Deximune 25 mg soft capsules

Deximune 50 mg soft capsules

Deximune 100 mg soft capsules

Each soft capsule contains 25 mg, 50 mg or 100 mg Ciclosporin.

For full list of excipients, see Section 6.1

Capsule, soft

Deximune 25mg soft capsules are gray soft gelatin capsules with imprinting 'DX 25 mg'.

Deximune 50 mg soft capsules are gray soft gelatin capsules with imprinting 'DX 50 mg'.

Deximune 100 mg soft capsules are gray soft gelatin capsules with imprinting 'DX 100 mg'.

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

Deximune Capsules are indicated in patients with severe psoriasis in whom conventional therapy is ineffective or inappropriate.

Atopic Dermatitis

Deximune Capsules are indicated for short term treatment (8 weeks) of patients with severe atopic dermatitis in whom conventional therapy is ineffective or inappropriate.

Rheumatoid Arthritis

Deximune Capsules are indicated for the treatment of severe, active rheumatoid arthritis in patients in whom classical slow-acting anti-rheumatic agents are inappropriate or ineffective.

Nephrotic Syndrome

Deximune Capsules are indicated in the treatment of adults and children with steroid-dependent and steroid-resistant nephrotic syndrome owing to glomerular diseases such as minimal change nephropathy, focal segmental glomerulosclerosis or membranous glomerulonephritis.

Deximune Capsules can be used to induce remissions and for maintenance treatment.

Recommended Dosage Schedule

Due to differences in bioavailability between different oral formulations of ciclosporin it is important that health professionals and patients be aware that substitution of Deximune Capsules for other formulations may lead to alterations in ciclosporin blood levels.

Therefore patients should not be transferred to or from other oral formulations of ciclosporin without appropriate close monitoring of ciclosporin blood concentrations, serum creatinine levels and blood pressure.

Transplantation Dosage

Organ Transplantation

Initially, a dose of 10 to15 mg/kg body weight in two divided doses should be given within twelve hours before transplantation. As a general rule, treatment should continue at a dose of 10 to 15 mg/kg/day in two divided doses for one to two weeks post-operatively. Dosage should then be gradually reduced until a maintenance dose of 2 to 6mg/kg/day is reached. This total daily dose should be given in two divided doses. Dosage should be adjusted by monitoring ciclosporin blood levels and kidney function. When Deximune Capsules are given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy) lower doses (e.g. 3 to 6 mg/kg/day in two divided doses orally initially) may be used.

Bone Marrow Transplantation/Prevention and Treatment of Graft-Versus-Host Disease (GVHD)

Maintenance treatment with Deximune Capsules should continue using the oral forms at a dosage of 12.5 mg/kg/day 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 Deximune Capsules until a year after bone marrow transplantation. Higher oral doses or the use of I.V. ciclosporin therapy may be necessary in the presence of gastrointestinal disturbances which might decrease absorption.

If oral treatment is used to initiate therapy, the recommended dose is 12.5 to 15 mg/kg/day in two divided doses starting on the day before transplantation.

If GVHD develops after Deximune Capsules are withdrawn, it should respond to re-institution of therapy. Low doses should be used for mild, chronic GVHD.

Non-transplantation dosage

Psoriasis

Refer also to "Additional Precautions in Psoriasis" in Section 4.4.

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

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

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

Atopic Dermatitis

Refer also to "Additional Precautions in Atopic Dermatitis" in Section 4.4.

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

Once satisfactory response is achieved, the dose should be reduced gradually and if possible, Deximune Capsules should be discontinued. Subsequent relapse may be managed with a further course of treatment. Although a course of 8 weeks therapy may be sufficient to achieve clearing, up to one years' therapy with ciclosporin has been shown to be effective and well tolerated, provided the monitoring guidelines are followed.

Rheumatoid Arthritis

Refer also to "Additional Precautions in Rheumatoid Arthritis" in Section 4.4.

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

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.

Deximune Capsules can be given in combination with low-dose corticosteroids and/or non-steroidal anti-inflammatory drugs. Pharmacodynamic interactions can occur between ciclosporin and NSAIDs and therefore this combination should be used with care (see "Additional Precautions in Rheumatoid Arthritis" in Section 4.4 and “Interactions with other medicinal products and other forms of interactions” in 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 to "Additional Precautions in Nephrotic Syndrome" in Section 4.4.

To induce remission, the recommended dose is 5 mg/kg/day given orally in two divided doses for adults, and 6 mg/kg/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 2.5 mg/kg/day orally.

In focal segmental glomerulosclerosis, the combination of ciclosporin and corticosteroids may be of benefit.

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

The doses need to be adjusted individually according to efficacy (proteinuria) and safety (primarily serum creatinine), but should not exceed 5 mg/kg/day orally in adults or 6 mg/kg/day orally in children.

For maintenance treatment, the dose should be slowly reduced 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.

Administration

The total daily dosage should always be given in two divided doses. Deximune Capsules can be taken with or without food and should be taken with a mouthful of water and should be swallowed whole.

Ciclosporin should not be taken with grapefruit or grapefruit juice for 1 hour prior to dose administration (see Section 4.5).

