CAPSORIN 25MG SOFT CAPSULES
Active substance(s): CICLOSPORIN / CICLOSPORIN / CICLOSPORIN
NAME OF THE MEDICINAL PRODUCT
Capsorin 25 mg soft capsules
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 25 mg of ciclosporin.
Excipients with known effect:
Ethanol: 25 mg/capsule Macrogolglycerol hydroxystearate: 95 mg/capsule
For the full list of excipients see section 6.1.
Grey gelatin capsule
Solid organ transplantation
Prevention of graft rejection following solid organ transplantation. Treatment of
transplant cellular rejection in patients previously receiving other immunosuppressive
Bone marrow transplantation
Prevention of graft rejection following allogeneic bone marrow and stem cell
Prevention or treatment of graft-versus-host disease (GVHD).
Treatment of sight-threatening intermediate or posterior uveitis of non-infectious
aetiology in patients in whom conventional therapy has failed or caused unacceptable
Treatment of Behçet uveitis with repeated inflammatory attacks involving the retina
in patients without neurological manifestations.
Steroid-dependent and steroid-resistant nephrotic syndrome, due to primary
glomerular diseases such as minimal change nephropathy, focal and segmental
glomerulosclerosis, or membranous glomerulonephritis.
Capsorin can be used to induce and maintain remissions. It can also be used to
maintain steroid-induced remission, allowing withdrawal of steroids.
Treatment of severe, active rheumatoid arthritis.
Treatment of severe psoriasis in patients in whom conventional therapy is
inappropriate or ineffective.
Capsorin is indicated in patients with severe atopic dermatitis when systemic therapy
Posology and method of administration
The dose ranges given for oral administration are intended to serve as guidelines only.
The daily doses of Capsorin should be given in two divided doses equally distributed
throughout the day. It is recommended that Capsorin be administered on a consistent
schedule with regard to time of day and in relation to meals.
Capsorin should only be prescribed by, or in close collaboration with, a physician
with experience of immunosuppressive therapy and/or organ transplantation.
Solid organ transplantation
Treatment with Capsorin is initiated within 12 hours before surgery at a dose of 10 to
15 mg/kg given in two divided doses. This dose should be maintained as the daily
dose for 1 to 2 weeks post-operatively, being gradually reduced in accordance with
blood levels according to local immunosuppressive protocols until a recommended a
maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached.
When Capsorin is given with other immunosuppressants (e.g. with corticosteroids or
as part of a triple or quadruple medicinal product therapy), lower doses (e.g. 3 to 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,
ciclosporin concentrate for solution for infusion is preferred for this purpose. The
recommended intravenous dose is 3 to 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 Capsorin 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 Capsorin is used to initiate therapy, the recommended daily dose is 12.5 to
15mg/kg, given in two divided doses, starting on the day before transplantation.
Higher doses of ciclosporin, or the use of ciclosporin intravenous therapy, may be
necessary in the presence of gastrointestinal disturbances which might decrease
In some patients, GVHD occurs after discontinuation of ciclosporin treatment, but
usually responds favourably to re-introduction of therapy. In such cases an initial oral
loading dose of 10 to 12.5 mg/kg should be given, followed by daily oral
administration of the maintenance dose previously found to be satisfactory. Low
doses of Capsorin should be used to treat mild, chronic GVHD.
When using Capsorin in any of the established non-transplantation indications, the
following general rules should be adhered to:
Before initiation of treatment a reliable baseline level of renal function should be
established by at least two measurements. The estimated glomerular filtration rate
(eGFR) by the MDRD formula can be used for estimation of renal function in adults
and an appropriate formula should be used to assess eGFR in paediatric patients.
Since Capsorin can impair renal function, it is necessary to assess renal function
frequently. If eGFR decreases by more than 25% below baseline at more than one
measurement, the dosage of Capsorin should be reduced by 25 to 50%. If the eGFR
decrease from baseline exceeds 35%, further reduction of the dose of Capsorin should
be considered. These recommendations apply even if the patient`s values still lie
within the laboratory`s normal range. If dose reduction is not successful in improving
eGFR within one month, Capsorin treatment should be discontinued (see section 4.4).
Regular monitoring of blood pressure is required.
The determination of bilirubin and parameters that assess hepatic function are
required prior to starting therapy and close monitoring during treatment is
recommended. Determinations of serum lipids, potassium, magnesium and uric acid
are advisable before treatment and periodically during treatment.
