Novartis Pharmaceuticals UK Ltd

Known hHypersensitivity to ciclosporin or to any of the other excipients of NEORAL. 

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 Ssection 4.4).

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

Precautions

NEORAL should be prescribed only by physicians who are experienced in immunosuppressive therapy, and can provide adequate follow-up, including regular full physical examination, measurement of blood pressure, and control of laboratory safety parameters. Transplantation patients receiving the drug should be managed in facilities with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should receive complete information for the follow-up of the patient.

Like other immunosuppressants, Cciclosporin increases the risk of developing lymphomas and other malignancies including lymphomas, particularly those of the 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, in particular those treated for psoriasis or atopic dermatitis, should be warned to avoid excess unprotected sun ultraviolet light exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

Like other immunosuppressants, Cciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections with a variety of pathogens including bacteria, parasites, viruses and other often with 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.

Ciclosporin can impair renal function.  Close monitoring of serum creatinine and urea is required and dosage adjustment may be necessary. A frequent and potentially serious complication, an  Iincreases in serum creatinine and urea may occurring during the first few weeks of ciclosporin NEORAL therapy. These functional changes are generally dose-dependent and reversible, and usually responding to dosage reduction.  During long-term treatment, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant recipientspatients, must be distinguished differentiated from changes due to chronic rejection.  Ciclosporin NEORAL may also cause dose-dependent, reversible increases in serum bilirubin and, occassionally, in liver enzymes (see section 4.8).affect liver function and dosage adjustment, based on the results of bilirubin and liver enzyme monitoring, may be necessary. There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.8). Close monitoring of parameters that assess renal and hepatic function is required. Abnormal values may necessitate dose reduction.

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

For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent drug) is preferred; a HPLC method, which also measures the parent drug, can be used as well. If plasma or serum is used, a standard separation protocol (time and temperature) should be followed. For the initial monitoring of liver transplant patients, either the specific monoclonal antibody should be used, or parallel measurements using both the specific monoclonal antibody and the nonspecific monoclonal antibody should be performed, to ensure a dosage that provides adequate immunosuppression.

It must be remembered that the ciclosporin concentration in blood, plasma, or serum is only one of many factors contributing to the clinical status of the patient. Results should therefore serve only as a guide to dosage in relationship to other clinical and laboratory parameters.

Regular monitoring of blood pressure is required during treatment with NEORAL therapyciclosporin.; Iif hypertension develops, appropriate anti-hypertensive treatment must be instituted.

Since, on rare occasions, NEORALCiclosporin has been reported to can induce a reversible slight increase in blood lipids.,  Iit is therefore advisable to perform lipid determinations before treatment and thereafter as appropriateafter the first month of therapy. In the event of increased lipids being found, restriction of dietary fat and, if appropriate, a dose reduction, should be considered.

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.

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 Ssection 4.5).

Ciclosporin may increase blood levels of concomitant medications that are substrates of P-glycoprotein (Pgp) such as aliskiren (see section 4.5).

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.

NEORAL contains Polyoxyl 40 hydrogenated castor oil which may cause stomach upsets and diarrhoea.

NEORAL oral formulations contain around 12% vol. ethanol. A 500 mg dose of  NEORAL contains 500 mg of ethanol equivalent to nearly 15 ml of beer or 5 ml of wine. This may be harmful in  alcoholic patients and should be taken into account in pregnant or breast feeding women, in patients presenting with liver disease or epilepsy, or if the medicine is being given to a child.

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

Additional precautions in non-transplant indications

Patients with impaired renal function (except in nephrotic syndrome patients with a permissible degree of renal impairment), uncontrolled hypertension, uncontrolled infections, or any kind of malignancy should not receive ciclosporin.

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

Since ciclosporin NEORAL 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 -to 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 nephrotic syndrome itself. 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. This explains why, in rare cases, NEORAL-associated structural kidney alterations have been observed without increases in serum creatinine. Renal biopsy should be considered for patients with steroid-dependent minimal-change nephropathy, in whom NEORAL therapy has been maintained for more than 1 year.

