Pharmacology: Pharmacodynamics: Mechanism of Action:
Ciclosporin (also known as ciclosporin 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 (GVHD), 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
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 hemopoiesis 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. Ciclosporin has been used successfully both in Hepatitis C Virus (HCV) positive and HCV negative liver transplants recipients. Beneficial effects of Sandimmun Neoral therapy have also been shown in a variety of conditions that are known, or may be considered to be of autoimmune origin.
Transplantation Indications: Solid Organ Transplantation: The efficacy of ciclosporin has been demonstrated in 13 global studies which evaluated the success transplantation rate using ciclosporin versus other immunosuppressive agents. Clinical trials have been performed in various regions (Europe, Australia and North America). Some of these trials included the evaluation of different solid organs including kidney, liver, heart, combined heart-lung, lung or pancreas allogenic transplantation. In the clinical trials performed, the ciclosporin dose used in transplanted patients ranged from 10 to 25 mg/kg per day as initial treatment dose and ranged from 6 to 8 mg/kg per day as maintenance dose (see Dosage & Administration).
Clinical studies are displayed in Tables 1 to 5.
Kidney and Pancreas Transplantation: Table 1 presents clinical studies that were mainly performed in kidney transplanted patients and Table 2 presents clinical studies performed only in kidney transplanted patients. Table 1 also includes pancreas-transplanted patients. The included studies in these tables confirm that ciclosporin used in combination with steroids is an effective treatment in renal transplantation. The one year graft survival was significantly improved in these ciclosporin-treated patients over control therapy. (See Tables 1 and 2.)
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In addition to the previously mentioned clinical studies performed in kidney-transplanted patients, two studies were performed for safety and tolerability assessment of the Sandimmun Neoral formulation. These 2 studies (Table 3) where Sandimmun was converted to Sandimmun Neoral in 1:1 protocols have shown based on stable steady-state trough concentration, that comparable doses of Sandimmun Neoral to Sandimmun, led to higher Cmax
and AUC values with Sandimmun Neoral compared to Sandimmun. (See Table 3.)
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Liver Transplantation: In the liver transplantation (see Table 4), the clinical studies demonstrated that one year patient survival rate was higher in the ciclosporin group than historical controls that were under previous immunosuppressive regimens.
Most of the thirteen deaths were attributed to surgical complications, acute infections (usually developing in the immediate period after transplantation, and possibly caused by organ procurement, and preservation procedure) or recurrence of the original disease.
The episodes of acute rejection were generally controlled by increased steroid administration, whereas several episodes of nephrotoxicity were noted which resolved on dosage reduction of ciclosporin. The clinical studies demonstrated that ciclosporin and steroid therapy offers considerable advantage over standard therapy using azithromycin and steroids. (See Table 4.)
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Heart and Heart-Lung Transplantation: In heart transplantation, the clinical studies demonstrated that one year and 18 months patient survival rates were significantly higher in the ciclosporin-treated patients than in the control-group patients. Ten of the 28 patients enrolled in heart transplantation had no rejection episodes following transplantation.
In heart-lung transplantation, the one year survival rate was 67% in the ciclosporin-treated patients.
In both heart and heart-lung transplantation, episodes of suspected hepatotoxicity and nephrotoxicity were controlled by dosage reduction of ciclosporin. Serious lung infections were observed and the majority was successfully treated.
Results of the clinical trials performed in heart and heart-lung transplanted patients are summarized in Table 5 as follows. (See Table 5.)
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Bone Marrow Transplantation: The efficacy of Sandimmun has been demonstrated in bone marrow transplant (BMT) recipients in eight studies carried out in Europe and US with a total of 227 patients. Seven trials were conducted for the prevention of graft-versus host disease (GVHD), one trial for the treatment of acute GVHD. Five European centers (EU 1-5) and one U.S. center (US #6) conducted "open" non-randomized trials for the prevention of GVHD. One randomized trial (US #3) was conducted for the prevention of GVHD and one randomized trial (US #11) was conducted for the treatment of acute GVHD. Six patients in US #6 received ciclosporin in an effort to reverse established acute, severe (Grade III-IV) GVHD. These patients had not been previously treated with ciclosporin and the GVHD was resistant to other therapies. Results from these studies were compared to methotrexate (MTX) therapy in the prevention of GVHD trials (historical controls in the open trials) and to steroid therapy in the treatment of GVHD trial. These studies contained 227 patients: 204 patients were BMT recipients treated for prophylaxis of GVHD, and 23 patients treated for established GVHD. There were a total of 20 HLA mismatched patients in these studies.