Occasional monitoring of ciclosporin blood levels may be relevant in non-transplant
indications, e.g. when Capsorin is co-administered with substances that may interfere
with the pharmacokinetics of ciclosporin, or in the event of unusual clinical response
(e.g. lack of efficacy or increased drug intolerance such as renal dysfunction).
The normal route of administration is by mouth. If the concentrate for solution for
infusion is used, careful consideration should be given to administering an adequate
intravenous dose that corresponds to the oral dose. Consultation with a physician with
experience of use of ciclosporin is recommended.
Except in patients with sight-threatening endogenous uveitis and in children with
nephrotic syndrome, the total daily dose must never exceed 5 mg/kg.
For maintenance treatment the lowest effective and well tolerated dosage should be
In patients in whom within a given time (for specific information see below) no
adequate response is achieved or the effective dose is not compatible with the
established safety guidelines, treatment with Capsorin should be discontinued.
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 are 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 0.2 to 0.6 mg/kg prednisone or an
equivalent may be added if Capsorin alone does not control the situation sufficiently.
After 3 months, the dose of corticosteroids may be tapered to the lowest effective
For maintenance treatment, the dose should be slowly reduced to the lowest effective
level. During the remission phases, this should not exceed 5 mg/kg/day.
Infectious causes of uveitis should be ruled out before immunosuppressants can be
For inducing remission, the recommended daily dose is given in 2 divided oral doses.
If the renal function (except for proteinuria) is normal, the recommended daily dose is
- adults: 5 mg/kg
- children: 6 mg/kg
In patients with impaired renal function, the initial dose should not exceed 2.5
The combination of Capsorin with low doses of oral corticosteroids is recommended
if the effect of Capsorin alone is not satisfactory, especially in steroid-resistant
Time to improvement varies from 3 to 6 months depending on the type of
glomerulopathy. If no improvement has been observed after this time to improvement
period, Capsorin therapy should be discontinued.
The doses need to be adjusted individually according to efficacy (proteinuria) and
safety, 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 t
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 Capsorin therapy may be required.
For maintenance treatment the dose has to be titrated to the lowest effective level
according to tolerability.
Capsorin can be given in combination with low-dose corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs)(see section 4.4). Capsorin can also be
combined with low-dose weekly methotrexate in patients who have insufficient
response to methotrexate alone, by using 2.5 mg/kg Capsorin in 2 divided doses per
day initially, with the option to increase the dose as tolerability permits.
Capsorin treatment should be initiated by physicians with experience in the diagnosis
and treatment of psoriasis. Due to the variability of this condition, treatment must be
individualised. For inducing remission, the recommended initial dose is 2.5
mg/kg/day orally given in two 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 (see section 4.4).
Initial doses of 5 mg/kg/day are justified in patients whose condition requires rapid
improvement. Once satisfactory response is achieved, Capsorin may be discontinued
and subsequent relapse managed with re-introduction of Capsorin 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
Capsorin treatment should be initiated by physicians with experience in the diagnosis
and treatment of atopic dermatitis. Due to the variability of this condition, treatment
must be individualised. The recommended dose range is 2.5 to 5 mg/kg/day given in
two divided oral doses. If initial starting dose of 2.5 mg/kg/day does not achieve a
satisfactory response within 2 weeks, the daily dose may be rapidly increased to
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 gradually reduced and, if possible, Capsorin
should be discontinued. Subsequent relapse may be managed with a further course of
Although an 8-week course of therapy may be sufficient to achieve clearing, up to 1
year of therapy has been shown to be effective and well tolerated, provided the
monitoring guidelines are followed.
Switching between oral ciclosporin formulations
The switch from one oral ciclosporin formulation to another should be made under
physician supervision, including monitoring of blood levels of ciclosporin for
Patients with renal impairment
Ciclosporin undergoes minimal renal elimination and its pharmacokinetics are not
extensively affected by renal impairment (see section 5.2). However, due to its
nephrotoxic potential (see section 4.8), careful monitoring of renal function is
recommended (see section 4.4).
With the exception of patients being treated for nephrotic syndrome, patients with
impaired renal function should not receive ciclosporin (see subsection on additional
precautions in non-transplantation indications in section 4.4). In nephrotic syndrome
patients with impaired renal function, the initial dose should not exceed 2.5
Patients with hepatic impairment
Ciclosporin is extensively metabolised by the liver. An approximate 2- to 3-fold
increase in ciclosporin exposure may be observed in patients with hepatic
impairment. Dose reduction may be necessary in patients with severe liver
impairment to maintain blood levels within the recommended target range (see
sections 4.4 and 5.2) and it is recommended that ciclosporin blood levels are
monitored until stable levels are reached.
