitis patients with abnormal renal function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy other than that of the skin (see Section 4.4).

NEORAL is contraindicated in rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy.

NEORAL should not be used to treat rheumatoid arthritis in patients under the age of 18 years.

NEORAL is contraindicated in nephrotic syndrome patients with uncontrolled hypertension, uncontrolled infections, or any kind of malignancy.

Concomitant use of tacrolimus is specifically contraindicated.

Concomitant use of rosuvastatin is specifically contraindicated (see Section 4.5).

Precautions

Ciclosporin can impair renal function. Close monitoring of serum creatinine and urea is required and dosage adjustment may be necessary. Increases in serum creatinine and urea occurring during the first few weeks of ciclosporin therapy are generally dose-dependent and reversible and usually respond to dosage reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant recipients, must be distinguished from chronic rejection.

In elderly patients, renal function should be monitored with particular care.

Ciclosporin may also affect liver function and dosage adjustment, based on the results of bilirubin and liver enzyme monitoring, may be necessary.

Ciclosporin enhances the risk of hyperkalaemia, especially in patients with renal dysfunction. Caution is also required when ciclosporin is co-administered with potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) and potassium containing drugs as well as in patients on a potassium rich diet (see Section 4.5). Control of potassium levels in these situations is advisable.

Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peri-transplant period, particularly in the presence of neurological symptom/signs. If considered necessary, magnesium supplementation should be given.

Caution is required in treating patients with hyperuricaemia.

Ciclosporin increases the risk of malignancies including lymphomas, skin and other tumours. 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.

In view of the potential risk of skin malignancy, patients on NEORAL should be warned to avoid excess ultraviolet light exposure.

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.

There are differences in bioavailability between different oral formulations of ciclosporin, however NEORAL Soft Gelatin Capsules are bioequivalent to NEORAL Oral Solution.

Regular monitoring of blood pressure is required during treatment with ciclosporin. If hypertension develops, appropriate anti-hypertensive treatment must be instituted.

Ciclosporin can induce a reversible increase in blood lipids. It is therefore advisable to perform lipid determinations before treatment and thereafter as appropriate.

Ciclosporin may increase the risk of Benign Intracranial Hypertension. Patients presenting with signs of raised intracranial pressure should be investigated and if Benign Intracranial Hypertension is diagnosed, ciclosporin should be withdrawn due to the possible risk of permanent visual loss.

During treatment with ciclosporin, vaccination may be less effective; the use of live attenuated vaccines should be avoided.

Caution should be observed while co-administering lercanidipine with ciclosporin (see Section 4.5).

Additional precautions in psoriasis and atopic dermatitis (see also Section 4.2)

Careful dermatological and physical examinations, including measurements of blood pressure and renal function on at least two occasions prior to starting therapy should be performed to establish an accurate baseline status.

Development of malignancies (particularly of the skin) have been reported in psoriatic patients treated with ciclosporin as well as during treatment with conventional therapy. A search for all forms of pre-existing tumours, including those of the skin and cervix should be carried out. Skin lesions which are not typical for psoriasis should be biopsied before starting NEORAL treatment to exclude skin cancers, mycosis fungoides or other pre-malignant disorders. Patients with malignant or pre-malignant alterations of the skin should be treated with NEORAL only after appropriate treatment of such lesions and only if no other option for successful therapy exists.

Because of the possibility of renal dysfunction or renal structural changes, serum creatinine should be measured at two weekly intervals during the first three months of therapy. Thereafter, if creatinine remains stable, measurements should be made at monthly intervals. If serum creatinine increases and remains increased to more than 30% above baseline at more than one measurement, NEORAL dosage must be reduced by 25 to 50%. These recommendations apply even if the patient's values still lie within the laboratory's normal range. If dosage reduction is not successful in reducing levels within one month, NEORAL treatment should be discontinued.

In atopic dermatitis patients serum creatinine should be measured at two weekly intervals throughout the treatment period.

If hypertension develops which cannot be controlled by NEORAL dosage reduction or appropriate antihypertensive therapy, discontinuation of NEORAL is recommended.

Elderly patients should be treated only in the presence of disabling psoriasis or atopic dermatitis, and renal function should be monitored with particular care.