Use in the Elderly

Experience with ciclosporin 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.

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

Experience with ciclosporin in young children is still limited. 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 or to any of the excipients.

Deximune is also contraindicated in psoriatic and atopic dermatitis patients with abnormal renal function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy other than of the skin (see Section 4.4).

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

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

Deximune is contra-indicated 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).

Herbal preparations containing St. John's Wort (hypericum perforatum) must not be used while taking Deximune Capsules due to the risk of decreased plasma concentrations and reduced clinical effects of Deximune Capsules (see Section 4.5).

Precautions

Only physicians experienced in management of systemic immunosuppresive therapy for the indicated disease should prescribe Deximune. Because of the doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and organ transplant recipients should prescribe Deximune. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information necessary for the follow-up of the patient.

In all patients treated with ciclosporin, renal and liver functions should be assessed repeatedly by measurement of serum creatinine, urea, bilirubin, and liver enzymes. Serum lipids, magnesium, and potassium should also be monitored. Ciclosporin blood concentrations should be routinely monitored in transplant patients, and periodically monitored in rheumatoid arthritis patients.

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 (eg. 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.

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 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.

Ciclosporin should preferably not be administered with other immunosuppressive agents except corticosteroids. However, some transplant centres use ciclosporin together with azathioprine and corticosteroids or other immunosuppressive agents (all in low doses) with the aim of reducing the risk of ciclosporin-induced renal dysfunction or renal structural changes. When ciclosporin is used with other immunosuppressive agents, there is a risk of over-immunosuppression, which can lead to increased susceptibility to infection and to possible development of lymphoma.

In view of the potential risk of skin malignancy, patients using ciclosporin 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.

Regular monitoring of blood pressure is required during treatment with ciclosporin. If hypertension develops, appropriate antihypertensive treatment must be instituted. If hypertension develops which cannot be controlled by Deximune dosage reduction or appropriate antihypertensive therapy, discontinuation of the drug is recommended.

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 are 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.

Since, on rare occasions, ciclosporin has been reported to induce a reversible slight increase in blood lipids, it is advisable to perform lipid determinations before treatment and after 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 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.

Caution is required in treating patients with hyperuricaemia because ciclosporin can aggravate this condition (see Section 4.8).

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 or repaglinide with ciclosporin (see Section 4.5).

After renal transplantation, ciclosporin has been associated with an increased risk of unilateral or bilateral, but benign, breast fibroadenomas (See Section 4.8).

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.

Additional Precautions in Psoriasis and Atopic Dermatitis (see also Section 4.2)

Deximune treatment and its monitoring should be carried out under the supervision of a dermatologist experienced in the management of severe skin diseases. Only the oral forms of ciclosporin are recommended for the treatment of patients with psoriasis or atopic dermatitis.

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 Deximune 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 Deximune 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, Deximune dosage must be reduced by 25 to 50%. The 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, Deximune 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 Deximune dosage reduction or appropriate antihypertensive therapy, discontinuation of the drug 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.

In view of the potential risk of skin malignancy, patients on Deximune should be warned to avoid excess unprotected sun exposure and 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 Deximune 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 contraindication for Deximune 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.

As experience with ciclosporin in children with atopic dermatitis is still limited, its use in children under 16 years of age cannot be recommended.

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 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 dose by 25-50%. Patients with abnormal baseline renal function are at higher risk, they should initially be treated with 2.5mg/kg/day orally and must be controlled very carefully.

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

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 Deximune 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 Deximune 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, Deximune treatment should be discontinued.

Discontinuation of the drug may also become necessary if hypertension developing during Deximune 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 Deximune 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. Deximune 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 Deximune is used in combination with methotrexate.

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 co-medications 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, probucol, and intravenous sulphadimidine.

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; 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, histamine H2-receptor antagonists (e.g. cimetidine, ranitidine), 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 eg 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 of ciclosporin. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Coadministration of ciclosporin significantly increases blood levels of everolimus and sirolimus.

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

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).

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, as the concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, most probably caused by a reduction of its first-pass effect. When diclofenac is given concomitantly with ciclosporin the dose of diclofenac should be reduced by approximately half (see section 4.2 Posology & Administration).

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.

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

Ciclosporin does not demonstrate teratogenicity in experimental animals. Limited experience regarding the safety of administration of ciclosporin to pregnant women has shown no indications of teratogenicity. Ciclosporin does pass into the placenta. Initial experience with transplantation patients, however, did indicate that ciclosporin, as with other immunosuppressive agents, increases the probability of specific complications during pregnancy, such as pre-eclampsia and premature births with decreased birth weights. Ciclosporin should only be given in pregnancy when the benefits outweigh the risks. Pregnant women who are being treated with ciclosporin should be observed carefully.

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

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

a). Summary of the safety profile

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. Serious and/or fatal outcomes have been reported. The most common infections observed during long-term post-marketing surveillance of solid-organ transplant patients, occurring in 1 case per 10 patients or more, were lower respiratory tract infection including cases of bronchiolitis, urinary tract infection, cytomegalovirus infection, upper respiratory tract infection. Sepsis, herpes infections, and candidal infection occurred in less than 1 case per 10 patients.