Clinical studies have included children from 1 year of age. In several studies,
paediatric patients required and tolerated higher doses of ciclosporin per kg body
weight than those used in adults.
Use of Capsorin in children for non-transplantation indications other than nephrotic
syndrome cannot be recommended (see section 4.4).
Elderly population (age 65 years and above)
Experience with ciclosporin in the elderly is limited
In rheumatoid arthritis clinical trials with ciclosporin, patients aged 65 or older were
more likely to develop systolic hypertension on therapy, and more likely to show
serum creatinine rises ≥50% above the baseline after 3 to 4 months of therapy.
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 medication and increased
susceptibility for infections.
Method of administration
Capsorin capsules should be swallowed whole.
Hypersensitivity to the active substance or to any of the excipients listed in section
Combination with products containing Hypericum perforatum (St John´s Wort) (see
Combination with medicines that are substrates for the multidrug efflux transporter Pglycoprotein or the organic anion transporter proteins (OATP) and for which elevated
plasma concentrations are associated with serious and/or life-threatening events, e.g.
bosentan, dabigatran etexilate and aliskiren (see section 4.5).
Special warnings and precautions for use
Capsorin 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 this medicinal product 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.
Lymphomas and other malignancies
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.
A treatment regimen containing multiple immunosuppressants (including ciclosporin)
should therefore 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 Capsorin, in particular
those treated for psoriasis or atopic dermatitis, should be warned to avoid excess
unprotected sun exposure and should not receive concomitant ultraviolet B irradiation
or PUVA photochemotherapy.
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 outcomes 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 Capsorin therapy. These functional changes are dosedependent and are initially reversible, usually responding to dose reduction. During
long-term treatment, some patients may develop structural changes in the kidney (e.g.
interstitial fibrosis) which, in renal transplant patients, must be differentiated from
changes due to chronic rejection. Frequent monitoring of renal function is therefore
required according to local guidelines for the indication in question (see sections 4.2
Capsorin may also cause dose-dependent, reversible increases in serum bilirubin and
in liver enzymes (see section 4.8). There have been solicited and spontaneous reports
of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver
failure in patients treated with ciclosporin. Most reports included patients with
significant co-morbidities, underlying conditions and other confounding factors
including infectious complications and co-medications with hepatotoxic potential. In
some cases, mainly in transplant patients, fatal outcomes have been reported (see
section 4.8). Close monitoring of parameters that assess hepatic function is required
and abnormal values may necessitate dose reduction (see sections 4.2 and 5.2).
Elderly population (age 65 years and above)
In elderly patients, renal function should be monitored with particular care.
Monitoring ciclosporin levels (see section 4.2)
When Capsorin is used in transplant patients, routine monitoring of ciclosporin blood
levels is an important safety measure. For monitoring ciclosporin levels in whole
blood, a specific monoclonal antibody (measurement of parent compound) is
preferred; a high-performance liquid chromatography (HPLC) method, which also
measures the parent compound, 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 non-specific monoclonal antibody should be performed, to ensure a dosage
that provides adequate immunosuppression.
In non-transplant patients, occasional monitoring of ciclosporin blood levels is
recommended, e.g. when Capsorin is co-administered with substances that may
interfere with the pharmacokinetics of ciclosporin, or in the event of unusual clinical
response (e.g. lack of efficacy or increased drug intolerance such as renal
It must be remembered that the ciclosporin concentration in blood, plasma, or serum
is only one of many factors contributing to the clinical status of the patient. Results
should therefore serve only as a guide to dosage in relationship to other clinical and
Regular monitoring of blood pressure is required during Capsorin therapy. If
hypertension develops, appropriate antihypertensive treatment must be instituted.
Preference should be given to an antihypertensive agent that does not interfere with
the pharmacokinetics of ciclosporin, e.g. isradipine (see section 4.5).
Blood lipids increased
Since Capsorin 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 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
enzyme (ACE) inhibitors, angiotensin II receptor antagonists) and
potassium containing medicinal products as well as in patients on a potassium rich
diet. 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 when treating patients with hyperuricaemia.