NEORAL treatment and its monitoring should be carried out under the supervision of a dermatologist experienced in the management of severe skin diseases.

The safety and efficacy of NEORAL has not been established for the treatment of psoriasis or atopic dermatitis in children and adolescents, and an appropriate dose has not been defined.

Patients on NEORAL should not receive concomitant therapeutic ultraviolet B irradiation or PUVA photochemotherapy.

Additional precautions in atopic dermatitis (see also Section 4.2)

Active Herpes simplex infections should be allowed to clear before initiating treatment with NEORAL but are not necessarily a reason for drug withdrawal if they occur during treatment unless infection is severe.

Skin infections with Staphylococcus aureus are not an absolute contra-indication for NEORAL therapy but should be controlled with appropriate antibacterial agents. Oral erythromycin, known to have the potential to increase the blood concentration of ciclosporin (see Section 4.5) should be avoided or, if there is no alternative, its concomitant use must be accompanied by close monitoring of the blood levels of ciclosporin.

Benign lymphadenopathy is commonly associated with flares in atopic dermatitis, and invariably disappears spontaneously or with general improvement in the disease. Lymphadenopathy observed on treatment with ciclosporin should be regularly monitored. Lymphadenopathy which persists despite improvement in disease activity should be examined by biopsy as a precautionary measure to ensure the absence of lymphoma.

Additional precautions in rheumatoid arthritis (see also Section 4.2)

Since ciclosporin can impair renal function, a reliable baseline level of serum creatinine should be established by at least two measurements prior to treatment, and serum creatinine should be monitored at 2 weekly intervals during the first 3 months of therapy. Thereafter, measurements can be made every 4 weeks, but more frequent checks are necessary when the NEORAL dose is increased or concomitant treatment with a non-steroidal anti-inflammatory drug is initiated or its dosage increased. Because the pharmacodynamic interaction between ciclosporin and NSAIDs may adversely affect renal function, caution should be exercised if NSAID therapy is to be continued.

If the serum creatinine remains increased by more than 30% above baseline at more than one measurement, the dosage of NEORAL should be reduced. If the serum creatinine increases by more than 50%, a dosage reduction by 50% is mandatory. These recommendations apply even if the patient's values still lie within the laboratory normal range. If dosage reduction is not successful in reducing levels within one month, NEORAL treatment should be discontinued.

Discontinuation of the drug may also become necessary if hypertension developing during NEORAL therapy cannot be controlled by appropriate antihypertensive therapy.

The combination of non-steroidal anti-inflammatory drugs and ciclosporin should be used with caution in patients with rheumatoid arthritis and should be accompanied by particularly close monitoring of renal function as detailed above. (Please also see Section 4.5 ).

As hepatotoxicity is a potential side effect of non-steroidal anti-inflammatory drugs, regular monitoring of hepatic function is advised when NEORAL is co-administered with these drugs in rheumatoid arthritis patients.

The use of ciclosporin therapy for the treatment of patients with rheumatoid arthritis requires careful monitoring and follow-up. NEORAL should only be used provided that the necessary expertise and adequate equipment, laboratory and supportive medical resources are available.

Patients with rheumatoid arthritis have an increased incidence of malignancies compared to the general population. Use of disease modifying drugs increases the risk of malignancy further. The use of ciclosporin in the treatment of rheumatoid arthritis has not been shown to increase the incidence of malignancies more than other disease-modifying drugs.

Special caution should be observed if NEORAL is used in combination with methotrexate.

Additional precautions in nephrotic syndrome: (see also Section 4.2)

Development of malignancies, (including Hodgkin's lymphoma) has occasionally been reported in nephrotic syndrome patients treated with ciclosporin, as well as during treatment with other immunosuppressive agents. However, malignancy may be related to the pathogenesis of the disease.

Since ciclosporin can impair renal function, it is necessary to assess renal function frequently and if the serum creatinine remains increased by more than 30% above baseline at more than one measurement, to reduce the dosage of NEORAL by 25-50%. Patients with abnormal baseline renal function are at higher risk. They should initially be treated with 2.5mg/kg per day orally and must be monitored very carefully.

