Deximune

Deximune

ciclosporin

Manufacturer:

Dexcel Pharma/AmediusTec

Distributor:

Apex Pharma Marketing
Full Prescribing Info
Contents
Ciclosporin.
Description
Deximune also contains the following excipients: Capsule Content: Polysorbate 20, sorbitan oleate, lecithin, glyceroltri(decanoate), macrogolglycerol hydroxystearate, ethyl lactate. Capsule Shell Gelatin, glycerol, ferric oxide black (E172), titanium dioxide (E171) and purified water.
Deximune is a new pharmaceutical form of ciclosporin based on the microemulsion principle, which reduces the variability of pharmacokinetic parameters and provides dose linearity of ciclosporin exposure with a more consistent absorption profile and less influence from concomitant food intake. The formation of the microemulsion itself takes place in the presence of water, in the form of the gastric fluid.
Action
Selective immunosuppressive agent.
Pharmacology: Pharmacodynamics: Ciclosporin (also known as cyclosporin A) is a cyclic polypeptide consisting of 11 amino acids. It is a potent immunosuppressive agent, which in animals prolongs survival of allogeneic transplants of skin, heart, kidney, pancreas, bone marrow, small intestine or lung. Studies suggest that ciclosporin inhibits the development of cell-mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-versus-host disease (GVDH), and also T-cell-dependent antibody production. At the cellular level, it inhibits production and release of lymphokines including interleukin 2, T-cell growth factor (TCGF). Ciclosporin appears to block the resting lymphocytes in the G0 or G1 phase of the cell cycle, and inhibits the antigen-triggered release of lymphokines by activated T-cells.
All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not depress haemopoiesis and has no effect on the function of phagocytic cells. Patients treated with ciclosporin are less prone to infection than those receiving other immunosuppressive therapy.
Successful solid organ and bone marrow transplantations have been performed in man using ciclosporin to prevent and treat rejection and GVHD. Beneficial effects of ciclosporin therapy have also been shown in a variety of conditions that are known, or may be considered to be of autoimmune origin.
Pharmacokinetics: When Deximune is given, it provides improved dose linearity in ciclosporin exposure (AUCa), a more consistent absorption profile, and less influence from concomitant food intake and from diurnal rhythm than does Sandimmun. These properties combined yield a lower within-patient variability in pharmacokinetics of ciclosporin, and a stronger correlation between trough concentration and total exposure (AUCa). As a consequence of these additional advantages, the time schedule of Deximune administration need no longer take that of meals into account. In addition, Deximune produces a more uniform exposure to ciclosporin throughout the day, and from day to day on a maintenance regimen.
Ciclosporin is distributed largely outside the blood volume in the blood, 33-47% is present in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.
Ciclosporin is extensively biotransformed to approximately 15 metabolites. There is no single major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is excreted in the urine as unchanged drug.
There is a high variability in the data reported on the terminal half-life (t½) of ciclosporin depending on the assay applied and on the target population. The terminal t½ ranged from 6.3 hrs in healthy volunteers to 20.4 hrs in patients with severe liver disease.
Toxicology: Preclinical Safety Data: Ciclosporin gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg/day orally). At toxic doses (rats at 30 mg/kg and rabbits at 100 mg/kg/day orally), ciclosporin was embryo- and fetotoxic as indicated by increased prenatal and postnatal mortality, and reduced fetal weight together with related skeletal retardations.
In 2 published research studies, rabbits exposed to ciclosporin in utero (10 mg/kg/day SC) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension, and progressive renal insufficiency up to 35 weeks of age.
Pregnant rats which received 12 mg/kg/day of ciclosporin IV (twice the recommended human IV dose) had foetuses with an increased incidence of ventricular septal defect.
These findings have not been demonstrated in other species and their relevance for humans is unknown.
Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4 and 16 mg/kg/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 8 mg/kg/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 analyzing sister chromatid exchange (SCE) induction by ciclosporin using human lymphocytes in vitro gave indication of a positive effect (ie, induction of SCE) at high concentrations in this system.
An increased incidence of malignancy is a recognized 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 the lesions to regress.