During treatment with ciclosporin, vaccination may be less effective. The use of live
attenuated vaccines should be avoided (see section 4.5).
Caution should be observed when co-administering ciclosporin with drugs that
substantially increase or decrease ciclosporin plasma concentrations, through
inhibition or induction of CYP3A4 and/or P-glycoprotein (see section 4.5).
Renal toxicity should be monitored when initiating ciclosporin use together with
active substances that increase ciclosporin levels or with substances that exhibit
nephrotoxic synergy (see section 4.5).
Concomitant use of ciclosporin and tacrolimus should be avoided (see section 4.5).
Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter Pglycoprotein and organic anion transporter proteins (OATP) and may increase plasma
levels of co-medications that are substrates of this enzyme and/or transporter. Caution
should be observed while co-administering ciclosporin with such drugs or
concomitant use should be avoided (see section 4.5). Ciclosporin increases the
exposure to HMG-CoA reductase inhibitors (statins). When concurrently
administered with ciclosporin, the dosage of the statins should be reduced and
concomitant use of certain statins should be avoided according to their 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 (see
Following concomitant administration of ciclosporin and lercanidipine, the AUC of
lercanidipine was increased three-fold and the AUC of ciclosporin was increased
21%. Therefore the simultaneous combination of ciclosporin and lercanidipine should
be avoided. Administration of ciclosporin 3 hours after lercanidipine yielded no
change of the lercanidipine AUC, but the ciclosporin AUC was increased by 27%.
This combination should therefore be given with caution with an interval of at least 3
Special excipients: Macrogolglycerol hydroxystearate
Capsorin contains macrogolglycerol hydroxystearate, which may cause stomach upset
Special excipients: Ethanol
contains around 12.7% vol. ethanol. i.e. up to 525 mg per dose, equivalent to 13 ml
beeror 6 ml wine per dose. This may be harmful in alcoholic patients andshould be
taken into account in pregnant or breast-feeding women, in patients presenting with
liver disease or epilepsy, or if the patients is a child.
Additional precautions in non-transplantation indications
Patients with impaired renal function (except nephrotic syndrome patients with a
permissible degree of renal impairment), uncontrolled hypertension, uncontrolled
infections, or any kind of malignancy should not receive ciclosporin.
Before initiation of treatment a reliable baseline assessment of renal function should
be established by at least two measurements of eGFR. Renal function must be
assessed frequently throughout therapy to allow dosage adjustment (see section 4.2).
Additional precautions in endogenous uveitis
Capsorin should be administered with caution in patients with neurological Behcet`s
syndrome. The neurological status of these patients should be carefully monitored.
There is only limited experience with the use of ciclosporin in children with
Additional precautions in nephrotic syndrome
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 ciclosporin-induced renal dysfunction
because of changes in renal function related to the nephrotic syndrome itself. This
explains why, in rare cases, ciclosporin-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 ciclosporin therapy has been maintained for more than 1 year.
In patients with nephrotic syndrome treated with immunosuppressants (including
ciclosporin), the occurrence of malignancies (including Hodgkin's lymphoma) has
occasionally been reported.
Additional precautions in rheumatoid arthritis
After 6 months of therapy, renal function needs to be assessed every 4 to 8 weeks
depending on the stability of the disease, its co- medication, and concomitant
diseases. More frequent checks are necessary when the Capsorin dose is increased, or
concomitant treatment with an NSAID is initiated or its dosage increased.
Discontinuation of Capsorin may also become necessary if hypertension developing
during treatment cannot be controlled by appropriate 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 Capsorin is used in combination with methotrexate due to nephrotoxic
Additional precautions in psoriasis
Discontinuation of Capsorin therapy is recommended if hypertension developing
during 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 ciclosporin 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 Capsorin treatment is started. Patients with malignant or
pre-malignant alterations of the skin should be treated with Capsorin only after
appropriate treatment of such lesions, and if no other option for successful therapy
In a few psoriatic patients treated with Capsorin, lymphoproliferative disorders have
occurred. These were responsive to prompt discontinuation.
Patients on Capsorin should not receive concomitant ultraviolet B irradiation or
Additional precautions in atopic dermatitis
Discontinuation of Capsorin is recommended if hypertension developing during
treatment cannot be controlled with appropriate therapy.
Experience with ciclosporin 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
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
Capsorin is initiated, but are not necessarily a reason for treatment withdrawal if they
occur during therapy unless infection is severe.
