INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo CICLOHEXAL 25 (soft gelatine capsules)
CICLOHEXAL 100 (soft gelatine capsules)
CICLOHEXAL ORAL (100 mg/1 mL oral solution)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

CICLOHEXAL 25 (soft gelatine capsules)
CICLOHEXAL 100 (soft gelatine capsules)
CICLOHEXAL ORAL (100 mg/1 mL oral solution)

COMPOSITION
Each CicloHexal 25 soft gelatine capsule contains 25 mg
ciclosporin.
Ethanol content 25,8%v/v (absolute)
Each CicloHexal 100 soft gelatine capsule contains 100 mg ciclosporin.
Ethanol content 25,8%v/v (absolute)
Each 1 mL oral solution contains 100 mg ciclosporin.
Ethanol content 25,8%v/v (absolute).

PHARMACOLOGICAL CLASSIFICATION
A 34 Other.

PHARMACOLOGICAL ACTION
Ciclosporin is a cyclic polypeptide consisting of 11 amino acids and it is a potent immunosuppressive agent.
The exact mechanism of action of ciclosporin is not yet known. It has been suggested, based on animal studies, that ciclosporin inhibits the development of cell mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund adjuvant arthritis, graft versus host disease and also T-cell dependent anti-body production. It seems as though ciclosporin blocks the resting lymphocytes in the G
0or early G1 phase of the cell cycle. Lymphokine production, as well as the release of interleukin2, (T cell growth factor -TCGF), is also inhibited.
Evidence suggests that ciclosporin acts specifically and reversibly on the lymphocytes.
Pharmacokinetics.
CicloHexal soft gelatine capsules and CicloHexal oral solution are bio-equivalent.
The substance is extensively bio-transformed to approximately 15 metabolites, possessing little or no pharmacological activity.
Parent drugs and the metabolites are excreted mainly via the bile, with only 6% of the oral dose excreted in the urine and 0,1% is excreted in the urine as unchanged drug.
The terminal half life ranges from 6,3 hours, in healthy volunteers to 20,4 hours in patients with severe liver disease.
Ciclosporin is 90% bound to proteins, mostly lipoproteins.

INDICATIONS
1. Transplantation indications
Ciclosporin is indicated as an immunosuppressive agent for the prophylaxis of graft rejection, following transplantation of kidney, liver, pancreas, heart, combined heart-lung and bone marrow allogeneic transplantation. It is also used for the prevention of graft versus host disease, following bone marrow transplantation. It can also be used in the treatment of transplant rejection in patients previously receiving other immuno-suppressive agents. Ciclosporin may be used alone or in combination with corticosteroids.
2. Psoriasis
Ciclosporin is indicated in patients with severe psoriasis, in whom conventional therapy is ineffective or inappropriate and the risks of treatment are justified.

CONTRA-INDICATIONS
Known hypersensitivity to ciclosporin or to any of the other ingredients of this formulation.
Psoriatic patients with abnormal renal function, uncontrolled hypertension or infections or any kind of malignancy.
Safety of use during pregnancy has not been established.
Since ciclosporin passes into the breast milk, breast feeding should be discontinued.

WARNINGS
The physician should be aware that ciclosporin is potentially nephrotoxic and hepatotoxic. This awareness is particularly important when treating patients with pre-existing renal or hepatic disease. The risk versus benefit ratio should be determined in each case. Only physicians, experienced in immuno-suppressive therapy and the management of bone marrow and solid organ transplantation, should prescribe ciclosporin.
Patients receiving the medicine should be managed in adequate facilities.
Psoriasis-patients with abnormal renal function, uncontrolled hypertension or infections or any kind of malignancy, as well as patients receiving concomitant immunosuppressive- or radiotherapy should not receive ciclosporin.
Effect on Renal impairment- caution is required in patients with hyperuricaemia or hyperkalaemia. The addition of other medications should be carefully monitored for interactions.
Since ciclosporin can impair renal function, a reliable baseline level of serum creatinine should be established by at least two measurements prior to treatment, and serum creatinine should be monitored at 2-weekly intervals for the first three months of therapy. Thereafter, if creatinine remains stable, measurements should be done every 2 months in patients who are administered 2,5 mg per kilogram per day and at monthly intervals in patients who require higher doses. If the serum creatinine remains increased by more than 30% above creatinine levels recorded before starting ciclosporin therapy at more than one measurement, the dosage of ciclosporin must be reduced by 25-50%.
These recommendations apply even if the patient’s values still lie within the laboratory normal range. If dose reduction is not successful within one month, ciclosporin treatment should be discontinued.
Blood pressure : At least two blood pressure measurements on separate occasions should be done before ciclosporin treatment is started. Discontinuation of ciclosporin therapy is also recommended if hypertension developing during ciclosporin therapy cannot be controlled with appropriate therapy.
Ciclosporin blood levels may be of value in cases of possible medicine interactions as well as in assessing compliance.
In psoriatic patients on ciclosporin as well as on conventional therapy, development of malignancies (in particular of the skin) has been reported. In a few psoriatic patients treated with cyclosporin, lymphoproliferative disorders have occurred. These were responsive to prompt discontinuation of treatment (see also section “Side Effects”). Although relapse occurs commonly after discontinuation of cyclosporin therapy for psoriasis, maintenance therapy is not recommended for longer than one year.