Indications/Uses
Transplantation: Solid Organ Transplantation: Prevention of graft rejection following kidney, liver, heart, combined heart-lung, lung or pancreas allogeneic transplantations.
Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.
Bone Marrow Transplantation: Prevention of graft rejection following bone marrow transplantation.
Prevention or treatment of graft-versus-host disease (GVHD).
Non-Transplantation: Endogenous Uveitis: Active sight-threatening intermediate or posterior uveitis of noninfectious aetiology where conventional therapy fails or causes unacceptable side effects.
Behcet's uveitis with repeated inflammatory attacks involving the retina in patients whose kidney function is normal.
Nephrotic Syndrome: Steroid-dependent and steroid-resistant nephrotic syndrome in adults and children, due to glomerular diseases eg, minimal change nephropathy, focal and segmental glomerulosclerosis, or membranous glomerulonephritis and in whom conventional cytostatic therapy is ineffective, but only if kidney function indices are at least 50% of normal. Deximune can be used to induce remissions and to maintain them. It can also be used to maintain steroid-induced remission, allowing withdrawal of steroids.
Rheumatoid Arthritis: Treatment of severe, active rheumatoid arthritis in whom conventional therapy is ineffective or inappropriate.
Psoriasis: Treatment of severe psoriasis in patients in whom conventional therapy is ineffective or inappropriate.
Atopic Dermatitis: Patients with severe atopic dermatitis in which conventional therapy is ineffective or inappropriate.
Dosage/Direction for Use
Dosage: The daily doses of Deximune should always be given in 2 divided doses.
Transplantation: Solid Organ Transplantation: Treatment with Deximune should be initiated within 12 hrs before surgery at a dose of 10-15 mg/kg given in 2 divided doses. This dose should be maintained as the daily dose for 1-2 weeks postoperatively before being gradually reduced in accordance with blood levels until a maintenance dose of about 2-6 mg/kg given in 2 divided doses is reached.
When Deximune is given with other immunosuppressants (eg, with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (eg, 3-6 mg/kg given in 2 divided doses for the initial treatment) may be used.
Bone Marrow Transplantation: The initial dose should be given on the day before transplantation. In most cases, IV infusion is preferred for this purpose; the recommended dose is 3-5 mg/kg/day. Infusion is continued at this dose level during the immediate post-transplant period of up to 2 weeks, before a change is made to oral maintenance therapy with Deximune at daily doses of about 12.5 mg/kg given in 2 divided doses. Maintenance treatment should be continued for at least 3 months (and preferably for 6 months) before the dose is gradually decreased to zero by 1 year after transplantation. If Deximune is used to initiate therapy, the recommended daily dose is 12.5-15 mg/kg given in 2 divided doses, starting on the day before transplantation.
Higher doses of Deximune, or the use of IV therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease drug absorption. In some patients, GVHD occurs after discontinuation of ciclosporin treatment, but usually responds favourably to re-introduction of therapy. Low doses of Deximune should be used to treat mild, chronic GVHD.
Non-Transplantation: Endogenous Uveitis: For inducing remission, initially 5 mg/kg/day orally given in 2 divided doses are recommended until remission of active uveal inflammation and improvement in visual acuity is achieved. In refractory cases, the dose can be increased to 7 mg/kg/day for a limited period.
To achieve initial remission, or to counteract inflammatory ocular attacks, systemic corticosteroid treatment with daily doses of prednisone 0.2-0.6 mg/kg or an equivalent may be added if Deximune alone does not control the situation sufficiently.
For maintenance treatment, the dose should be slowly reduced to the lowest effective level, which, during the remission phases, should not exceed 5 mg/kg/day.
Deximune should be withdrawn if there is no improvement after 3 months.
Nephrotic Syndrome: For inducing remission, the recommended daily dose, given in 2 divided oral doses, is 5 mg/kg for adults and 6 mg/kg for children if, except for proteinuria, renal function is normal. In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.
The combination of Deximune with low doses of oral corticosteroids is recommended if the effect of Deximune alone is not satisfactory, especially in steroid-resistant patients.