Skin infections with Staphylococcus aureus are not an absolute contraindication for
Capsorin therapy, but should be controlled with appropriate antibacterial agents. Oral
erythromycin, which is known to have the potential to increase the blood
concentration of ciclosporin (see section 4.5), should be avoided. 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 Capsorin should not receive concomitant ultraviolet B irradiation or
Paediatric use in non-transplantation indications
Except for the treatment of nephrotic syndrome, there is no adequate experience
available with Capsorin. Its use in children under 16 years of age for nontransplantation indications other than nephrotic syndrome cannot be recommended.
Interaction with other medicinal products and other forms of interaction
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, the multidrug efflux transporter Pglycoprotein and organic anion transporter proteins (OATP) and may increase plasma
levels of co-medications that are substrates of this enzyme and/or transporters.
Medicinal products known to reduce or increase the bioavailability of ciclosporin: In
transplant patients frequent measurement of ciclosporin levels and, if necessary,
ciclosporin dosage adjustment is required, particularly during the introduction or
withdrawal of the co-administered medication. In non-transplant patients the
relationship between blood level and clinical effects is less well established. If
medicinal products 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.
Drugs that decrease ciclosporin levels
All inducers of CYP3A4 and/or P-glycoprotein are expected to decrease ciclosporin
levels. Examples of drugs that decrease ciclosporin levels are: Barbiturates,
carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine i.v. probucol,
orlistat, , Hypericum perforatum (St. John’s Wort), ticlopidine, sulfinpyrazone,
Products containing Hypericum perforatum (St John´s Wort) must not be used
concomitantly with Capsorin due to the risk of decreased blood levels of ciclosporin
and thereby reduced effect (see section 4.3).
Rifampicin induces ciclosporin intestinal and liver metabolism. Ciclosporin doses
may need to be increased 3- to 5-fold during co-administration.
Octreotide decreases oral absorption of ciclosporin and a 50% increase in the
ciclosporin dose or a switch to intravenous administration could be necessary.
Drugs that increase ciclosporin levels
All inhibitors of CYP3A4 and/or P-glycoprotein may lead to increased levels of
cyclosporine. Examples are:
Nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high dose),
allopurinol, cholic acid and derivatives, protease inhibitors, imatinib, colchicine,
Macrolide antibiotics: Erythromycin can increase ciclosporin exposure 4- to 7-fold,
sometimes resulting in nephrotoxicity. Clarithromycin has been reported to double
the exposure of ciclosporin. Azitromycin increases ciclosporin levels by around 20%.
Azole antibiotics: Ketoconazole, fluconazole, itraconazole and voriconazole could
more than double ciclosporin exposure.
Verapamil increases ciclosporin blood concentrations 2- to 3-fold.
Co-administration with telaprevir resulted in approximately 4.64-fold increase in
ciclosporin dose normalised exposure (AUC).
Amiodarone substantially increases the plasma ciclosporin concentration concurrently
with an increase in serum creatinine. This interaction can occur for a long time after
withdrawal of amiodarone, due to its very long half-life (about 50 days).
Danazol has been reported to increase ciclosporin blood concentrations by
Diltiazem (at doses of 90 mg/day) can increase ciclosporin plasma concentrations by
up to 50%.
Imatinib could increase ciclosporin exposure and Cmax by around 20%.
The concomitant intake of grapefruit and grapefruit juice has been reported to
increase the bioavailability of ciclosporin.
Combinations with increased risk for nephrotoxicity
Care should be taken when using ciclosporin together with other active substances
that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamycin,
tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+
sulfamethoxazole); fibric acid derivatives (e.g. bezafibrate, fenofibrate); NSAIDs
(including diclofenac, naproxen, sulindac); melphalan histamine H2-receptor
antagonists (e.g. cimetidine, ranitidine); methotrexate (see section 4.4).
During the concomitant use of a drug that may exhibit nephrotoxic synergy, close
monitoring of renal function should be performed. If a significant impairment of renal
function occurs, the dosage of the co-administered medicinal product should be
reduced or alternative treatment considered.
Concomitant use of ciclosporin and tacrolimus should be avoided due to the risk for
nephrotoxicity and pharmacokinetic interaction via CYP3A4 and/or P-gp (see section
Effects of ciclosporin on other drugs
Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter Pglycoprotein (P-gp) and organic anion transporter proteins (OATP). Coadministration of drugs that are substrates of CYP3A4, P-gp and OATP with
ciclosporin may increase plasma levels of co-medications that are substrates of this
enzyme and/or transporter.