The dosage of ciclosporin varied in the different studies. For prevention of GVHD the usual dosage was 12.5 mg/kg/day. However, several European centers started higher (20-25 mg/kg/day) during the first few days then tapered to 12.5 mg/kg/day. Most centers held the dose constant and tapered after several months, usually discontinuing after 4-6 months. The dosage of ciclosporin used for treatment of GVHD was approximately 15 mg/kg/day. This was tapered over time and discontinued at about 6 months. Ciclosporin was given mostly once or twice daily, but at one center, three times daily. In most studies, if the I.V. formulation of ciclosporin was used, it was given at about 1
the oral dose.
Efficacy results from the European studies demonstrated a reduction of severity and perhaps frequency of GVHD, with one-year survival for all Ciclosporin patients with matched grafts approximately 70%. For historical controls treated with MTX the figure was only 52% for one-year survival. Death associated with GVHD was only 10/132 patients (8%), much lower that what was previously found with MTX in matched grafts (fatal in >25% cases). The efficacy results from the US studies support the European efficacy results, and demonstrate that Ciclosporin is at least as efficacious as and probably superior to MTX therapy in the prevention of GVHD in BMT, with a significantly faster time to engraftment and a relative risk of approximately 50% of developing GVHD greater than Grades II or III (p=N.S.). US Study #6 also demonstrated that ciclosporin reversed established acute severe (Grade III-IV) GVHD in patients not previously treated with ciclosporin and resistant to other therapies.
Non-Transplantation Indications: Endogenous Uveitis Including Behcet's Uveitis: The efficacy of ciclosporin was demonstrated in 11 open uncontrolled studies from Europe, the U.S., Japan, Africa and Asia, including 242 patients suffering from endogenous uveitis, in most of whom conventional therapy failed or caused unacceptable adverse events. In 4 controlled masked studies from Israel, Japan, the Netherlands and the U.S., 202 patients were randomly assigned to receive ciclosporin (97 patients) or conventional therapy-prednisolone, chlorambucil, colchicine - (92 patients) or placebo (13 patients). Of the 339 patients treated with ciclosporin, 161 were diagnosed with Behcet's uveitis and the remaining 178 predominantly with intermediate or posterior uveitis of non-infectious aetiology. Males patients were 201 and females were 138; the mean age was 35.8 years. Most patients receiving ciclosporin had an initial loading dose of 5 to 10 mg/kg/day followed by a dose reduction according to ocular inflammatory activity and tolerability. Improvement of visual acuity from baseline was the primary endpoint most commonly used in the clinical program, and the incidence of ocular attacks was used for Behcet's uveitis. Over 60% of patients treated with ciclosporin had improvement in visual acuity from baseline as measured at 3 and 6 months after the initiation of ciclosporin therapy. The initial limiting factor for improvement in the majority of the remaining 40% being irreversible changes that developed during the disease process before the initiation of ciclosporin therapy. The incidence of ocular attacks in patients with Behcet's uveitis was significantly reduced (p=0.001) in patients treated with ciclosporin compared to patients treated with colchicine.
Nephrotic Syndrome: The efficacy of Sandimmun has been demonstrated in four randomized controlled and 5 uncontrolled studies. The clinical results from these nine clinical studies were analyzed using a pooling of data from all studies (controlled and uncontrolled).
Two double-blind placebo controlled multicenter studies (9515 and 9516) and a multicenter study to comparing Ciclosporin with cyclophosphamide in steroid-resistant patients (9508) had to be stopped prematurely because of a lack of suitable patients consenting to receive placebo or a cytostatic agent.
A retrospective collection of data from patients treated with ciclosporin was performed in a trial entitled OL 03.