If no improvement has been observed after 3-month treatment, Deximune 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 in adults and 6 mg/kg/day in children.
For maintenance treatment, the dose should be slowly reduced to the lowest effective level.
Rheumatoid Arthritis: For the first 6 weeks of treatment, the recommended dose is 3 mg/kg/day orally given in 2 divided doses. If the effect is insufficient, the daily dose may then be increased gradually as tolerability permits, but should not exceed 5 mg/kg. To achieve full effectiveness, up to 12 weeks of Deximune therapy may be required. For maintenance treatment, the dose has to be titrated individually according to tolerability.
Deximune can be given in combination with low-dose corticosteroids and/or nonsteroidal anti-inflammatory drugs.
Treatment should be withdrawn if no response is apparent after 3 months.
Psoriasis: Due to the variability of this condition, treatment must be individualized. For inducing remission, the recommended initial dose is 2.5 mg/kg/day orally given in 2 divided doses. If there is no improvement after 1 month, the daily dose may be gradually increased, but should not exceed 5 mg/kg. Treatment should be discontinued in patients in whom sufficient response of psoriatic lesions cannot be achieved within 6 weeks on 5 mg/kg/day, or in whom the effective dose is not compatible with the established safety guidelines.
Initial doses of 5 mg/kg/day are justified in patients whose condition requires rapid improvement. Once satisfactory response is achieved, Deximune may be discontinued and subsequent relapse managed with re-introduction of Deximune at the previous effective dose. In some patients, continuous maintenance therapy may be necessary.
For maintenance treatment, doses have to be titrated individually to the lowest effective level, and should not exceed 5 mg/kg/day.
Atopic Dermatitis: Due to the variability of this condition, treatment must be individualized. The recommended dose range in adults and adolescents >16 years is 2.5-5 mg/kg/day given in 2 divided oral doses. If a starting dose of 2.5 mg/kg/day does not achieve a satisfactory response within 2 weeks of therapy, the daily dose may be rapidly increased to a maximum of 5 mg/kg. In very severe cases, rapid and adequate control of the disease is more likely to occur with a starting dose of 5 mg/kg/day. Once satisfactory response is achieved, the dose should be reduced gradually and if possible, Deximune should be discontinued. Subsequent relapse may be managed with a further course of Deximune.
Experience with ciclosporin in the long-term treatment of atopic dermatitis is limited and it is therefore recommended that individual treatment cycles be limited to a maximum of 8 weeks.
Treatment should be withdrawn in patients who do not respond adequately following 1 month of treatment at 5 mg/kg/day.
Conversion Between Oral Ciclosporin Formulations: Switching from 1 oral ciclosporin formulation to another should be made with caution and under physician supervision. The introduction of the new formulation must be made with monitoring of blood levels of ciclosporin to ensure that preconversion levels are attained.
Administration: The dose ranges given for oral administration is intended to serve as guidelines only. Routine monitoring of ciclosporin blood levels is required; this can be carried out by means of a RIA method based on monoclonal antibodies. The results obtained will serve as a guide for determining the actual dosage required to achieve the desired target concentrations in individual patients.
Oral Administration: The daily doses of Deximune should always be given in 2 divided doses. Capsules should be swallowed whole.
Overdosage
The oral LD50 of ciclosporin is 2329 mg/kg in mice, 1480 mg/kg in rats and >1000 mg/kg in rabbits.
No experience of acute overdosage of Deximune is available. Renal dysfunction, which would be expected to resolve following drug withdrawal, may occur. If indicated, general supportive measures should follow. Elimination can be achieved only by nonspecific measures, including gastric lavage, as ciclosporin is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion.
Contraindications
Hypersensitivity to ciclosporin or to any of the excipients of Deximune.
The following additional contraindications apply to the non-transplant indications: Kidney failure, except in patients with nephrotic syndrome, in whom disease-related moderate increases in baseline serum creatinine values (maximum 200 micromol/L in adults and maximum 140 micromol/L in children) improve and cautious therapy (maximum 2.5 mg/kg/day) is thus permitted.
Uncontrolled hypertension.