DOSAGE AND DIRECTIONS FOR USE
Organ transplantation and dose adjustment :
treatment with ciclosporin should be initiated with-in 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 one to two weeks postoperaratively before being gradually reduced in accordance with blood levels until a maintenance dose of about 2 to 6 mg/kg given in two divided doses is reached.
When ciclosporin is given together with low doses of corticosteroids some patients may need lower doses (e.g. 3 to 6 mg/kg given in two divided doses for the initial treatment). Some centres have successfully lowered the ciclosporin dose to such levels in selected renal transplant patients without an apparent rise in the rejection rate. See also “Practical recommendation”.
Bone marrow transplantation : The day before transplantation 12,5 to 15 mg/kg should be given in two divided doses. This daily dose is maintained for about 5 days. For continuation of treatment 12,5 mg/kg/day is given for at least 3 to 6 months (preferable 6 months), before gradually decreasing the dose to zero, which sometimes may require up to 1 year. In some patients graft-versus-host disease occurs after discontinuation of ciclosporin treatment, but usually responds favourably to re-introduction of therapy (in low doses of mild chronic graft-versus-host disease).
See also “Practical recommendations”.
The recommended dosage for treatment of established graft-versus-host disease (GVHD) :. A dose of 12,5 to 15 mg/kg/day given in two divided doses, is recommended. This dosage should continue for 50 days and then be reduced by 5% per week until 2 mg/kg/day is reached. The agent may then be discontinued.
Psoriasis : For inducing remission, the recommended initial dose is 2,5 mg/kg/day given in two divided oral doses. If there is no improvement after 1 month, the daily dose may be gradually increased but should not exceed 5 mg/kg/day.
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 safety guidelines given below. (see “Warning”).
Initial dose of 5 mg/kg/day in two divided doses is justified in patients whose condition requires rapid improvement.
For maintenance treatment, doses have to be titrated individually to the lowest effective level. Dose adjustments should be made in increments of 0,5 to 1 mg/kg body mass and should not exceed 5 mg/kg/day.
Practical recommendations : Oral Drink Solution : CicloHexal oral drink solution should be diluted with preferably orange or apple juice; however, other drinks such as soft drinks can be used according to individual taste. The solution should be stirred well and drunk at once. Owing to its possible interference with the P450-dependent enzyme system, grapefuit juice should be avoided for dilution. (Also see storage instructions).
Capsules : Capsules should be swallowed whole. Leave capsules in blister pack until required for use. Capsules should not be stored above 30°C.
When a blister pack is opened, a characteristic smell is noticeable. This is normal and does not mean there is anything wrong with the capsules.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The following side effects can be observed during administration of ciclosporin : A subjective burning sensation may occur in the hands and feet, usually in the first week of oral administration. The most frequently observed side effects in organ transplant patients are tremor, hirsutism, impaired renal function, hepatic dysfunction, gingival hypertrophy and gastro-intestinal disturbances (anorexia, nausea, vomiting). The most frequently observed side effects in bone marrow transplant patients are tremor, gastrointestinal disturbances (anorexia, nausea, vomiting), hirsutism and impaired renal function. Facial oedema and angio-oedema have also been observed.
In about one quarter of the patients reversible impairment of renal function has been observed; and ciclosporin may cause increases in serum bilirubin, liver enzymes, urea and creatine. These changes appear to be dose-related and reversible. Serum creatinine and urea levels may also be elevated during ciclosporin therapy even in the presence of good renal function. Impaired renal function requires close monitoring of these parameters and frequently dosage adjustment.
Due to its potent immunosuppressive activity, the use of ciclosporin may lead to an increased susceptibility to infection.
Do not give concomitantly with other immunosuppressive agents except corticosteroids, since this is known to lead to an increase in the incidence and severity of infections.
Hyperkalaemia and hyperuricaemia may occur
Patients receiving ciclosporin should avoid high dietary potassium intake and potassium containing or potassium-sparing medication.
Hypertension has been observed in most heart transplant patients given ciclosporin
The combination of hypertension, fluid retention and convulsions has been observed mainly in children. Vaccination may be less effective in children receiving ciclosporin, and attenuated live vaccines should not be used.
A syndrome of thrombocytopaenia, thromboembolic complications and Microangiopathic haemolytic anaemia (which may result in graft failure) has been reported.
There is an increased incidence of lympho proliferative disorders in patients receiving ciclosporin therapy.
Experience of administration of ciclosporin to young children is limited

