Immunosuppressant’s

Question 1

Immunosuppressant’s are used to

Answer 1

suppress transplant injections and treat chronic or inflammatory or autoimmune diseases.

Question 2

Myelosuppression =

Answer 2

suppression of immune system

Question 3

Azathioprine + SE

Answer 3

Azathioprine is an immunosuppressant which is metabolised to mercaptopurine.

Side effects:
• Hypersensitivity reactions including malaise, dizziness, vomiting, diarrhoea, fever, rigors, myalgia, arthralgia, rash, hypotension and renal dysfunction require immediate withdrawal.
• Neutropoenia and thrombocytopenia: Neutropoenia is dose-dependent. Management of neutropoenia and thrombocytopenia requires careful monitoring and dose adjustment.
• Nausea is common in the early stages of treatment and usually resolves in a few weeks without changing the dose. Moderate nausea can be managed by using divided daily doses, taking doses after food, prescribing antiemetics or temporarily reducing the dose.
• REDUCE dose with allopurinol = toxicity.

Question 4

Azathioprine - Pre-treatment screening

Answer 4

• The enzyme thiopurine methyltransferase (TPMT) metabolises thiopurine drugs (azathioprine, mercaptopurine, tioguanine)
• The risk of myelosuppression is increased in patients with reduced activity of this enzyme. Thus, TPMT activity should be measured before starting therapy.
• Patients with absent TPMT activity should NOT receive this drug, those with reduced TPMT activity may be treated under specialist supervision.

Question 5

Azathioprine - monitoring

Answer 5

• Monitor for toxicity throughout treatment
• Monitor full blood count weekly (more frequently with higher doses, or if severe hepatic or renal impairment) for the first 4 weeks… thereafter reduce the frequency of monitoring to every 3 months.
• Blood tests and monitoring for myelosuppression are essential in long-term treatment.
- Azathioprine is BRAND-SPECIFIC - prescribe by brand name.

Question 6

Azathioprine - Patients should be warned to report…

Answer 6

symptoms of bone marrow suppression e.g. inexplicable bruising or bleeding, infection

Question 7

Ciclosporin + SE

Answer 7

 Ciclosporin is a potent immunosuppressant and works by supressing the immune response. It does not cause myelosuppression, but it is nephrotoxic (toxic to the kidneys).
 Ciclosporin should be prescribed by BRAND-NAME. Patients should be stabilised on a particular brand because switching between formulations without close monitoring can lead to important changes in blood-ciclosporin concentration.
 Side effects: (when used as eye drops): common side effects include eye discomfort + inflammation… as well as blurred vision.
 Avoid excessive exposure to UV light including sunlight.
 In psoriasis + atopic dermatitis avoid use of UVB or PUVA

Question 8

Ciclosporin - Warning signs (report immediately to a doctor)

Answer 8

 Neurotoxicity (tremor, headache, encephalopathy (e.g. confusion, convulsions))
 Blood disorders (signs of infection e.g. fever, sore throat, mouth ulcers, unexplained bruising/ bleeding)
 Liver toxicity (jaundice, nausea, vomiting, abdominal discomfort, dark urine)
 Nephrotoxicity (elevated serum creatinine concentrations)
 Vomiting, drowsiness, tachycardia
 Hypertension (common; monitor blood pressure regularly)
 Benign intracranial hypertension (headache, visual disturbances; discontinue if occurs)
 Gingivial hyperplasia

Question 9

Ciclosporin - Monitoring requirements

Answer 9

 Whole blood ciclosporin concentration should be monitored throughout treatment
 Renal function should be monitored – an increase in serum creatinine and urea may call for a dose reduction (in transplant patients) or discontinuation of treatment (in non-transplant patients)
 Blood pressure should be monitored  discontinue if hypertension develops that cannot be controlled with antihypertensives.
 Blood pressure and renal function should be measured atleast twice before starting therapy for psoriasis or eczema.
 Blood lipids should be measured before and after the first month of treatment
 Monitor liver function.
 Monitor serum potassium especially in renal dysfunction (risk of hyperkalaemia)
 Monitor serum magnesium
 In rheumatoid arthritis, measure serum creatinine atleast twice before treatment. During treatment, monitor serum creatinine every 2 weeks for first 3 months + then every month for a further 3 months.
 In psoriasis + atopic dermatitis measure serum creatinine every 2 weeks for first 3 months then every month
 Investigate lymphadenopathy that persists despite improvement in atopic dermatitis.
 Monitor hepatic function if on NSAIDS

