Ciclosporin

Registered South African indications:

• Transplantation
• Psoriasis
• Rheumatoid arthritis
• Atopic dermatitis

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe renal impairment
• Coadministration with St John's wort
• Coadministration with substrates of the multidrug efflux transporter P-glycoprotein
• Coadministration with substrates of the organic anion transporter proteins (e.g bosentan, dabigatran, etexilate and aliskiren)

Cautions

• Pregnancy
• Breastfeeding
• Mild to moderate renal impairment
• Severe hepatic impairment
• Elderly
• Children
• Inexperienced managing physician
• Treatment regime containing multiple immunosuppressants
• Exposure to direct sunlight or ultraviolet radiation
• Hyperuricaemia
• Uncontrolled hypertension
• Uncontrolled infections
• Malignancy
• Epilepsy
• Premalignant skin lesions
• Skin infections
• Dyslipidaemia
• Hyperkalaemia
• Hypomagnesaemia
• Live-attenuated vaccines
• Coadministration with CYP3A4 inhibitors

Forms avail. in SA and covered in this monograph: cap, inj, sol

Solid organ transplantation

• Oral (sol, cap): Initial: 10-15mg/kg/day, in 2 divided doses, start 4-12hrs before surgery and continued for 1-2 weeks then downtitrated; Maintenance: 2-6mg/kg/day, in 2 divided doses

Bone marrow transplantation

• IV: Initial: 3-5mg/kg, dly, start 24hrs before surgery; continue for 1-2 weeks before switching to oral maintenance
• Oral (sol, cap): Initial: 12.5-15mg/kg, in 2 divided doses, started 24hrs before surgery and continued for 1-2 weeks then downtitrated; Maintenance: 10-12.5mg/kg/day, in 2 divided doses; Treatment duration: 3-6 months then downtitrate slowly to a dose of 0 by 1yr post transplantation

---

See additional prescribing points for administration instructions

---

For bone marrow transplantation, IV administration is the preferred route for initiation of treatment

---

In transplant patients, routine monitoring of cyclosporin trough levels are required and should be used to guide dosing

---

Psoriasis

• Oral (cap, sol): Initial: 2.5mg/kg/day, in 2 divided doses; Uptitrate after 1 month if needed; Maintenance: Titrate by 0.5-1.0mg/kg individually to lowest effective level; Max: 5mg/kg/24hrs

---

For psoriasis discontinue if inadequate response after 6 weeks at 5mg/kg/day

---

See additional prescribing points for administration instructions

---

Rheumatoid arthritis

• Oral (cap, sol): Initial: 2.5mg/kg/day, in 2 divided doses; Uptitrate after 6 weeks if needed; Maintenance: After being stable fo 3 months, downtitrate individually by 0.5mg/kg at intervals of 2-4 weeks to lowest effective level; Max: 5mg/kg/24hrs

---

For rheumatoid arthritis discontinue if inadequate response after 3 months at 5mg/kg/day

---

See additional prescribing points for administration instructions

---

Atopic dermatitis

• Oral (cap, sol): Initial: 2.5mg/kg/day, in 2 divided doses; Uptitrate to 5mg/kg/day after 2 weeks if needed

---

Once satisfactory response achieved, reduce dose gradually  and discontinue if possible

---

Max duration of use depends on the patient, co-morbidities, response to treatment, risk assessment and follow-up monitoring

Max duration as per manufacturer is 8 weeks

---

See additional prescribing points for administration instructions

Paed. forms avail. in SA and covered in this monograph: cap, inj, sol

Solid organ transplantation

• Refer to adult dosage

Bone marrow transplantation

• Refer to adult dosage

---

Children may require, and are able to tolerate, higher doses than adults

Pregnancy

• Caution
• 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 

Breastfeeding

• Caution; not recommended
• Ciclosporin passes into breast milk. The ethanol content of the ciclosporin formulations should also be taken into account in women who are breastfeeding. Mothers receiving treatment with ciclosporin should not breastfeed because of the potential of ciclosporin to cause serious adverse drug reactions in breastfed newborns/infants. A decision should be made whether to abstain from breastfeeding or to abstain from using the medicinal drug, taking into account the importance of the medicinal product to the mother