Uncontrolled Infection.
History of known or diagnosed malignancy of any kind except premalignant or malignant skin changes.
Special Precautions
Deximune 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, ciclosporin increases the risk of developing lymphomas and other malignancies, particularly those of the skin. 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 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 Deximune should be warned to avoid excess ultraviolet light exposure.
Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. 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 outcome have been reported. Effective pre-emptive and therapeutic strategies should be employed particularly in patients on multiple long-term immunosuppressive therapy. A frequent and potentially serious complication, an increase in serum creatinine and urea may occur during the 1st few weeks of Deximune therapy.
These functional changes are dose-dependent and reversible, usually responding to dose reduction. During long-term treatment, some patients may develop structural changes in the kidney (eg, interstitial fibrosis) which, in renal transplant patients, must be differentiated from changes due to chronic rejection. Deximune may also cause dose-dependent, reversible increases in serum bilirubin and, occasionally, in liver enzymes. There have been solicited and spontaneous post-marketing 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 co-medications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported. Close monitoring of parameters that assess renal and hepatic function is required. Abnormal values may necessitate dose reduction.
Ciclosporin may increase blood levels of concomitant medications that are substrates of P-glycoprotein (Pgp) eg, aliskiren (see Interactions).
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 1 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 Deximune therapy; if hypertension develops, appropriate antihypertensive treatment must be instituted. 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 1st 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 (eg, 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 Interactions). 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 Interactions).
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 Endogenous Uveitis: Since Deximune can impair renal function, it is necessary to assess renal function frequently, and if serum creatinine remains increased to >30% above baseline at >1 measurement, to reduce the dosage of Deximune by 25-50%. These recommendations apply even if the patient's values still lie within the laboratory's normal range.
There is only limited experience with the use of Deximune in children with endogenous uveitis.
Additional Precautions in Nephrotic Syndrome: Since Deximune can impair renal function, it is necessary to assess renal function frequently, and if the serum creatinine remains increased to >30% above baseline at >1 measurement, to reduce the dosage of Deximune by 25-50%. Patients with abnormal baseline renal function should initially be treated with 2.5 mg/kg/day and must be monitored very carefully.
In some patients, it may be difficult to detect Deximune-induced renal dysfunction because of changes in renal function related to the nephrotic syndrome itself. This explains why, in rare cases, Deximune-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 Deximune therapy has been maintained for >1 year.
In patients with nephrotic syndrome treated with immunosuppressants (including ciclosporin), the occurrence of malignancies (including Hodgkin's lymphoma) has been occasionally reported.
Additional Precautions in Rheumatoid Arthritis: Since Deximune can impair renal function, a reliable baseline level of serum creatinine should be established by at least 2 measurements prior to treatment, and serum creatinine should be monitored at 2-weekly intervals during the first 3 months of therapy and thereafter, once a month. After 6 months of therapy, serum creatinine needs to be measured every 4-8 weeks depending on the stability of the disease, its comedication, and concomitant diseases. More frequent checks are necessary when Deximune dose is increased, or concomitant treatment with a nonsteroidal anti-inflammatory drug is initiated or its dosage increased.
If the serum creatinine remains increased to >30% above baseline at >1 measurement, the dosage of Deximune should be reduced. If the serum creatinine increases by >50%, a dosage reduction by 50% is mandatory. These recommendations apply even if the patient's values still lie within the laboratory's normal range. If dose reduction is not successful in reducing levels within 1 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.
As with other long-term immunosuppressive treatments, an increased risk of lymphoproliferative disorders must be borne in mind. Special caution should be observed if Deximune is used in combination with methotrexate.
Additional Precautions in Psoriasis: Since Deximune can impair renal function, a reliable baseline level of serum creatinine should be established by at least 2 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 the serum creatinine increases and remains increased to >30% above baseline at >1 measurement, the dosage of Deximune must be reduced by 25-50%. These recommendations apply even if the patient's values still lie within the laboratory's normal range. If dose reduction is not successful in reducing levels within 1 month, Deximune treatment should be discontinued.