Some examples are listed below:
Ciclosporin may reduce the clearance of digoxin, colchicine, HMG-CoA reductase
inhibitors (statins) and etoposide. If any of these drugs are used concurrently with
ciclosporin, close clinical observation is required in order to enable early detection of
toxic manifestations of the medicinal products, followed by reduction of its dosage or
its withdrawal. When concurrently administered with ciclosporin, the dosage of the
statins should be reduced and concomitant use of certain statins should be avoided
according to their label recommendations. Exposure changes of commonly used
statins with ciclosporin are summarised in Table 1. 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.
Summary of exposure changes of commonly used statins with
Fold change in exposure
Caution is recommended when co-administering ciclosporin with lercanidipine (see
Following concomitant administration of ciclosporin and aliskiren, a P-gp substrate,
the Cmax of aliskiren was increased approximately 2.5-fold and the AUC
approximately 5-fold. However, the pharmacokinetic profile of ciclosporin was not
significantly altered. Co-administration of ciclosporin and aliskiren is not
recommended (see section 4.3).
Concomitant administration of dabigatran extexilate is not recommended due to the
P-gp inhibitory activity of ciclosporin (see section 4.3).
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.
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 high first-pass effect. If
NSAIDs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with
ciclosporin, no increase in their bioavailability is to be expected.
Elevations in serum creatinine were observed in the studies using everolimus or
sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is
often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a
minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin
significantly increases blood levels of everolimus and sirolimus.
Caution is required with concomitant use of potassium-sparing medicinal products
(e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor
antagonists) or potassium-containing medicinal products since they may lead to
significant increases in serum potassium (see section 4.4).
Ciclosporin may increase the plasma concentrations of repaglinide and thereby
increase the risk of hypoglycaemia.
Co-administration of bosentan and ciclosporin in healthy volunteers increases the
bosentan exposure several-fold and there was a 35% decrease in ciclosporin exposure.
Co-administration of ciclosporin with bosentan is not recommended (see above
subsection “Drugs that decrease ciclosporin levels” and section 4.3).
Multiple dose administration of ambrisentan and ciclosporin in healthy volunteers
resulted in an approximately 2-fold increase in ambrisentan exposure, while the
ciclosporin exposure was marginally increased (approximately 10%).
A significantly increased exposure to anthracycline antibiotics (e.g. doxorubicine,
mitoxanthrone, daunorubicine) was observed in oncology patients with the
intravenous co-administration of anthracycline antibiotics and very high doses of
During treatment with ciclosporin, vaccination may be less effective and the use of
live attenuated vaccines should be avoided.
Interaction studies have only been performed in adults.
Fertility, pregnancy and lactation
Animal studies have shown reproductive toxicity in rats and rabbits.
Experience with ciclosporin in pregnant women is limited. Pregnant women receiving
immunosuppressive therapies after transplantation, including ciclosporin and
ciclosporin-containing regimens, are at risk of premature delivery (<37 weeks).A
limited number of observations in children exposed to ciclosporin in utero are
available, up to an age of approximately 7 years. Renal function and blood pressure in
these children were normal. However, there are no adequate and well-controlled
studies in pregnant women and therefore ciclosporin should not be used during
pregnancy unless the potential benefit to the mother justifies the potential risk to the
foetus. The ethanol content of the ciclosporin formulations should also be taken into
account in pregnant women (see section 4.4).
Breast-feeding Ciclosporin passes into breast milk. The ethanol content of the
Capsorin formulations should also be taken into account in women who are breastfeeding (see section 4.4). Mothers receiving treatment with Capsorin should not
breast-feed because of the potential of Capsorin to cause serious adverse drug
reactions in breast-fed newborns/infants. A decision should be made whether to
abstain from breast-feeding or to abstain from using the medicinal drug, taking into
account the importance of the medicinal product to the mother.
There is limited data on the effect of ciclosporin human fertility (see section 5.3).
Effects on ability to drive and use machines
No data exist on the effects of ciclosporin on ability to drive and use machines.
Summary of the safety profile
The principal adverse reactions observed in clinical trials and associated with the
administration of ciclosporin include renal dysfunction, tremor, hirsutism,
hypertension, diarrhoea, anorexia, nausea and vomiting.
