Predicting, preventing and managing adverse effects of AEDs Piero Perucca, MD Departments of Medicine and Neurology The Royal Melbourne Hospital, The University of Melbourne Melbourne, Australia Pharmacological Treatment of Epilepsy, Teaching Course, Stockholm, July 3rd, 2014 11th European Congress on Epileptology Disclosure Form No conflict of interest Off-Label Product Usage This presentation may include reference to off-label use of antiepileptic products Adverse effects of AEDs Background Leading cause of failure of AED therapy Result in AED discontinuation in up to 25% of patients Preclude attainment of fully effective dosages Affect patient adherence Deterrent of health-related quality of life Major source of disability, morbidity and mortality Burden on health care and costs Perucca P & Gilliam FG. Lancet Neurol 2012;11:792-802 Patient and clinician priorities in epilepsy treatment uncertainties Thomas RH et al. J Neurol Neurosurg Psychiatry 2010;81:918-921 How to minimise adverse effects of AEDs? Minimisation of adverse effects of AEDs A multi-stage process Tailor choice of the drug to patient characteristics and preferences Factors to be considered in AED selection Individual Age Gender Ethnicity Lifestyle Disease-related Epilepsy Comorbidities Past medical hx Family hx Drug-related Comedications Previous adverse drug effects 517 patients with epilepsy treated with LEV 53 (10.1%) developed psychiatric AEs OR (95% C.I.) p value Hx of febrile convulsions 2.90 (1.48–5.84) 0.002 Hx of status epilepticus 2.56 (1.17–5.58) 0.018 Previous psychiatric hx 1.19 (1.070–1.328) 0.001 0.40 (0.17–0.92) 0.031 LTG co-therapy Mula M et al. Neurology 2003;61:704-6 Treatment recommendations for psychiatric comorbidities in patients with epilepsy Psychiatric comorbidity Avoid Consider Mood lability/bipolar disorder - CBZ, LTG, OXC, PHT, VPA FLB, LEV, LTG, TGB BZD, GBP, PBG Depression Barbiturates, LEV, PGB, TGB, TPM, VGB, ZNS LTG Psychoses ETX, FLB, LEV, PHT, TGB, TPM, VGB, ZNS - Anxiety Perucca P & Mula M. Epilepsy Behav 2013;26:440-9 HLA-B*1502 CBZ-SJS (n=44) CBZ-tolerant (n=101) Normal (n=93) 44 (100%) 3 (3%)a 8 (8.6%)b aOR (CBZ-SJS/CBZ-tolerant): 2,504 (95% CI, 126-49,522); p=3.13 x 10-27 bOR (CBZ-SJS/Normal): 895 (95% CI, 50-15,869); p=1.38 x 10-21 Chung WH et al. Nature 2004;428:486 HLA-A*3101 positive/Tot OR (95% CI) p value CBZ-reaction Controls Hypersensitivity syndrome 10/27 (37%) 10/257 (4%) 12.41 (1.27-121.03) 0.03 Maculopapular esanthema 23/106 (22%) 10/257 (4%) 8.33 (3.59-19.36) 8.0 x 10-7 5/12 (42%) 10/257 (4%) 25.93 (4.93-116.18) 8.0 x 10-5 38/145 (26%) 10/257 (4%) 9.12 (4.03-20.65) 1.0 x10-7 SJS All phenotypes McCormack M et al. N Engl J Med 2011;364:1134-43 Recommendations for HLA genetic testing prior to commencement of carbamazepine therapy Who should be tested? Level of recommendation Sensitivity of the test Positive predictive value HLA-B*1502 HLA-A*3101 Patients originating from populations where HLA-B*1502 is common*, its frequency is unknown or origin unknown All patients Level A (strong) Level B (moderate) 80-97%a 26-61%b 1-5%a 12-42%b *e.g. Chinese, Thai, Indian, Malay, Filipino, and Indonesian aSJS/TEN; ball rashes Amstutz U et al. Epilepsia 2014;55:496-506 Plasma nisolodipine concentration (ng/mL) Effect of enzyme inducing AEDs on plasma nisoldipine levels after a single nisoldipine dose 0.8 Subjects not on PHT (n=12, 20 mg) Subjects on PHT (n=12, 40 mg) 0.4 LOQ 0.0 0 10 20 30 40 Time (h) Michelucci et al. Epilepsia 1996;37:1107-10 Effect of enzyme inducing AEDs and valproate on lamotrigine-associated rash 19.5% 12.2% 10.3% 6.7% 5.1% 2.0% 2.0% 0.1% 0.5% Messenheimer J et al. Drug Saf 1998;18:281-96 Discontinuation rates due to common adverse effects in lacosamide trials by type of concurrent AED 31.0% Discontinuation rates (%) + 14.4% 7.8% 7.2% 5.5% 6.9% 2.9% 3.7% Lacosamide dose (mg/day) Sake JK et al. CNS Drugs 2010;24:1055-68 Minimisation of adverse effects of AEDs A multi-stage process Tailor choice of the drug to patient characteristics and preferences Start at low dose & up-titrate gradually Influence of lamotrigine starting dose and dose escalation on the development of rash Starting lamotrigine