In some patients it may be difficult to detect NEORAL-induced renal dysfunction because of changes in renal function related to the underlying renal disease. If NEORAL is indicated for more than one year in the long-term management, then renal biopsies should be performed at 1 yearly intervals to assess the progression of the renal disease and the extent of any NEORAL-associated changes in the renal morphology that may co-exist.

The use of NEORAL therapy for the treatment of patients with nephrotic syndrome requires careful monitoring and follow-up. NEORAL should only be used provided that the necessary expertise and adequate equipment, laboratory and supporting medical resources are available.

Food interactions

The concomitant intake of grapefruit juice has been reported to increase the bioavailability of ciclosporin.

Drug interactions

Of the many drugs reported to interact with ciclosporin, those for which the interactions are adequately substantiated and considered to have clinical implications are listed below.

Various agents are known to either increase or decrease plasma or whole blood ciclosporin levels usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular CYP3A4. 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.

Drugs that decrease ciclosporin levels:

Barbiturates, carbamazepine, oxcarbazepine, phenytoin; rifampicin, octreotide, orlistat, hypericum perforatum (St John's Wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase ciclosporin levels:

Macrolide antibiotics (e.g. erythromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high dose); allopurinol; amiodarone; ursodeoxycholic acid; protease inhibitors, imatinib; colchicine.

Other relevant drug interactions

Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); non-steroidal anti-inflammatory drugs (including diclofenac, naproxen, sulindac); melphalan, methotrexate (see Section 4.4).

Concomitant use with tacrolimus should be avoided due to increased potential for nephrotoxicity.

The concurrent administration of nifedipine with ciclosporin may result in an increased rate of gingival hyperplasia compared with that observed when ciclosporin is given alone.

Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased threefold and the AUC of ciclosporin was increased 21%. Therefore caution is recommended when co-administering ciclosporin together with lercanidipine (see Section 4.4).

The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its first-pass effect. If non-steroidal anti-inflammatory drugs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.

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

Severe digitalis toxicity has been seen within days of starting ciclosporin in several patients taking digoxin.

Administration of ciclosporin may enhance the potential of HMG-CoA reductase inhibitors (statins) and colchicine to induce muscular toxicity e.g. muscle pain and weakness, myositis and occasionally rhabdomyolysis. If ciclosporin is to be concomitantly administered with a statin then the prescriber should refer to the product information for the relevant statin as the dose may need to be reduced. Rosuvastatin is specifically contraindicated with ciclosporin (see Section 4.3).

Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus and sirolimus.

Caution is required for concomitant use of potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium containing drugs since they may lead to significant increases in serum potassium (see Section 4.4).

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

Recommendations

If the concomitant use of drug known to interact with ciclosporin cannot be avoided, the following basic recommendations should be observed.

During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered drug should be reduced or alternative treatment considered.

In graft recipients there have been isolated reports of considerable but reversible impairment of kidney function (with corresponding increase in serum creatinine) following concomitant administration of fibric acid derivatives (e.g. bezafibrate, fenofibrate). Kidney function must therefore be closely monitored in these patients. In the event of significant impairment of kidney function the co-medication should be withdrawn.

Drugs known to reduce or increase the bioavailability of ciclosporin: in transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment are required, particularly during the introduction or withdrawal of the co-administered drug. In non-transplant patients the value of ciclosporin blood level monitoring is questionable, as in these patients the relationship between blood level and clinical effect is less well established. If drugs known to increase ciclosporin levels are given concomitantly, frequent assessment of renal function and careful monitoring for ciclosporin related side-effects may be more appropriate than blood level measurement.

The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of ciclosporin.

Non-steroidal anti-inflammatory drugs known to undergo strong first-pass metabolism (e.g. diclofenac) should be given at doses lower than those that would be used in patients not receiving ciclosporin. When diclofenac is given concomitantly with ciclosporin the dose of diclofenac should be reduced by approximately half (see Section 4.2).

If digoxin, colchicine or HMG-CoA reductase inhibitors (statins) are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the drugs, followed by reduction of its dosage or its withdrawal.