Adults and pediatric patients included in the studies were mainly steroid resistant or steroid dependent patients or patients with signs of steroid toxicity needing alternate treatment.
The controlled studies included 47 patients amongst which 43 were pediatric patients (defined as patients up to 16 years of age). These patients were presenting with focal segmental glomerulosclerosis (FSGS), Minimal change nephropathy (MCN) and Membranous glomerulonephritis (MG) and were steroid dependent and steroid resistant. Additionally, 24 adult patients with IgA nephropathy (an entity that may present with nephrotic syndrome, particularly common in patients with Asian origin) were studied as well. The studies compared ciclosporin either with cyclophosphamide (OL9511), chlorambucil (OL9505), placebo (OL9509) or "no treatment" or palliative care (OL9510).
The uncontrolled trials studied 361 adult patients and 178 pediatric patients (aged 1-17 years of age) with FSGS, MCN and MG nephrotic syndrome and were steroid dependent or steroid resistant. In addition, 9 adult and 27 pediatric patients with frequently relapsing forms of FSGS and MCN nephrotic syndrome were studied.
Of the 9 studies described in this document, seven included pediatric patients between 1 to 17 years of age. One controlled study (OL9505) and one uncontrolled study (OL9504) were performed exclusively in the pediatric population. A total of 398 children (319 treated with ciclosporin) were included in these studies.
The efficacy and safety results from the studies including pediatrics were similar to those in the adult population. Most of the steroid dependent patients achieved complete remission. The elimination of ciclosporin is influenced by the age of the patients. Pediatric patients clear the drug more rapidly than adults on a body weight basis. Therefore pediatric patients require higher doses of ciclosporin per kilogram of body weight to achieve blood concentrations of the drug similar to those observed in adults patients (see Dosage & Administration).
Rheumatoid Arthritis (RA): The efficacy of Sandimmun Neoral in the treatment of severe rheumatoid arthritis was evaluated in 5 clinical studies involving a total of 728 ciclosporin-treated patients and 273 placebo-treated patients.
A summary of the results is presented for the "responder" rates per treatment group, with a responder being defined as a patient having completed the trial with a 20% improvement in the tender and the swollen joint counts and a 20% improvement in 2 of 4 of investigator global, patient global, disability, and erythrocyte sedimentation rates (ESR) for the Studies 651 and 652 and 3 of 5 of investigator global, patient global, disability, visual analog pain, and ESR for Studies 2008, 654, and 302.
Study 651 enrolled 264 patients with active rheumatoid arthritis with at least 20 involved joints, who had failed at least one major RA drug, using a 3:3:2 randomization to one of the following three groups: (1) ciclosporin dosed at 2.5-5 mg/kg/day, (2) methotrexate at 7.5-15 mg/week, or (3) placebo. Treatment duration was 24 weeks. The mean ciclosporin dose at the last visit was 3.1 mg/kg/day. (See figure.)
Study 652 enrolled 250 patients with active RA with >6 active painful or tender joints who had failed at least one major RA drug. Patients were randomized using a 3:3:2 randomization to 1 of 3 treatment arms: (1) 1.5-5 mg/kg/day of ciclosporin, (2) 2.5-5 mg/kg/day of ciclosporin, and (3) placebo. Treatment duration was 16 weeks. The mean ciclosporin dose for group 2 at the last visit was 2.92 mg/kg/day. (See figure.)
Study 2008 enrolled 144 patients with active RA and >6 active joints who had unsuccessful treatment courses of aspirin and gold or Penicillamine. Patients were randomized to 1 of 2 treatments groups (1) ciclosporin 2.5-5 mg/kg/day with adjustments after the first month to achieve a target trough level and (2) placebo. Treatment duration was 24 weeks. The mean ciclosporin dose at the last visit was 3.63 mg/kg/day. (See figure.)
Study 654 enrolled 148 patients who remained with active joint counts of 6 or more despite treatment with maximally tolerated methotrexate doses for at least three months. Patients continued to take their current dose of methotrexate and were randomized to receive, in addition, one of the following medications: (1) ciclosporin 2.5 mg/kg/day with dose increases of 0.5 mg/kg/day at weeks 2 and 4 if there was no evidence of toxicity and further increases of 0.5 mg/kg/day at weeks 8 and 16 if a <30% decrease in active joint count occurred without any significant toxicity; dose decreases could be made at any time for toxicity or (2) placebo. Treatment duration was 24 weeks. The mean ciclosporin dose at the last visit was 2.8 mg /kg/day (range: 1.3-4.1). (See figure.)
