HIGH RISK: TACROLIMUS

Question 1

What class is Tacrolimus?

Answer 1

A Calcineurin inhibitor - mediates T cells activation immunosuppressant

Question 2

Incidence of neurotoxicity is greater in tacrolimus than ciclosporin

Nephrotoxicity, hepatotoxicity, cardiovascular disorders, neurotoxicity, bone marrow suppression, eye disorders, skin, hyperglycaemia

Monitoring: BP, ECG, fasting blood glucose, Renal function, LFTs, Serum electrolyte (K), haematological, neurological and coagulation parameter

Answer 2

STABILISE ON PARTICULAR BRAND

Oral tacrolimus: reminder to maintain on the same brand. Includes generic products and prolonged-release formulations. Report of toxicity and transplant rejection on switching between products.

Examples of brands: adoport, prograf, advagraf, modigraf, envarsus

Question 3

INTERACTIONS

Answer 3

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 4

When should I refer a person taking a DMARD?

Answer 4

For people on any DMARD, consider stopping treatment and referring urgently to rheumatology if monitoring results show any of the following:

• White cell count less than 3.5 x 109/L.
• Mean cell volume more than 105 fL.
  
  • Check B12, folate, thyroid-stimulating hormone levels – if abnormal treat, if normal discuss with a specialist team.
• Neutrophils less than 1.6 x 109/L.
• Creatinine has increased more than 30% over 12 months and/or calculated GFR is less than 60 mL/min.
  
  • Repeat in 1 week, if still more than 30% from baseline, withhold and discuss with a specialist team.
• Unexplained eosinophilia more than 0.5 x 109/L.
• ALT and/or AST more than 100 U/L.
• Platelet count less than 140 x 109/L.
• Unexplained reduction in albumin less than 30 g/L.
• Blood pressure more than 140/90mmHg.
  
  • Manage in accordance with hypertension guidelines, unless on ciclosporin — stop treatment and discuss with a specialist team.
• Urinary protein 2+ or more — check mid-stream urine sample.
  
  • If evidence of an infection, treat appropriately.
  • If sterile and 2+ proteinuria or more persists on two consecutive measurements, withhold until discussed with a specialist team.

For people on any DMARD, consider stopping treatment and referring urgently to rheumatology if the person develops any of the following signs or symptoms:

• Skin/mucosal reaction — for example rash, pruritus, mouth or throat ulceration.
• Sore throat.
• Fever.
• Unexplained bruising or bleeding.
• Nausea, vomiting, diarrhoea or weight loss.
• Diffuse alopecia.
• Breathlessness, infection or cough.
• Peripheral neuropathy.

For a person on a biologic DMARD, consider stopping treatment and referring urgently to rheumatology if the person develops any of the following:

• Cough, haemoptysis, or weight loss (symptoms of tuberculosis).
• Signs or symptoms of heart failure, or worsening heart failure. For more information, see the CKS topic on Heart failure - chronic.
• Shortness of breath or dry cough (symptoms of interstitial lung disease).
• Skin rashes (be aware of lupus-like syndrome and erythema nodosum for people taking azathioprine).
• Abdominal pain, or new abdominal symptoms.

Question 5

Monitoring

Answer 5

FBC, CrCl, LFT (ALT, ALP and albumin), Blood glucose, blood pressure

• Every 2 weeks until the dose is stable for 6 weeks.
• Then monthly.
• People who have been stable for 12 months can be considered for reduced monitoring frequency (every 3 months) on an individual basis.
• More frequent monitoring is appropriate in patients at higher risk of toxicity.
• Dose increases Every 2 weeks until the dose is stable for 6 weeks, then revert to the previous schedule.

After initial dosing, and for maintenance treatment, tacrolimus doses should be adjusted according to whole-blood concentration.

Monitor whole blood-tacrolimus trough concentration (especially during episodes of diarrhoea)—consult local treatment protocol for details. - 12 hours post dose

The therapeutic range for tacrolimus is 3 - 12 µg/L - personal target