Ciclosporin is not teratogenic in animals. There is currently no clinical experience with NEORAL and experience with SANDIMMUN is still limited. However data available from organ transplant recipients indicate that, compared with other immunosuppressive agents, ciclosporin treatment imposes no increased risk of adverse effects on the course and outcome of pregnancy. However there are no adequate and well controlled studies in pregnant women, therefore ciclosporin should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Ciclosporin passes into breast milk. Mothers receiving treatment with ciclosporin should not therefore breast-feed their infants.

No data exists on the effects of NEORAL on the ability to drive and use machines.

Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction. In the various indications the overall spectrum of side effects is essentially the same; there are, however, differences in incidence and severity. As a consequence of the higher initial doses and longer maintenance therapy required after transplantation, side effects are more frequent and usually more severe in transplant patients than in patients treated for other indications.

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.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

The increased risk of developing malignancies and lymphoproliferative disorders (including lymphomas), some with reported fatalities, appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents (refer to Section 4.4). The most frequently observed neoplasms during long-term post-marketing surveillance were:

Common: Skin papillomas, basal cell carcinoma, squamous cell carcinoma of skin, Bowen's disease, lymphoproliferative disorders.

Uncommon: Seborrhoeic keratosis, melanoma, squamous cell carcinoma.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: 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), including isolated reports.

Table 1

No experience of acute overdosage with NEORAL is available and little experience is available with regards to overdosage with SANDIMMUN. Symptomatic treatment and general supportive measures should be followed in all cases of overdosage. Forced emesis could be of value within the first few hours after intake. Signs of nephrotoxicity might occur which should be expected to resolve following drug withdrawal. Ciclosporin is not dialysable to any great extent nor is it well cleared by charcoal haemoperfusion. Hypertension and convulsions have been reported in some patients receiving ciclosporin therapy at doses above the recommended range and in others with high trough blood levels of ciclosporin. This might therefore, be expected as a feature of overdosage.

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

Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide consisting of 11 amino acids. It is a potent immunosuppressive agent which prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, cornea, bone marrow, small intestine and lung in animals.

Successful solid organ and bone marrow allogeneic transplants have been performed in man, using ciclosporin to prevent and treat rejection and GVHD. Marked beneficial effects of ciclosporin therapy have also been shown in patients with severe psoriasis, atopic dermatitis, rheumatoid arthritis and nephrotic syndrome, conditions that may be considered to have an immunological mechanism.

Studies in animals suggest that ciclosporin inhibits the development of cell mediated reactions. It appears to block the resting lymphocytes in the G₀ or early G₁ phase of the cell cycle, and also inhibits lymphokine production and release, including interleukin 2 (T cell growth factor, TCGF). The available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. It does not depress haemopoiesis and has no effect on the function of phagocytic cells.

NEORAL is an improved pharmaceutical form of the active ingredient ciclosporin. NEORAL is a pre-concentrate formulation of ciclosporin which undergoes a microemulsification process in the presence of water, either in the form of a beverage or in the form of the gastrointestinal fluid. NEORAL reduces the intra-patient variability of pharmacokinetic parameters, with a more consistent absorption profile and less influence of concomitant food intake and the presence of bile. In pharmacokinetic and clinical studies it has been demonstrated that the correlation between trough concentration (Cmin) and total exposure (AUC) is significantly stronger when ciclosporin is given as NEORAL than when it is given as SANDIMMUN. NEORAL therefore allows greater predictability and consistency of ciclosporin exposure.

The data available indicate that following a 1:1 conversion from SANDIMMUN Soft Gelatin Capsules and SANDIMMUN Oral Solution to NEORAL, trough concentrations in whole blood are comparable, thereby remaining in the desired therapeutic trough level range. Compared to oral administration of SANDIMMUN (with which peak blood concentrations are achieved within 1 to 6 hours), NEORAL is more quickly absorbed (resulting in a 1 hour earlier mean t_max and a 59% higher mean C_max) and exhibits, on average, a 29% higher bioavailability. In a clinical trial involving maintained renal transplant patients the correlation (r²) between trough concentration (C_min) and exposure (AUC) was good (0.8).

Ciclosporin is distributed largely outside the blood volume. In the blood, 33-47% is present in plasma, 4-9% in lymphocytes, 5-12% in granulocytes, and 41-58% in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.

Ciclosporin is extensively biotransformed to approximately 15 metabolites. There is no single major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine, only 0.1% is excreted in the urine as unchanged drug.