Many side effects associated with ciclosporin therapy are dose dependent and
responsive to dose reduction. In the various indications the overall spectrum of side
effects is essentially the same; there are, however, differences in incidence and
severity. As a consequence of the higher initial doses and longer maintenance therapy
required after transplantation, side effects are more frequent and usually more severe
in transplant patients than in patients treated for other indications.
Anaphylactoid reactions have been observed following i.v. administration (see
Infections and Infestations
Patients receiving immunosuppressive therapies, including ciclosporin and
ciclosporin containing regimens, are at increased risk of infections (viral, bacterial,
fungal, parasitic) (see section 4.4). Both generalised and localized infections can
occur. Pre-existing infections may also be aggravated and reactivation of
Polyomavirus infections may lead to Polyomavirus associated nephropathy (PVAN)
or to JC virus associated progressive multifocal leukopathy (PML). Serious and/or
fatal outcomes have been reported.
Neoplasms benign, malignant and 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
section 4.4). Some malignancies may be fatal.
Tabulated summary of adverse drug reactions from clinical trials
Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system
organ class. Within each system organ class, the adverse drug reactions are ranked by
frequency, with the most frequent reactions first. Within each frequency grouping,
adverse drug reactions are presented in order of decreasing seriousness. In addition
the corresponding frequency category for each adverse drug reaction is based on the
following convention (CIOMS III):
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)
Not known (cannot be estimated from the available data)
Table 1: Adverse drug reactions from clinical trials
Blood and lymphatic system disorders
Microangiopathic haemolytic anaemia, haemolytic uraemic
Thrombotic microangiopathy, thrombotic thrombocytopenic
Metabolism and nutrition disorders
Hyperglycaemia, anorexia, hyperuricaemia, hyperkalaemia,
Nervous system disorders
Encephalopathy including Posterior Reversible Encephalopathy
Syndrome (PRES), signs and symptoms such as convulsions,
confusion, disorientation, decreased responsiveness, agitation,
insomnia, visual disturbances, cortical blindness, coma, paresis
and cerebellar ataxia
Optic disc oedema, including papilloedema, with possible
visual impairment secondary to benign intracranial
Nausea, vomiting, abdominal discomfort/pain, diarrhoea,
gingival hyperplasia, peptic ulcer
Hepatic function abnormal (see section 4.4)
Hepatotoxicity and liver injury including cholestasis,
jaundice, hepatitis and liver failure with some fatal outcome
(see section 4.4)
Skin and subcutaneous tissue disorders
Musculoskeletal and connective tissue disorders
Muscle cramps, myalgia
Muscle weakness, myopathy
Renal and urinary disorders
Renal dysfunction (see 4.4)
Reproductive system and breast disorders
Menstrual disturbances, gynaecomastia
General disorders and administration site conditions
Oedema, weight increase
* Adverse events reported from post marketing experience where the ADR frequency
is not known due to the lack of a real denominator.
Other adverse drug reactions from post-marketing experience
There have been solicited and spontaneous reports of hepatotoxicity and liver injury
including cholestasis, jaundice hepatitis and liver failure in patients treated with
ciclosporin. Most reports included patients with significant co-morbidities, underlying
conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients,
fatal outcomes have been reported (see section 4.4).
Acute and chronic nephrotoxicity
Patients receiving calcineurin inhibitor (CNI) therapies, including ciclosporin and
ciclosporin-containing regimens, are at increased risk of acute or chronic
nephrotoxicity. There have been reports from clinical trials and from the postmarketing setting associated with the use of ciclosporin. Cases of acute
nephrotoxicity reported disorders of ion homeostasis, such as hyperkalaemia,
hypomagnesaemia, and hyperuricaemia. Cases reporting chronic morphological
changes included arteriolar hyalinosis, tubular atrophy and interstitial fibrosis (see
Clinical studies have included children from 1 year of age using standard ciclosporin
dosage with a comparable safety profile to adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
The oral LD50 of ciclosporin is 2,329 mg/kg in mice, 1,480 mg/kg in rats and > 1,000
mg/kg in rabbits. The i.v. LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46
mg/kg in rabbits.
Experience with acute overdosage of ciclosporin is limited.. Oral doses of ciclosporin
of up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical
consequences, such as vomiting, drowsiness, headache, tachycardia and in a few
patients moderately severe, reversible impairment of renal function. However, serious
symptoms of intoxication have been reported following accidental parenteral
overdosage with ciclosporin in premature neonates.