Question 10

Ciclosporin Interactions

Answer 10

 Increased plasma concentration with clarithromycin, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, miconazole, metoclopramide, verapamil, and tacrolimus
 Increased risk of nephrotoxicity and myotoxicity with colchicine
 Decreased plasma concentration with carbamazepine, orlistat, phenobarbital, phenytoin, rifampicin, St John’s wort
 Increased risk of hyperkalaemia when ciclosporin given with ACE inhibitors or ARBs, or aldosterone
 antagonists
 Increased risk of nephrotoxicity when ciclosporin given with NSAIDs, plus increases plasma concentration of diclofenac
 Ciclosporin increases plasma concentration of digoxin (increased risk of toxicity)
 Increased risk of myopathy when ciclosporin given with statins (avoid)

Question 11

Tacrolimus + SE

Answer 11

• Tacrolimus is a calcineurin inhibitor which acts to supress the immune response.
• Side effect: Cardiomyopathy (disease of heart muscle) has been reported to occur primarily in children with tacrolimus blood trough conc. much higher than recommended max. levels. Monitor patients by echocardiography for hypertrophic changes - consider dose reduction or discontinuation if these occur.
• Avoid excessive exposure to sunlight/UV light. Use wide spectrum SPF
• May affect driving
• Patients must not receive immunisation with live vaccines
• Avoid a high potassium diet and grapefruit juice

Question 12

Tacrolimus - MHRA: Brand-specific prescribing + dispensing

Answer 12

Switching between oral tacrolimus products has been associated with reports of toxicity and transplant rejection. To ensure a maintained therapeutic response, oral tacrolimus should be prescribed by brand name:

1. Adoport, Prograf, Capexion are immediate-release capsules that are taken TWICE daily (once in the morning and once in the evening)
2. Modigraf granules make an immediate release oral suspension which is taken TWICE daily (once in the morning and once in the evening)
3. Advagraf is a prolonged-release capsule that is taken ONCE daily in the morning.

Question 13

Tacrolimus - Monitor:

Answer 13

• Monitor: BP, ECG, fasting blood glucose conc, renal function, liver function, Serum electrolytes (particularly K+), Haematological, neurological (including visual) and coagulation parameters

Question 14

Tacrolimus • Warning signs (report immediately to a doctor)

Answer 14

o Neurotoxicity (tremor, headache)
o Nephrotoxicity (elevated serum creatinine concentrations)
o Eye disorders (blurred vision, photophobia)
o Skin disorders (rash, toxic epidermal necrolysis)
o Blood disorders (signs of infection e.g. fever, sore throat, mouth ulcer, unexplained bruises/bleeds)
o Hyperglycaemia (diabetes mellitus e.g. increased thirst or excessive urination)
o Cardiovascular disorders (cardiomyopathy, arrhythmias, hypertension)
o Liver toxicity (jaundice, nausea, vomiting, abdominal discomfort, dark urine)

Question 15

Tacrolimus Interactions

Answer 15

• Increased plasma concentration with clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, nifedipine, omeprazole, ranolazine
• Reduced plasma concentration with phenobarbital, St. John’s Wort, rifampicin, phenytoin
• Increased risk of nephrotoxicity when given with aminoglycosides, amphotericin and NSAIDs (especially ibuprofen), certain antivirals (e.g. aciclovir, ganciclovir)
• Tacrolimus increases plasma concentration of ciclosporin
• Increased risk of hyperkalaemia when given with potassium-sparing diuretics (e.g. amiloride, spironolactone), potassium salts, angiotensin II receptor antagonist