dose and treatment withdrawal due to rash Mean lamotrigine dose in first 5 weeks and treatment withdrawal due to rash Messenheimer J et al. Drug Saf 1998;18:281-96 Minimisation of adverse effects of AEDs A multi-stage process Tailor choice of the drug to patient characteristics and preferences Start at low dose & up-titrate gradually Target the lowest effective maintenance dose AEP total scores p=0.75 37.3 (n=216, 94.2% on low doses) 36.5 (n=206) Perucca P et al. Neurology 2011;76:273-9 Tomson T et al. Lancet Neurol 2011;10:609-17 Minimisation of adverse effects of AEDs A multi-stage process Tailor choice of the drug to patient characteristics and preferences Start at low dose & up-titrate gradually Target the lowest effective maintenance dose Regular clinical monitoring Gilliam FG et al. Neurology 2004;62:23-7 p=0.01 Change in QOLIE-89 score % Improvement in AEP score p<0.008 Yes No Physicians received AEP ≤0 0-15 ≥15 Change in AEP score AED dose change (p<0.0001): Mean change in seizure freq (p=0.75): AEP-provided group: 21/32 (66%) pts AEP-provided group: -17.2% AEP-inaccessible group: 3/30 (10%) pts AEP-inaccessible group: +5.6% Gilliam FG et al. Neurology 2004;62:23-7 Minimisation of adverse effects of AEDs Management of adverse effects A multi-stage process Tailor choice of the drug to patient characteristics and preferences Start at low dose & up-titrate gradually Target the lowest effective maintenance dose Regular clinical monitoring Management of adverse effects of AEDs Type of adverse effect Examples Management Common, acute Drowsiness Dizziness Cognitive impairment Mood/behavioral problems Reduce dose Modify dosing scheme Discontinue AED if measures to prevent or ameliorate toxicity are ineffective Perucca P & Gilliam FG. Lancet Neurol 2012;11:792-802 Management of adverse effects of AEDs Type of adverse effect Examples Management Common, acute Drowsiness Dizziness Cognitive impairment Mood/behavioral problems Reduce dose Modify dosing scheme Discontinue AED if measures to prevent or ameliorate toxicity are ineffective Idiosyncratic Skin rashes Aplastic anemia Liver toxicity Glaucoma Discontinue AED promptly Symptomatic or supportive management Substitute AED with least risk for cross-reactivity reactions or worsening of underlying condition Perucca P & Gilliam FG. Lancet Neurol 2012;11:792-802 Management of adverse effects of AEDs Type of adverse effect Examples Management Common, acute Drowsiness Dizziness Cognitive impairment Mood/behavioral problems Reduce dose Modify dosing scheme Discontinue AED if measures to prevent or ameliorate toxicity are ineffective Idiosyncratic Skin rashes Aplastic anemia Liver toxicity Glaucoma Discontinue AED promptly Symptomatic or supportive management Substitute AED with least risk for cross-reactivity reactions or worsening of underlying condition Common, chronic Decreased BMD Weight gain/loss Symptomatic or replacement treatment Discontinuation of AED if required Perucca P & Gilliam FG. Lancet Neurol 2012;11:792-802 Management of adverse effects of AEDs Type of adverse effect Examples Management Common, acute Drowsiness Dizziness Cognitive impairment Mood/behavioral problems Reduce dose Modify dosing scheme Discontinue AED if measures to prevent or ameliorate toxicity are ineffective Idiosyncratic Skin rashes Aplastic anemia Liver toxicity Glaucoma Discontinue AED promptly Symptomatic or supportive management Substitute AED with least risk for cross-reactivity reactions or worsening of underlying condition Common, chronic Decreased BMD Weight gain/loss Symptomatic or replacement treatment Discontinuation of AED if required Drug interactions Increased risk of rash after adding lamotrigine to valproate Adjust doses according to clinical response and, if necessary, serum drug concentrations Perucca P & Gilliam FG. Lancet Neurol 2012;11:792-802 Conclusions Conclusions Understand (and listen to) the patient Implement strategies (type of AED, dosing, information) to prevent/minimize adverse effects Monitor clinical response carefully If adverse effects develop, take corrective actions promptly, as appropriate - Thank you
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