Study 302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive or intolerant to at least one prior major RA drug. Patients were randomized to 1 of 2 treatment groups (1) Neoral and (2) ciclosporin, both of which were started at 2.5 mg/kg/day and increased after 4 weeks for inefficacy in increments of 0.5 mg/kg/day to a maximum of 5 mg/kg/day and decreased at any time for toxicity. Treatment duration was 24 weeks. The mean ciclosporin dose at the last visit was 2.91 mg/kg/day (range: 0.72-5.17) for Neoral and 3.27 mg/kg/day (range: 0.73-5.68) for ciclosporin. (See figure.)
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Psoriasis: The efficacy of ciclosporin has been demonstrated in 1,270 patients with severe psoriasis in 13 clinical studies. Three main double blind placebo controlled trial enrolling overall 296 patients, of whom 199 treated with ciclosporin and 97 with placebo, have been conducted over a 12-16 week treatment period (Study US299, US501 and US502); smaller placebo controlled studies including overall 105 patients, of whom 53 treated with ciclosporin and 52 treated with placebo (Study OL8002, OL8003, OL8006 and CyA40) supported the short term use. Two larger studies (Study OL8013 and OL8014) including 405 patient of whom 192 treated with ciclosporin and 38 with etretinate, provided information on long term efficacy, safety and tolerability of different ciclosporin dosing. The two formulation of ciclosporin were directly compared in a multicenter randomized double blind study including 309 patients (Study OLP302), supported by a smaller PK study including 39 patients (Study N101) and by an investigational study (Study OL8095) in which the microemulsion formulation was given intermittently to 41 patients.
Patients treated in the clinical programme were adult patients with severe psoriasis in whom conventional therapy was ineffective or inappropriate. A number of different primary measures of efficacy were used in the clinical studies i.e. the overall and global evaluation scores assessed by the investigators, the time to relapse, the evaluation of the body surface area (BSA), the evaluation of the psoriasis area and severity index (PASI score).
The results of a pooled analysis of the 3 main double blind placebo controlled trials (Study US299, US501 and US502) showed a reduction at least of 75% in PASI in a range from 76% of the patients treated with a starting dose of 3 mg/kg/day to 100% of the patients treated with a starting dose of 7.5 mg/kg/day, being 83% in patients treated with 5 mg/kg/day. The highest percentage of patients in the placebo group was 4%. The results of the pooled analysis of a pooled analysis of other trials (Study 8002, 8003, 8006, CyA-40, 8013 and 8014) showed a reduction at least of 75% in PASI in 55% of the patients treated with a starting dose of 2.5 mg/kg/day to 87% of the patients treated with a starting dose of 5 mg/kg/day. Reduction of at least 75% in PASI was observed in72% of the 152 patients treated with Sandimmun Neoral and in 62% of the 156 patients treated with Sandimmun (Study OLP302); in both arms the starting dose was 2.5 mg/kg/day.
Atopic Dermatitis: The efficacy of ciclosporin has been demonstrated in severe atopic dermatitis in 2 prospective, double-blind, placebo-controlled crossover trials conducted over an 8-week treatment period (SIM 79 and SIM 80) and a double-blind, placebo-controlled study conducted over a 6-week treatment period (SIM 24). A dose of 5 mg/kg per day was used throughout these three studies. In addition three open label uncontrolled studies (SIM AD01, SIM AD02 and OL10085), a randomized controlled dose finding study (SIM AD 5-4-3/3-4-5) and a single center study (SIM SF04) were performed to examine relapse rates following ciclosporin withdrawal or the effects of long-term therapy and different dosing strategies.