Question 16

Mycophenolate mofetil

Answer 16

• Mycophenolate Mofetil is an immunosuppressant (purine synthesis inhibitor).
 Patients should report signs of bone marrow suppression (infection, unexplained bruising or bleeding)
 MHRA: Genotoxic – MEN: use effective contraception during treatment + 3 months after discontinuation. WOMEN: use 2 methods of effective contraception during treatment + 6 weeks after discontinuation

Question 17

Mycophenolate mofetil - cautions

Answer 17

Measure serum immunoglobulin levels if recurrent infections develop and consider bronchiectasis (abnormal widening of the bronchi causing infection) or pulmonary fibrosis if persistent respiratory symptoms such as cough and dyspnoea (difficulty breathing) develop.

Question 18

Methotrexate - Important safety information, dose

Answer 18

The dose is a weekly dose. To avoid error with low-dose methotrexate, it is recommended that:

• The patient is carefully advised of the dose and frequency and the reason for taking methotrexate, as well as any other prescribed medicine (e.g. folic acid)
• Only one strength of methotrexate tablet (usually 2.5mg) is prescribed and dispensed.
• The prescription and dispensing label show the dose + frequency of methotrexate administration
• The patient is warned to report immediately the onset of any blood disorders (sore throat, bruising, mouth ulcers), liver toxicity (nausea, vomiting, dark urine) + respiratory effects (e.g. SOB)

Question 19

Methotrexate - Cautions:

Answer 19

1. Blood count: bone-marrow suppression can occur abruptly. A significant drop in white cell count or platelet count calls for immediate withdrawal of methotrexate.
2. Gastro-intestinal toxicity: withdraw treatment if stomatitis occurs – may be the first sign of G.I. toxicity
3. Liver toxicity: liver cirrhosis reported. Treatment should not be started or should be discontinued if any abnormality of liver function tests or liver biopsy develops. Abnormalities can return to normal within 2 weeks after which treatment may be recommenced.
4. Pulmonary toxicity: may be a special problem in rheumatoid arthritis. Patients should seek medical attention if dyspnoea, cough or fever develops.

Question 20

Methotrexate - Monitoring requirements

Answer 20

• Patients should have full blood count and renal + liver function tests repeated every 1-2 weeks until therapy is stabilised. Thereafter, patients should be monitored every 2-3 months.
• Patients should be advised to report all symptoms and signs suggestive of infection, especially sore throat.

Question 21

Methotrexate - Patient and carer advice

Answer 21

• Patients should be warned to report immediately the onset of any blood disorders (sore throat, bruising, mouth ulcers), liver toxicity (nausea + vomiting) + respiratory effects (e.g. shortness of breath)
• Advise patients to avoid self-medication with OTC Ibuprofen or Aspirin
• Issue methotrexate treatment booklets.
• Avoid pregnancy – teratogenic. Use contraception for at least 6 months after treatment male + female

Question 22

Methotrexate - Interactions

Answer 22

• Increased plasma concentration and risk of hepatotoxicity with acitretin (avoid)
• Excretion reduced by NSAIDs and penicillins, therefore increased risk of toxicity; also increased risk of toxicity with ciprofloxacin, doxycycline, tetracycline, ciclosporin, PPIs, and leflunomide
• Increased risk of haematological toxicity when given with trimethoprim or co-trimoxazole

Question 23

Methotrexate + Folinic acid

Answer 23

Folinic acid following methotrexate administration helps to prevent methotrexate-induced mucositis and myelosuppression.

Question 24

Tamoxifen

Answer 24

• There is an increased risk of endometrial cancer. Patients should report abnormal vaginal bleeding including menstrual irregularities, vaginal discharge and pelvic pain/pressure
• There is an increased risk of thromboembolism and patients should be made aware of the symptoms and advised to report sudden breathlessness and any pain in the calf of one leg.