Renal Impairment

• Mild to moderate: Caution; dose adjustment recommended
• Severe: Contraindicated
  Therapeutic drug monitoring (TDM) is required during the course of ciclosporin therapy (trough level monitoring). For patients with severe renal impairment prior to immunosuppressant therapy, Ciclosporin is contraindicated

eGFR (ml/minute)	Dose
≥50-89	Reduce recommended dose by 25%; Check serum ciclosporin levels (TDM) prior to the next dosing
≥19-49	Reduce recommended dose by 50%; Check serum ciclosporin levels (TDM) prior to the next dosing; Record eGFR values and if eGFR continues to fall and/or TDM reveals ciclosporin toxicity discontinue use
<10	Contraindicated
Dialysis (RRT)	No adjustment necessary; Monitor for systemic toxicities: serum electrolytes, LFT, blood pressure, lipid profile, and HbA1c

Hepatic Impairment

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended
  Check serum ciclosporin levels (TDM) prior to the next dosing; Record any changes in ALT levels; Reduce dose by 25% if changes in ALT observed
• Severe (Child-Pugh class C): Caution; dose adjustment recommended
  Reduce recommended dosage by 25%-50%
  If two dosage adjustments do not reverse the increase in serum creatinine levels, treatment should be discontinued

Elderly

• Caution; no dose adjustment recommended
  Consider initiating at lower end of the dosage range

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Tremor
• Headache
• Seizures
• Confusion
• Paraesthesia
• Encephalopathy including Posterior Reversible Encephalopathy Syndrome
• Decreased responsiveness
• Agitation
• Insomnia
• Coma
• Paresis
• Cerebellar ataxia
• Motor polyneuropathy
• Benign intracranial hypertension
• Migraine
• Fatigue

Cardiovascular Disorders

• Hypertension
• Flushing
• Oedema

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal discomfort or pain
• Diarrhoea
• Gingival hyperplasia
• Peptic ulcer
• Pancreatitis

Hepatobiliary Disorders

• Abnormal hepatic function
• Hepatotoxicity
• Liver injury
• Cholestasis
• Jaundice
• Hepatitis
• Liver failure with some fatal outcomes

Genitourinary Disorders

• Renal dysfunction

Endocrine and Metabolic Disorders

• Dyslipidaemia
• Hyperglycaemia
• Anorexia
• Hyperuricaemia
• Hyperkalaemia
• Hypomagnesaemia
• Menstrual disturbances
• Gynaecomastia
• Increased weight

Musculoskeletal Disorders

• Myalgia
• Muscle cramps
• Muscle weakness
• Myopathy
• Pain of lower extremities

Skin and Subcutaneous Tissue Disorders

• Hirsutism
• Acne
• Hypertrichosis
• Allergic rashes

Immune, Blood and Lymphatic System Disorders

• Leucopenia
• Thrombocytopenia
• Anaemia
• Haemolytic uraemic syndrome
• Microangiopathic haemolytic anaemia
• Thrombotic microangiopathy
• Thrombotic thrombocytopenic purpura
• Pyrexia

Sensory Disorders

• Visual disturbances
• Cortical blindness
• Optic disc oedema, including papilloedema

• St John's wort
• Substrates of the multidrug efflux transporter P-glycoprotein
• Substrates of the organic anion transporter proteins (e.g bosentan, dabigatran, etexilate and aliskiren)
• Agents that increase serum potassium
• Live-attenuated vaccines
• CYP3A4 inhibitors
• CYP3A4 inducers
• Nifedipine
• Diclofenac
• Everolimus
• Sirolimus
• Repaglinide
• Ambrisentan
• Anthracycline antibiotics

• Renal function
• Blood pressure
• Lipid profile

Specific cases may require

• Ciclosporin trough levels
• Hepatic function
• Electrolytes

Administration instructions

• IV infusion: Dilute with normal saline or 5% glucose to 1:20 or 1:100 solution; Infuse over 2-6hrs OR as a continuous infusion over 24hrs
• Capsule: should be swallowed whole
• Solution: Dilute with small glass of orange or apple juice (other juice according to taste can also be used) in a glass container (not plastic); Stir well immediately before drinking; Owing to its possible interference with the cytochrome P450-dependent enzyme system, grapefruit or grapefruit juice should be avoided for dilution

Ciclosporin is a calcineurin inhibitor which inhibits the antigen-triggered release of lymphokines from activated T-cells. In addition, it also appears to block resting lymphocytes in the Gap 0 and Gap 1 phase of the cell cycle.

Capsule 25mg

• Ciclohexal  (Sandoz)
• Sandimmun neoral (Novartis) originator

Capsule 100mg

• Ciclohexal  (Sandoz)
• Sandimmun neoral (Novartis) originator

Solution (per ml) 100mg

• Sandimmun neoral drink (Novartis) originator

Injection (per ml) 50mg

• Sandimmun (Novartis) originator