Neurological toxicity of Tri-azole Antifungals

1. Neurological toxicity ofTri-azole Antifungals DR CAROLINE BAXTER Clinical Research Fellow www.aspergillus.org.uk

2. Tri-azole Antifungals Voriconazole Posaconazole Itraconazole

3. Type 1 and 3 hypersensitivity ABPA ‘ASPERGILLUS BRONCHITIS’ SAFS ASPERGILLOMA CPA

4. Tri-azole side effects • 216 patients taking itraconazole • 46% experienced adverse side effect • Neurological: 21% sleep disturbance/poor memory and concentration, 11% peripheral neuropathy, 4% tremor. • Seizures described but rare. Lestner et al, Clin Infect Dis, 2009 Sep 15;49(6):928-30

5. Toxicity and drug levels Lestner et al, Clin Infect Dis, 2009 Sep 15;49(6):928-30

6. Therapeutic Drug Level Monitoring

7. Tremor • 216 patients on itraconazole • 5 cases reported – confirmed by accelerometry • Onset 3wk-12 months • 3 of 5 cases itraconazole level>15mg/l • Dose reduction did not alter symptoms • 1 case resolved off treatment and recurred with recommencement of the drug • Also described with voriconazole and posaconazole. • Unlikely class effect Lestner et al, J Neurol Neurosurg Psychiatry. 2010 Mar;81(3):327-9

8. Peripheral Neuropathy • Retrospective study • Patients with aspergillosis commenced on tri-azoles between 2007-2010. • 222 patients were commenced on tri-azole antifungals: 107 itraconazole, 75 voriconazole and 40 posaconazole. • 24 patients described symptoms of PN, 1 excluded as diagnosed median nerve palsy. • 3 patients described symptoms with both itraconazole and voriconazole. • Total of 26 ‘clinical episodes’ of PN. Baxter et al. J Antimicrob Chemother. 2011 Sep;66(9):2136-9

9. Peripheral Neuropathy • 22 presented as a sensory disturbance of the hands and/or feet developing over a median of 3 months. • 4 presented with acute predominant lower limb weakness and difficulty walking over 1 to 4 weeks. • 12 male, 11 female. Mean age 59. • 26 episodes: 18 itraconazole, 7 voriconazole, 1 posaconazole

10. Drug Levels • 11 of the 26 had persistently elevated drug levels (despite dose reductions) in the 3 months prior to onset of symptoms. • 10 of the 11 were high itraconazole levels and 1 elevated posaconazole level. All 7 patients experiencing symtoms with voriconazole had therapeutic drug levels.

11. NCS • 15 of the 26 episodes had formal nerve conduction studies performed. • 12 of the 15 had confirmed PN: - 6 sensory predominant axonal neuropathy - 2 small fibre sensory neuropathy - 3 motor predominant axonal neuropathy - 1 mixed axonal/demyelinating neuropathy • Of the 3 negative studies – no baseline, no small fibre studies, all spent >1 month off therapy prior to NCS

12. Outcome • 2 patients had persistent symptoms despite cessation of medication. • 2 resolved with dose reduction • All others resolved with stopping medication • 3 patients had symptoms with both itraconazole and voriconazole • 3 patients successfully changed to an alternative triazole

13. Discussion • Remarkably high rate of PN: itra 17%, vori 9%. • No direct relationship to drug levels but some on itraconazole with high levels do respond to a reduction in dose. • First ever described case of posaconazole PN. • Most sensory predominant axonal neuropathy but must note 4 cases of rapid debilitating motor axonal neuropathy. • Must screen for other causes of PN. • Pathogenesis unknown – metronidazole (imidazole), mitochondrial disorders, accumulation in phospholipids in neurons.

14. Discussion • Risk, although low, of non recovery • Early detection vital • Neuropathy scales (chemotherapy, diabetes) • Baseline NCS and small nerve studies

15. Clinical Case • HR • Female • 20 years old • Cystic fibrosis ∆F508/∆F508 • Transferred to adult services (MACFU) in March 2007

16. Clinical Case CF past history: • Hearing loss due to iv aminoglycosides. • Chronic transmissible strain Pseudomonas auerginosa. Intermittent Staphylococcus aureus. • 1998 RLL lobectomy - aspergilloma (histology). Post surgery treatment with itraconazole 200mg bd.

17. Clinical Case • Clinically stable since surgery. Itraconazole 200mg bd continued. DRUG LEVEL MONITORING • 01.11.02  Random 0.5mg/L • 03.02.03  Random <0.4 no drug detected • 25.03.03  Post-dose 2.1 • 03.07.03  Random 1.8 • 27.08.03  Post-dose 1.6 • 17.11.03  Post-dose 2.9 • 16.01.04  Random 2.3 • 14.06.04  Random 2.8

18. Clinical Case • Compliance • Brand • Time taken/food • Other medication • CF – GI absorption

19. Clinical Case • 2004 - Developed bilateral hand weakness and parasthesia. • Seen by neurologist – peripheral neuropathy secondary to itraconazole. Itraconazole stopped. No recovery but no progression. • Poor fine motor skills.

20. Clinical Case • After transfer to MACFU, HR remained well with no complications • Annual november 2008 – FEV1 1.8, FVC 2.15 (approx 65% predicted) • Total IgE 880 KIU/l • Specific IgE Aspergillus 15.2 KUa/l • Eosinophils 0.13

21. Clinical Case • January 2009 • Attended clinic feeling unwell • Increasing shortness of breath and cough • FEV1 1.7, FVC 2.0 • CXR – no acute changes • Last sputum culture – Pseudomonas aeruginosa and Candida glabrata. • Given 2 weeks oral ciprofloxacin and increased dose of azithromycin. • Deterioration despite antibiotics (FEV1 1.0, CRP<5, culture negative) • Admitted to hospital

22. Clinical Case • Improved in hospital with oral steroids and physiotherapy • Rapid decline on discharge as steroids weaned ?

23. Altered mental function • Wide description of different symptoms associated with all tri-azoles. • Common – 20% patients • Sleep disturbance and nightmares • Poor concentration • Impaired memory - STM • Depression

24. Conclusions • Side effects with tri-azoles are common and often limit their use. • The three most common neurological side effects of tri-azoles are poor sleep/altered mental function, tremor and peripheral neuropathy. • Drug level monitoring is important. • First ensure drug levels are in therapeutic range. If symptoms not severe can first trial a dose reduction but maintain therapeutic levels. • Risk balance of side effects and treatment benefit.

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