In one of these studies (SIM SF04), 5 mg/kg per day of the drug was given for 6 weeks, then the relapse rates were observed over a further 6 weeks; patients who relapsed were then given a second course of ciclosporin and monitored again for relapse. In the long-term studies (SIM AD02, OL 10085, SIM AD 5-4-3/3-4-5), the dose of ciclosporin was adjusted according to response and side-effects. In several of the open studies, patients were started on a low ciclosporin dose (2.5-3.0 mg/kg/day), which was then adjusted if necessary. In all of the clinical studies except OL 10901 where the ciclosporin microemulsion was used, the ciclosporin oil-based formulation was used. Overall 376 patients were included in these 9 studies; 296 patients were treated with ciclosporin, 23 with placebo and 57 with both ciclosporin and placebo in the two cross-over studies (SIM 79, SIM 80). Overall 259 patients were treated with ciclosporin for a short term (89 for 6 weeks and 170 for 8 weeks); 117 patients were involved in long-term studies, 100 of whom were treated for at least 12 months. Patients treated in the clinical programme were adult patients with severe atopic dermatitis in whom conventional therapy was ineffective or inappropriate. In the controlled studies and in most of the open-label studies, the primary measures of efficacy were the area of skin involvement and the severity of the skin disease. Other measures included itch and loss of sleep scores.
The results of the placebo-controlled studies (SIM 79, SIM 80 and SIM 24) demonstrated that ciclosporin was effective in the majority of patients with severe atopic dermatitis; only 5 of the 80 patients treated with ciclosporin in these studies failed to respond to therapy. The results of the long-term studies showed that efficacy could be maintained at doses less than 5 mg/kg per day over the duration of these studies, although it is difficult to assess the effects of the natural course of the disease on the long-term results. In the study SIM SF04, 43% and 52% of patients relapsed 2 weeks after cessation of the first and second course of ciclosporin therapy respectively; the relapse rate climbed to 71 and 87% respectively after 6 weeks.
When Sandimmun Neoral is given, it provides improved dose linearity in ciclosporin exposure (AUCB
), 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 (AUCB
). As a consequence of these additional advantages, the time schedule of Sandimmun Neoral administration need no longer take that of meals into account. In addition, Sandimmun Neoral produces a more uniform exposure to ciclosporin throughout the day, and from day to day on a maintenance regimen.
Sandimmun Neoral soft gelatin capsules and Sandimmun Neoral oral solution are bioequivalent. The data available indicate that following a 1:1 conversion from Sandimmun to Sandimmun Neoral, trough concentrations in whole blood are comparable, thereby remaining in the desired therapeutic trough level range. Compared to Sandimmun (with which peak blood concentrations are achieved within 1 to 6 hours), Sandimmun Neoral is more quickly absorbed (resulting in a 1 hour earlier mean tmax
and a 59% higher mean Cmax
), and exhibits, on average, a 29% higher bioavailability.
Ciclosporin is distributed largely outside the blood volume. In the blood, 33 to 47% is present in plasma, 4 to 9% in lymphocytes, 5 to 12% in granulocytes, and 41 to 58% in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.
Ciclosporin is extensively biotransformed to approximately 15 metabolites. There is no single major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is excreted in the urine as unchanged drug.
There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the assay applied and on 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 (see Dosage & Administration and Precautions).
Renal Impairment: In a study performed in patients with terminal renal failure, following an intravenous infusion of 3.5 mg/kg over 4 hours mean peak blood levels of 1,800 ng/mL (range 1,536 to 2,331 ng/mL) resulted. The mean volume of distribution (Vdss) was 3.49 L/kg and systemic clearance (CL) was 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) in patients with normally functioning kidneys. Renal impairment had no significant effect on the elimination of ciclosporin.
Hepatic Impairment: In a study performed in severe liver disease patients with biopsy-proven cirrhosis, the terminal half-life was 20.4 hours (range between 10.8 to 48.0 hours compared to 7.4 to 11.0 hours in healthy subjects).
Toxicology: Nonclinical 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 per day orally). At toxic doses (rats at 30 mg/kg and rabbits at 100 mg/kg per 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 two published research studies, rabbits exposed to ciclosporin in utero (10 mg/kg/day subcutaneously) 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 intravenously (twice the recommended human intravenous dose) had fetuses 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 per 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 per 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 (i.e. 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.