There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the assay applied and the target population. The terminal half-life ranged from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease.

Ciclosporin gave no evidence of mutagenic or teratogenic effects in appropriate test systems. Only at dose levels toxic to dams were adverse effects seen in reproduction studies in rats. At toxic doses (rats at 30mg/kg and rabbits at 100mg/kg a day orally), ciclosporin was embryo- and fetotoxic as indicated by increased prenatal and post-natal mortality and reduced fetal weight together with related skeletal retardation. In the well-tolerated dose range (rats up to 17mg/kg and rabbits up to 30mg/kg a day orally), ciclosporin proved to be without any embryolethal or teratogenic effects.

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16mg/kg a day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study conducted at 0.5, 2 and 8mg/kg a day, pancreatic islet cell adenomas significantly exceeded the control rate at the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose-related.

No impairment in fertility was demonstrated in studies in male and female rats.

Ciclosporin has not been found mutagenic/genotoxic in the Ames test, the V79-HGPRT test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA repair test in sperm from treated mice. A study analysing sister chromatid exchange (SCE) induction by ciclosporin using human lymphocytes in vitro gave indication of a positive effect (i.e. induction of SCE) at high concentrations in this system.

An increased incidence of malignancy is a recognised complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin. The risk of malignancies during ciclosporin treatment is higher than in the normal, healthy population, but similar to that in patients receiving other immunosuppressive therapies. It has been reported that reduction or discontinuance of immunosuppression may cause lesions to regress.

Soft gelatin capsules

DL-α-tocopherol, absolute ethanol, propylene glycol, corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil.

Capsule shell

Iron oxide black (25- and 100-mg capsules), titanium dioxide, glycerol 85%, propylene glycol, gelatin.

Solution

DL-α-tocopherol, absolute ethanol, propylene glycol, corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil.

None known.

Soft gelatin capsules 36 months

Solution 36 months

NEORAL Soft Gelatin Capsules should be stored below 25°C.

NEORAL Soft Gelatin Capsules should be left in the blister pack until required for use. When a blister is opened, a characteristic smell is noticeable.

NEORAL Oral Solution should be stored below 30°C (preferably not below 15°C, as it contains oily components of natural origin which tend to solidify at low temperatures). A jelly-like formation may occur below 20°C which is however reversible at temperatures up to 30°C. Minor flakes or a slight sediment may still be observed. These phenomena do not affect the efficacy and safety of the product, and the dosing by means of the measuring device remains accurate.

NEORAL Soft Gelatin Capsules are available in 6 x 5 and 10 x 6 (10mg only) blister packs of double-sided aluminium consisting of an aluminium bottom foil and an aluminium covering foil.

NEORAL Oral Solution is available in 50mL amber glass bottles with an aluminium cap and rubber stopper. A dispenser set is also provided.

Initial use of NEORAL Oral Solution

1. Raise the plastic cap.

2. Tear off the sealing ring completely.

3. Remove the black stopper and throw it away.

4. Push the tube unit with the white stopper firmly into the neck of the bottle

5. Insert the syringe into the white stopper

6. Draw up prescribed volume of solution

7. Expel any large bubbles by depressing and withdrawing plunger a few times before removing syringe containing prescribed dose from bottle. The presence of a few tiny bubbles is of no importance and will not affect the dose in any way.

8. After use, wipe syringe on outside only with a dry tissue and replace in its case. Dispose of the tissue carefully. White stopper and tube should remain in bottle. Close bottle with cap provided.

Subsequent use

Commence at point 5.

Novartis Pharmaceuticals UK Ltd

Trading as: Sandoz Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

NEORAL Soft Gelatin Capsules 10mg: PL 00101/0483

NEORAL Soft Gelatin Capsules 25mg, 50mg and 100mg:

PL 00101/0387-0389

NEORAL Oral Solution: PL 00101/0390

PL 00101/0483. 3 April 1998

PL 00101/0387 27 March 1995 / 27 June 2001

PL 00101/0388 27 March 1995/ 27 June 2001

PL 00101/0389 27 March 1995 / 27 June 2001

PL 00101/0390. 27 March 1995 / 24 July 2001.

21 May 2009

Legal Category : POM