Discontinuation of Deximune therapy is also recommended if hypertension developing during Deximune treatment cannot be controlled with appropriate therapy.
Elderly patients should be treated only in the presence of disabling psoriasis and renal function should be monitored with particular care.
There is only limited experience with the use of Deximune in children with psoriasis.
In psoriatic patients on ciclosporin, as in those on conventional immunosuppressive therapy, development of malignancies (in particular of the skin) has been reported.
Skin lesions not typical for psoriasis, but suspected to be malignant or pre-malignant should be biopsied before Deximune treatment is started. Patients with malignant or pre-malignant alterations of the skin should be treated with Deximune only after appropriate treatment of such lesions, and if no other option for successful therapy exists.
In a few psoriatic patients treated with ciclosporin, lymphoproliferative disorders have occurred. These were responsive to prompt drug discontinuation.
Patients on Deximune should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.
Additional Precautions in Atopic Dermatitis: Since Deximune can impair renal function, a reliable baseline level of serum creatinine should be established by at least 2 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 the serum creatinine increases and remains increased to >30% above baseline at >1 measurement, the dosage of Deximune must be reduced by 25-50%. These recommendations apply even if the patient's values still lie within the laboratory's normal range. If dose reduction is not successful in reducing levels within 1 month, Deximune treatment should be discontinued.
Discontinuation of Deximune therapy is also recommended if hypertension developing during Deximune treatment cannot be controlled with appropriate therapy.
The experience with Deximune in children with atopic dermatitis is limited. Elderly patients should be treated only in the presence of disabling 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 treatment with Deximune is initiated, 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 Interactions) 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.
Patients on Deximune should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.
Effects on the Ability to Drive or Operate Machinery: No data exist on the effects of Deximune on the ability to drive and use machines.
Use in pregnancy: Animal studies have shown reproductive toxicity in rats and rabbits (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Experience with ciclosporin in pregnant women is limited. In pregnant transplant recipients who are being treated with immunosuppressants, the risk of premature births is increased.
A limited number of observations in children exposed to ciclosporin in utero is 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, Deximune should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.
Use in lactation: Ciclosporin passes into breast milk. Mothers receiving treatment with Deximune should not breastfeed.
Use in children: For non-transplant indications, data on the paediatric use of Deximune are limited except in the case of nephrotic syndrome. Its use in patients <16 years in non-transplantation indications other than nephrotic syndrome cannot therefore be recommended. In transplantation, the experience with Deximune in children is also still limited. However, children from 1 year of age have received ciclosporin in standard dosage with no particular problems. In several studies, paediatric patients required and tolerated higher doses of ciclosporin/kg body weight than those used in adults.
Use in the elderly: Experience with ciclosporin in the elderly is limited, but no particular problems have been reported following the use of the drug at the recommended dose.
In rheumatoid arthritis, clinical trials with ciclosporin, 17.5% of patients were ≥65 years. 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 ciclosporin in transplant and psoriasis patients did not include a sufficient number of subjects ≥65 years to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
Use In Pregnancy & Lactation
Use in pregnancy: Animal studies have shown reproductive toxicity in rats and rabbits (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Experience with ciclosporin in pregnant women is limited. In pregnant transplant recipients who are being treated with immunosuppressants, the risk of premature births is increased.
A limited number of observations in children exposed to ciclosporin in utero is 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, Deximune should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.
Use in lactation: Ciclosporin passes into breast milk. Mothers receiving treatment with Deximune should not breastfeed.
Adverse Reactions
Many adverse effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction. In the various indications, the overall spectrum of adverse 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, adverse effects are more frequent and usually more severe in transplant patients than in patients treated for other indications.
Frequency Estimate: Very common (≥10%), common (≥1% to <10%), uncommon (≥0.1% to <1%), rare (≥0.01% to <0.1%), very rare (<0.01%).
Renal: Very Common: Renal dysfunction (see Precautions).
Cardiovascular: Very Common: Hypertension.
Nervous System: Very Common: Tremor, headache. Common: Paraesthesia. Uncommon: Signs of encephalopathy eg, convulsions, confusion, disorientation, decreased responsiveness, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia. Rare: Motor polyneuropathy. Very Rare: Optic disc oedema including papilloedema, with possible visual impairment secondary to benign intracranial hypertension.