In all cases of overdosage, general supportive measures should be followed and
symptomatic treatment applied. Forced emesis and gastric lavage may be of value
within the first few hours after oral intake. Ciclosporin is not dialysable to any great
extent, nor is it well cleared by charcoal haemoperfusion.
Pharmacotherapeutic group: Immunosuppressive agents , calcineurin inhibitors, ATC
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, kidneys, 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 phase G0 or G1 in 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.
Successful solid organ and bone marrow transplantations have been performed in
manusing 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 ciclosporin therapy have alsobeen shown
in a variety of conditions that are known, or may be considered to be of autoimmune
Paediatric population: Ciclosporin has been shown to be efficacious in steroiddependent nephrotic syndrome.
Following oral administration of ciclosporin peak blood concentrations are reached
within 1 to 6 hours. The absolute oral bioavailability following administration of
ciclosporin is 20 to 50%. The absorption of ciclosporin is variable and may be
influenced by intake of food. About 37% increase in AUC Cmax was observed when
ciclosporin was administered with high-fat meal. Within the therapeutic dose range
the peak plasma concentration and the area under the plasma concentration/time
curve are proportional to the dose; for whole blood, however, the relationship is nonlinear. Capsorin oral solution and soft gelatin capsules are bioequivalent. The interand intra-subject variability ranges between 18 to 74%.
Ciclosporin is distributed largely outside the blood volume, with an average apparent
distribution volume of 3.5 l/kg In the blood there is 33 to47% is present in plasma, 4
to9% in lymphocytes, 5 to12% in granulocytes, and 41 to 58% in erythrocytes. In
plasma, approximately 90% is bound to proteins, mostly lipoproteins.
Ciclosporin is extensively metabolised to approximately 15 metabolites. Metabolism
mainly takes place in the liver via cytochrome P450 3A4 (CYP3A4), and the main
pathways of metabolism consist of mono- and dihydroxylation and N-demethylation
at various positions of the molecule. All metabolites identified so far contain the
intact peptide structure of the parent compound; some possess weak
immunosuppressive activity (up to one-tenth that of the unchanged drug).
There is a high variability in the data reported on the terminal elimination 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. The excretion is primarily biliary, with only 6% of an oral dose
excreted in the urine, and with less than 1% in the unchanged form (see sections 4.2
and 4.4). The elimination half-life in kidney-transplanted patients was approximately
11 hours, with a range between 4 and 25 hours.
Patients with renal impairment
In a study performed in patients with terminal renal failure, the systemic clearance
was approximately two thirds of the mean systemic clearance in patients with
normally functioning kidneys. Less than 1% of the administered dose is removed by
Patients with hepatic impairment
An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in
patients with 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.
Pharmacokinetic data from paediatric patients given ciclosporin are very limited. In
15 renal transplant patients aged 3 -16 years, ciclosporin whole blood clearance after
intravenous administration of ciclosporin was 10.6±3.7 ml/min/kg (assay: Cyclo-trac
specific RIA). In a study of 7 renal transplant patients aged 2-16 years, the ciclosporin
clearance ranged from 9.8 to15.5 ml/min/kg. In 9 liver transplant patients aged 0.65-6
years, clearance was 9.3±5.4 ml/min/kg (assay: HPLC). In comparison to adult
transplant populations, the differences in bioavailability between ciclosporin in
paediatrics are comparable to those observed in adults.
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/day 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 foetotoxicas indicated by increased prenatal and
postnatal mortality and reduced foetal weight together with related skeletal
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 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. No
impairment in fertility was demonstrated in studies in male and female rats.
Ciclosporin was tested in a number of in vitro and in vivo tests for genotoxicity with
no evidence for a clinically relevant mutagenic potential.
Carcinogenicity studies were carried out on 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.
List of excipients
Content of the soft capsules
all-rac-α-Tocopheryl acetate (E307)
Diethylene glycol monoethyl ether
Titanium dioxide (E171)
Iron oxide black (E172)
Special precautions for storage
This medicinal product does not require any special temperature storage conditions
Store in the original package in order to protect from light and moisture.
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.
Nature and contents of container
Blister packs consisting of Aluminium/Aluminium foil
Capsorin is available in pack sizes of 10, 20, 30, 50 and 60 capsules.
Not all pack sizes may be marketed.
Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local
MARKETING AUTHORISATION HOLDER
Morningside Healthcare Ltd
115 Narborough Road
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT
Source: Medicines and Healthcare Products Regulatory Agency
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