In patients with nephrotic syndrome treated with immunosuppressants (including ciclosporin), the occurrence of malignancies (including Hodgkin's lymphoma) has occasionally been reported.

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.

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.

Additional precautions in rheumatoid arthritis (see also Section 4.2)

Since ciclosporin NEORAL 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. and  Tthereafter once a month., measurements can be made every 4 weeks, but After 6 months of therapy, serum creatinine needs to be measured every 4 to 8 weeks depending on the stability of the disease, its co medication, and concomitant diseases. mMore 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 Ssection 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.

As with other long-term immunosuppressive treatments (including ciclosporin), an increased risk of lymphoproliferative disorders must be borne in mind. Special caution should be observed if NEORAL is used in combination with methotrexate.

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.

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. 

Since NEORAL 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 for the first 3 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, the dosage of 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.

If hypertension develops which cannot be controlled by NEORAL dosage reduction or appropriate antihypertensive therapy, discontinuation of NEORAL is recommended. Discontinuation of NEORAL therapy is also recommended if hypertension developing during NEORAL treatment cannot be controlled with appropriate therapy.

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

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.There is only limited experience with the use of  NEORAL  in children with psoriasis.

In psoriatic patients on ciclosporin, as in those on conventional immunosuppressive therapy, Ddevelopment of malignancies (in particularly of the skin) haves 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, but suspected to be malignant or pre-malignant should be biopsied before starting NEORAL treatment is startedto 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.

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

In a few psoriatic patients treated with NEORAL, lymphoproliferative disorders have occurred. These were responsive to prompt drug discontinuation.

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

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

Additional precautions in 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.

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. 

Since NEORAL 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 for the first 3 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, the dosage of 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.Discontinuation of NEORAL therapy is also recommended if hypertension developing during NEORAL treatment cannot be controlled with appropriate therapy.

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.The experience with NEORAL in children with atopic dermatitis is limited.

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

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.

Active Herpes simplex infections should be allowed to clear before initiating treatment with NEORAL is initiated, but isare 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 Ssection 4.5) should be avoided or, if there is no alternative, it is recommended to closely monitor blood levels of ciclosporin, renal function, and for side effects of ciclosporin.its concomitant use must be accompanied by close monitoring of the blood levels of ciclosporin.

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

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

Paediatric use in non-transplant indications

Except for the treatment of nephrotic syndrome, there is no adequate experience available with NEORAL; its use in children under 16 years of age for nontransplant indications other than nephrotic syndrome cannot be recommended.

Drugs that decrease ciclosporin levels:

Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine i.v.; rifampicin, octreotide, probucol, orlistat, hypericum perforatum (St John’s Wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase ciclosporin levels:

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

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, histamine H2-receptorantagonists (e.g. cimetidine, ranitidine); methotrexate (see Ssection 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 Ssection 4.4).

Ciclosporin is a highly potent Pgp inhibitor and may increase blood levels of concomitant medications that are substrates of Pgp such as aliskiren. Following concomitant administration of ciclosporin and aliskiren, the Cmax of aliskiren was increased by approximately 2.5 fold and the AUC by approximately 5 fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered. Caution is recommended when co-administering ciclosporin together with aliskiren (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. There are also reports on the potential of ciclosporin to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine is used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage or its withdrawal.

Literature and post marketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of ciclosporin with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely, fluvastatin. When concurrently administered with ciclosporin, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis.

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).

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 Ssection 4.4).

Drugs known to reduce or increase the bioavailability of ciclosporin: in transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment areis 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 Ssection 4.2).

Pregnancy

Animal studies have shown reproductive toxicity in rats and rabbits.

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. 

Experience with NEORAL in pregnant women is limited. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin containing regimens, are at risk of premature delivery (<37 weeks).