Gastrointestinal Tract and Liver: Common: Anorexia, nausea, vomiting, abdominal pain, diarrhoea, gingival hyperplasia, hepatic dysfunction. Rare: Pancreatitis.
Metabolic: Very Common: Hyperlipidaemia. Common: Hyperuricaemia, hyperkalaemia, hypomagnesaemia. Rare: Hyperglycaemia.
Musculoskeletal: Common: Muscle cramps, myalgia. Rare: Muscle weakness, myopathy.
Haemopoietic: Uncommon: Anaemia, thrombocytopenia. Rare: Microangiopathic haemolytic anaemia, haemolytic uraemic syndrome.
Skin and Appendages: Common: Hypertrichosis. Uncommon: Allergic rashes.
Body as a Whole: Common: Fatigue. Uncommon: Oedema, increased weight.
Endocrine: Rare: Menstrual disturbances, gynecomastia.
Infections and Infestations: Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Precautions). Both generalized and localized infections can occur. Preexisting 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.
Neoplasms, Benign and Malignant Unspecified (Including Cysts and Polyps): Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and duration of therapy (see Precautions). Some malignancies may be fatal.
Other Adverse Drug Reactions from Post-Marketing Experience: There have been solicited and spontaneous post-marketing reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant comorbidities, underlying conditions and other confounding factors including infectious complications and co-medications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see Precautions).
Drug Interactions
Food Interactions: The concomitant intake of grapefruit juice has been reported to increase the bioavailability of ciclosporin.
Drug Interactions: Ciclosporin is also an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein (Pgp) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter.
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 as follows.
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 cytochrome P-450 enzymes.
Drugs that Decrease Ciclosporin Levels: Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine IV; rifampicin; octreotide; probucol; orlistat; Hypericum perforatum (St. John's wort); ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Drug that Increase Ciclosporin Levels: Macrolide antibiotics (eg, erythromycin, azithromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high dose); allopurinol; amiodarone; cholic acid and derivatives; protease inhibitors, imatinib; colchicines, nefazodone.
Other Relevant Drug Interactions: Ciclosporin is a highly potent Pgp inhibitor and may increase blood levels of concomitant medications that are substrates of Pgp eg, aliskiren. Following concomitant administration of ciclosporin and aliskiren, the Cmax of allskiren 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 Precautions).
Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy eg, aminoglycosides (including gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); nonsteroidal anti-inflammatory drugs (including diclofenac, naproxen, sulindac); melphalan, histamine H2-receptor antagonists (eg, cimetidine, ranitidine); methotrexate (see Precautions).
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 3-fold and the AUC of ciclosporin was increased 21%. Therefore, caution is recommended when co-administering ciclosporin together with lercanidipine (see Precautions).
The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in 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 nonsteroidal anti-inflammatory drugs with a low first-pass effect (eg, acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.
Ciclosporin may reduce the clearance of digoxin, colchicines, prednisolone and 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 colchicines eg, myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine are 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.
Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only 3 minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increased blood levels of everolimus and sirolimus.
Caution is required for concomitant use of potassium-sparing drugs (eg, 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 Precautions).
Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.
Recommendations: If the concomitant use of drugs 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 (eg, 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 effects 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.
Nonsteroidal anti-inflammatory drugs known to undergo strong first-pass metabolism (eg, diclofenac) should be given at doses lower than those that would be used in patients not receiving ciclosporin.
If digoxin, colchicines or HMG-CoA reductase inhibitors (statins) are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the drugs, followed by reduction of dosage or by withdrawal.
Storage
Store in the original packaging. Do not store above 25°C.
Deximune should be left in the blister pack until required for use. When a blister is opened, a characteristic smell is noticeable. This is normal and does not mean that there is anything wrong with the capsule.
ATC Classification
L04AD01 - ciclosporin ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.
Presentation/Packing
Cap 25 mg x 50's. 50 mg x 50's. 100 mg x 50's.
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