Interactions
Hyperkalaemia may occur during ciclosporin therapy. Patients receiving ciclosporin should avoid high dietary potassium intake and potassium containing or potassium-sparing medication.
Vaccination may be less effective when administered during treatment with ciclosporin. The use of live attenuated vaccines should be avoided.
Care should be taken when co-administering ciclosporin and systemic antibiotics or other compounds which are known to have nephrotoxic effects eg. aminoglycosides, amphotericin B.
The trimethoprim component of cotrimoxazole, when co-administered with ciclosporin has been reported to cause a reversible deterioration in renal function.
Ketoconazole, erythromycin, doxycycline, oral contraceptives and some calcium channel blockers (diltiazem, nicardipine, verapamil), have been reported to increase the plasma concentration of ciclosporin.
Phenytoin, phenobarbitone, rifampicin, carbamazepine and isoniazid have been reported to cause a decrease in plasma / blood concentration of ciclosporin.
Intravenous administration of sulphadimidine and trimethoprim results in a marked decrease in serum ciclosporin levels.
Avoid co-administration of the above mentioned medicines and ciclosporin. Should it be essential to co-administer these medicines, the blood levels of ciclosporin must be closely monitored and the dosage of ciclosporin adjusted accordingly.
Prednisolone clearance is reduced in patients treated with ciclosporin and plasma levels of ciclosporin increase following the administration of high dose methyl prednisolone.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
No experience of acute overdose with ciclosporin is available. Signs of nephrotoxicity might occur. Symptomatic treatment and general supportive measures should be followed in all cases of overdosage. Forced emesis could be of value within the first few hours of intake. Ciclosporin is not dialysable to any great extent, nor is it effectively cleared with charcoal haemoperfusion.

IDENTIFICATION
CicloHexal 25
- red brown soft gelatine capsules. 5 minims oval.
Diameter - 7mm +1mm. Length - 11,5mm +1mm. Capsule content - clear solution
CicloHexal 100 - red brown soft gelatine capsules. 20 minims oblong.
Diameter - 9,5mm +1mm. Length - 24mm +1mm. Capsule content - clear solution
CicloHexal Oral - clear, colourless to yellowish, viscous solution, free from undissolved or foreign matters; smell of ethanol.

PRESENTATION
CicloHexal 25
- Aluminium/aluminium blisters - 10 tablets per blister strip, 5 blister strips per carton (50 tablets).
CicloHexal 100 - Aluminium/ aluminium blisters - 10 tablets per blister strip, 5 blister strips per carton (50 tablets).
CicloHexal Oral - round amber glass bottles (50 mL)

STORAGE INSTRUCTION
Capsules - Store below 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN
Oral Solution - Use contents within 2 months after opening the bottle. Store above 20°C and below 25°C. This is because the formulation contains oily components of natural origin which tend to solidify at low temperatures. A jelly like formation may occur at temperatures below 20°C, which is however reversible at temperatures up to 30°C.

REGISTRATION NUMBERS
CicloHexal 25 :         32/34/0682
CicloHexal 100 :         32/34/0683
CicloHexal Oral :         32/34/0681

NAME AND BUSINESS OF ADDRESS OF APPLICANT
Hexal Pharma (SA) (PTY) Ltd
UNIT A, 10 Fangio Rd
Mahogany Ridge
Westmead
3610

DATE OF PUBLICATION OF THIS PACKAGE INSERT       
December 2000

        CICP1

Updated on this site: January 2003
Source: Pharmaceutical Industry

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