A limited number of observations in children exposed to ciclosporin in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.

However there are no adequate and well controlled studies in pregnant women and, therefore ciclosporin NEORAL should not be used during pregnancy unless only if the potential benefit to the mother justifies the potential risk to the foetus.

            Lactation

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

Infections and infestations:

Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, as well as other immunosuppressive regimens are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Ssection 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.

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

Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin containing regimens, are at The increased risk of developing lymphomas malignancies and or lymphoproliferative disorders and other malignancies(including lymphomas), particularly of the skin., some with reported fatalities, The frequency of malignancies increases with appears to be related to the intensity degree and duration of therapy immunosuppression rather than to the use of specific agents (refer see to Ssection 4.4). Some malignancies may be fatal. The most frequently observed neoplasms during long-term post-marketing surveillance were:

Other adverse drug reactions from post-marketing experience

There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.4).

The oral LD₅₀ of ciclosporin is 2,329 mg/kg in mice, 1,480 mg/kg in rats and > 1,000 mg/kg in rabbits. The i.v. LD₅₀ is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

Symptoms

No eExperience of with acute overdosage of ciclosporin with NEORAL is limitedavailable and little experience is available with regards to overdosage with SANDIMMUN.  Oral doses of ciclosporin of up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with ciclosporin in premature neonates.

Treatment

In all cases of overdosage, Symptomatic treatment and general supportive measures should be followed and symptomatic treatment applied in all cases of overdosage.  Forced emesis and gastric lavage may could be of value within the first few hours after oral 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.

Section 6.3 for Capsules Only, the shelf life has been changed from 36 to 24 months.

Section 6.5 and 6.6 has been changed for Oral Solution only as follows:

Section 6.5
NEORAL Oral Solution is available in 20mL and 50mL amber glass bottles with an aluminium cap and rubber stopper.  A dispenser set is also provided. NEORAL Oral Solution is available in 20 mL and 50 mL brown glass bottles with a rubber stopper and aluminium tear-off cap. The tear-off cap indicates if the bottle has been previously opened. A white polypropylene cap is provided for closure of the bottle during the in-use period. A dispenser set is also provided with two different syringe sizes (1 mL and 4 mL, each in its own plastic case) for administration of the appropriate dose. The 1-mL syringe is used to measure doses less than or equal to 1 mL (each graduation of 0.05 mL corresponds to 5 mg of ciclosporin). The 4-mL syringe is used to measure doses greater than 1 mL and up to 4 mL (each graduation of 0.1 mL corresponds to 10 mg of ciclosporin).

Not all pack sizes may be marketed.

Section 6.6

    Initial use of NEORAL Oral Solution

                        1.         Raise the flap in centre of the plastic capmetal sealing ring.

                        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.         Choose the syringe depending on the prescribed volume. For volume less than 1 mL or equal to 1 mL, use the 1-mL syringe. For volume greater than 1 mL, use the 4-mL syringe. Insert the nozzle of the syringe into the white stopper.

6.         Do not withdraw the dose from an inverted or tilted bottle. Make sure the bottle is in an upright position. Draw up prescribed volume of solution (position the lower part of the plunger ring in front of the graduation corresponding to the prescribed volume).

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.         Push the medicine out of the syringe into a small glass with some liquid, but no grapefruit juice. Avoid any contact between the syringe and the liquid in the glass. The medicine can be mixed just before it is taken. Once mixed it should be taken immediately after preparation.

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

            Subsequent use

            Commence at point 5.

Any unused product or waste material should be disposed of in accordance with local requirements.

4.2       Posology and method of administration

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.

New paragraph added within section as below in blue:

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).

Conversion between oral ciclosporin formulations

Switching from one oral ciclosporin formulation to another should be made with caution and under specialist supervision. The introduction of the new formulation must be made with monitoring of blood levels of ciclosporin to ensure that pre-conversion levels are attained.

Administration

The total daily dosage of NEORAL Soft Gelatin Capsules 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.

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