There is an increased risk of developing malignancies and lymphoproliferative disorders (including lymphomas), some with reported fatalities that appear 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, occurring in less than 1 case per 10 patients were: skin papillomas, basal cell carcinoma, squamous cell carcinoma of skin, Bowen's disease, and lymphoproliferative disorders. Seborrheric keratosis, melanoma and squamous cell carcinoma occurred less frequently (less than 1 case per 100 patients).

Additionally, the most commonly reported adverse reactions during treatment are hyperlipidaemia, hypercholesterolaemia, tremor, headache, hypertension and renal dysfunction (see Section 4.4), which may occur in 1 case per 10 patients or more. Hepatic dysfunction has also been observed (occurring in less than 1 case per 10 patients).

b). Tabulated summary of adverse reactions

Adverse reactions (Table 1) are ranked under headings 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; not known (cannot be estimated from the available data).

Table 1

* Observed following renal transplantation.

c). Description of selected adverse reactions

Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction (refer to Section 4.2). 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. Refer to Section 4.4 for information about measures to be taken to avoid or minimise these reactions and Section 4.5 for information about reactions resulting from interactions with other medicines.

d). Paediatric population

Limited information is available regarding ciclosporin use in children. In general, the frequency, type and severity of adverse reactions in children are expected to be the same as in adults, although at dosages above the upper end of the recommended range, children seem to be more susceptible to fluid retention, convulsions and hypertension (see Section 4.2 – Use in Children).

Little experience is available with overdosage. 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 would 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: Calcineurin inhibitors (ATC code L04A D01).

Ciclosporin A is a cyclic undecapeptide with immunosuppressant properties. Studies suggest that ciclosporin A inhibits the development of cell-mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-versus-host disease and also T-cell dependent antibody production. It also inhibits lymphokine production and release, including interleukin 2 or T-cell growth factor (TCGF). Ciclosporin appears to block the resting lymphocytes in the G0 or G1 phase of the cell cycle.

All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents it does not depress haemopoieisis and has no effect on the function of phagocytic cells.

The maximal blood concentration (Cmax) is achieved within 1-2 hours (Tmax). The absolute bioavailability is ~30%. The inter- and intra-individual pharmacokinetic variability is 10-20% for AUC and Cmax in healthy volunteers.

Bioequivalence studies under both fasting and fed conditions were performed to compare the pharmacokinetic parameters of Deximune and the originator product, as follows:

1. A randomised, two-way cross-over study in 24 healthy male volunteers under fasting conditions.

The results of the study are presented in Table 1 below:

Table1 Pharmacokinetic parameters - fasting conditions

All pharmacokinetic parameters presented are mean (SD) values

¹ Geometric means of the individual ratios and 90% parametric CI

² Median Difference and 90% non parametric CI

2. A randomised, two-way cross-over study in 39 healthy male volunteers under fed conditions. The volunteers were fed with a standard high-fat high-calorie breakfast before administration of ciclosporin. The results of the study are presented in Table 2 below:

Table 2 Pharmacokinetic parameters - fed conditions

All pharmacokinetic parameters presented are mean (SD) values

¹ Geometric means of the individual ratios and 90% parametric CI

² Median Difference and 90% non parametric CI

3. A randomised, two-way cross-over, food effect study in which 16 healthy male volunteers received a standard high-fat high-calorie breakfast before administration of ciclosporin.

The results of the study are presented in Table 3 below:

Table 3 Pharmacokinetic parameters - fasting versus fed conditions

All pharmacokinetic parameters presented are mean (SD) values

¹ Geometric means of the individual ratios and 90% parametric CI

² Median Difference and 90% non parametric CI

The results show that food intake decreases AUC and Cmax by 7% and 15%, respectively, compared to the values obtained under fasting conditions.

The reduction in AUC and Cmax are not significant and Deximune can be administered with or without food.

Ciclosporin is distributed largely outside the blood volume. Within 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 in proteins, mainly lipoproteins.

Ciclosporin is extensively biotransformed to approximately 15 metabolites, there being 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 foetotoxic 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.

Polysorbate 20

Sorbitan oleate

Lecithin

Triglyceride

Macrogolglycerol hydroxystearate

Ethyl lactate

Ingredients of the capsule shell:

Gelatin

Glycerol

Ferric oxide black (E172)

Titanium dioxide (E171)

Not applicable.

2 years.

Do not store above 25°C.

Do not refrigerate and/or freeze.

Deximune capsules should be left in the blister pack until required for use. When a blister is opened, a characteristic smell is noticeable.

The capsules are available in blister packs of double-sided aluminium consisting of an aluminium bottom foil and an aluminium covering foil, which are contained within a printed cardboard carton.

Deximune Capsules are available in 30, 50 or 60 capsules in each carton.

Not all pack sizes may be marketed.

No special requirements.

DEXCEL-PHARMA LTD

1 Cottesbrooke Park

Heartlands Business Park

Daventry

Northants NN11 8YL

United Kingdom

23.04.2007 / 27.01.2010

15 September 2010