Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

Organ transplantation

Initially, a single oral dose of 10-15mg/kg body weight, should be given 4-12 hours before transplantation. As a general rule, treatment should continue at a dose of 10-15mg/kg/day for 1-2 weeks post-operatively. Dosage should then be gradually reduced until a maintenance dose of 2-6mg/kg/day is reached. Dosage should be adjusted by monitoring ciclosporin blood levels and kidney function. When SANDIMMUN is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy) lower doses (e.g. 3-6mg/kg/day orally initially) may be used.

The use of the concentrate for intravenous infusion is recommended in organ transplant patients who are unable to take SANDIMMUN orally (e.g. shortly after surgery) or in whom the absorption of the oral forms might be impaired during episodes of gastrointestinal disturbances. In such cases the intravenous dose is one third of the recommended oral dose. It is recommended, however, that patients are transferred to oral therapy as soon as the given circumstances allow.

Bone marrow transplantation/prevention and treatment of graft-versus-host disease (GVHD)

SANDIMMUN Concentrate for intravenous infusion is usually preferred for initiation of therapy, although the oral forms may be used. The recommended dosage by the intravenous route is 3-5mg/kg/day, starting on the day before transplantation and continuing during the immediate post-transplant period of up to two weeks until oral maintenance therapy begins.

Treatment with SANDIMMUN should continue using the oral forms at a dosage of 12.5mg/kg/day for at least three and preferably six months before tailing off to zero. In some cases higher oral doses or the use of i.v. therapy may be necessary in the presence of gastrointestinal disturbances which might decrease absorption. If oral treatment is used to initiate therapy the recommended dose is 12.5-15mg/kg/day starting on the day before transplantation.

If GVHD develops after SANDIMMUN is withdrawn it should respond to reinstitution of therapy. Low doses should be used for mild, chronic GVHD.

Intravenous administration

When SANDIMMUN is administered by the intravenous route, the intravenous dose is one third of the recommended oral dose.

SANDIMMUN concentrate should be diluted 1:20 to 1:100 with normal saline or 5% glucose before use and given by slow intravenous infusion over 2-6 hours.

Child Dosage

Experience with SANDIMMUN in young children is still limited. Transplant recipients from three months of age have received the drug at the recommended dosage with no particular problems, although at dosages above the upper end of the recommended range, children seem to be more susceptible to fluid retention, convulsions and hypertension. This responds to dosage reduction.

Elderly Dosage

Experience in the elderly is limited but no particular problems have been reported following the use of the drug at the recommended dose. However, factors sometimes associated with ageing, in particular impaired renal function, make careful supervision essential and may necessitate dosage adjustment.

In rheumatoid arthritis clinical trials with ciclosporin, 17.5% of patients were aged 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises 50% above the baseline after 34 months of therapy.

Clinical studies of Neoral in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Contra Indications

Known hypersensitivity to ciclosporin.

Concomitant use of tacrolimus is specifically contraindicated.

Concomitant use of rosuvastatin is specifically contraindicated.

SANDIMMUN Concentrate for Intravenous Infusion should not be used in patients known to be hypersensitive to polyethoxylated castor oils.

Special Precautions

Interactions

Food interactions

The concomitant intake of a fat rich meal or grapefruit juice has been reported to increase the bioavailability of ciclosporin.

Drug interactions

Of the many drugs reported to interact with ciclosporin, those for which the interactions are adequately substantiated and considered to have clinical implications are listed below.

Various agents are known to either increase or decrease plasma or whole blood ciclosporin levels usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular CYP3A4. Ciclosporin is also an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase plasma levels of comedications that are substrates of this enzyme and/or transporter.

Drugs that decrease ciclosporin levels:

Barbiturates, carbamazepine, oxcarbazepine, phenytoin; rifampicin, octreotide, orlistat, hypericum perforatum (St John's Wort); ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase ciclosporin levels:

Macrolide antibiotics (e.g. erythromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high dose); allopurinol; amiodarone; ursodeoxycholic acid; protease inhibitors, imatinib; colchicine.

Other relevant drug interactions

Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); non-steroidal anti-inflammatory drugs (including diclofenac, naproxen, sulindac); melphalan; methotrexate.

Concomitant use with tacrolimus should be avoided due to increased potential for nephrotoxicity.

The concurrent administration of nifedipine with ciclosporin may result in an increased rate of gingival hyperplasia compared with that observed when ciclosporin is given alone.

Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased threefold and the AUC of ciclosporin was increased 21%. Therefore caution is recommended when co-administering ciclosporin together with lercanidipine.

The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its first-pass effect. If non-steroidal anti-inflammatory drugs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.

Ciclosporin may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and etoposide.

Severe digitalis toxicity has been seen within days of starting ciclosporin in several patients taking digoxin.

Administration of ciclosporin may enhance the potential of HMG-CoA reductase inhibitors (statins) and colchicine to induce muscular toxicity e.g. muscle pain and weakness, myositis and occasionally rhabdomyolysis. If ciclosporin is to be concomitantly administered with a statin then the prescriber should refer to the product information for the relevant statin as the dose may need to be reduced. Rosuvastatin is specifically contraindicated with ciclosporin.

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 for concomitant use of potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium containing drugs since they may lead to significant increases in serum potassium.

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

Recommendations

If the concomitant use of drug known to interact with ciclosporin cannot be avoided, the following basic recommendations should be observed.

During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered drug should be reduced or alternative treatment considered.

In graft recipients there have been isolated reports of considerable but reversible impairment of kidney function (with corresponding increase in serum creatinine) following concomitant administration of fibric acid derivatives (e.g. bezafibrate, fenofibrate). Kidney function must therefore be closely monitored in these patients. In the event of significant impairment of kidney function the co-medication should be withdrawn.

Drugs known to reduce or increase the bioavailability of ciclosporin: in transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment are required, particularly during the introduction or withdrawal of the co-administered drug. In non-transplant patients the value of ciclosporin blood level monitoring is questionable, as in these patients the relationship between blood level and clinical effect is less well established. If drugs known to increase ciclosporin levels are given concomitantly, frequent assessment of renal function and careful monitoring for ciclosporin related side-effects may be more appropriate than blood level measurement.

The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of ciclosporin.

Non-steroidal anti-inflammatory drugs known to undergo strong first-pass metabolism (e.g. diclofenac) should be given at doses lower than those that would be used in patients not receiving ciclosporin. When diclofenac is given concomitantly with ciclosporin the dose of diclofenac should be reduced by approximately half.

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

Adverse Reactions

Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction.

Immune System Disorders

Not known: Anaphylactoid reactions can consist of non-cardiogenic pulmonary oedema, with acute respiratory distress, dyspnoea, wheezing, flushing of the face and upper thorax, and blood pressure changes and tachycardia.

Infections and infestations:

Patients receiving ciclosporin and ciclosporin-containing regimens as well as other immunosuppressive regimens are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalised and localised 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 leukoencephalopathy (PML). Serious and/or fatal outcomes have been reported.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

The increased risk of developing malignancies and lymphoproliferative disorders (including lymphomas), some with reported fatalities, appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports.

Table 1

Manufacturer

Drug Availability

Updated