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Hydroxyzine (Atarax®) and Risk of QT Interval Prolongation and Torsades De Pointes

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Hydroxyzine (Atarax®) and Risk of QT Interval Prolongation and Torsades De Pointes Hydroxyzine (Atarax®) and Risk of QT Interval Prolongation and Torsades de Pointes On June 6, 2016 Health Canada released a warning that hydroxyzine has been associated with QT interval prolongation and torsade de pointes (TdP) which may lead to dizziness, palpitations, syncope, seizures, and sudden cardiac death (SCD) http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc- sc/2016/58758a-eng.php.1 Both the FDA2 and European Medicines Agency (EMA)3 have released similar warnings. Hydroxyzine (ATARAX) is now contraindicated in patients with a history of: 1 - QTP (QT prolongation) and/or TdP (including congenital long QT syndromes) - Family history of sudden cardiac death - History of cardiac arrhythmias - Significant electrolyte imbalance (hypokalemia, hypomagnesemia, hypocalcemia) - Significant bradycardia - Concomitant use of other QT/QTc-prolonging drugs or inhibitors of hydroxyzine metabolism If use cannot be avoided, hydroxyzine should be used for as short a duration as possible and at the lowest effective dose up to a maximum daily oral dose of 100 mg in adults and 50 mg in the elderly (in divided doses).1 Periodic electrocardiography should be considered.4 What are these recommendations based on? Studies in animals and human cells have shown that hydroxyzine has the potential to block hERG channels and other types of cardiac channels, resulting in a potential risk of QT interval prolongation and cardiac arrhythmia. This potential risk was confirmed by clinical and post-marketing data (61 case reports). Most cases had other risk factors that could have been contributory, as listed above.1,3 The CredibleMeds® website and QTdrugs list has categorized hydroxyzine as a drug with conditional risk of TdP https://crediblemeds.org/new-drug-list/ .4 How does this apply to patients with Chronic Kidney Disease (CKD)? CKD itself has been associated with prolonged QTc interval.5 A prospective electrocardiographic study of 179 patients undergoing hemodialysis found that 49% of patients had a prolonged QT interval (QTc > 440 ms).5,6 The risk of SCD is 4 to 20 times higher in CKD patients compared to the general population and increases proportionally as kidney function declines.5,6 It is estimated that SCD is accountable for approximately 27% of all-cause mortality in dialysis patients.5 Patients with CKD, especially those receiving hemodialysis, are exposed to many potential risk factors for arrhythmia such as; rapid electrolyte and fluid shifts, electrolyte abnormalities, uremic cardiomyopathy, sympathetic over activity, autonomic dysregulation and inflammation.5 Hydroxyzine is commonly used for the treatment of pruritus in patients with CKD despite a lack of supporting data. Antihistamines, such as hydroxyzine, have limited efficacy for treating uremic pruritus, in which histamine is not a major trigger.7–11 Any reported benefit is likely related to decreased perception of pruritus due to sedation.7–11 Considering questionable efficacy and high risk patient population, hydroxyzine is not recommended for treatment of uremic pruritus. How should uremic pruritus be treated? Evidence to support specific therapies for uremic pruritus is limited. Most studies are retrospective or small open-label prospective studies in hemodialysis patients, which often use a cross-over design. Many uncontrolled studies showing positive results were not reproduced in controlled studies. In addition, positive effects reported as statistically significant may not be clinically relevant. Recommended treatments based on small RCTs include: aggressive use of moisturizing cream12–14, topical agents for localized pruritus (capsaicin cream15,16, pramoxine17) and systemic agents (gabapentin18–21, pregablain22, doxepin23,24).7–11,25,26 [See Figure 1] Figure 1: Stepwise approach to Uremic Pruritus7-11, 65, 66 Optimize elements of CKD care most relevant to pruritus: - Dialysis adequacy - Correct hyperparathyroidism and serum phosphorus and calcium levels Rule out other causes of pruritus such as: - Dermatologic (atopic eczema, psoriasis, contact dermatitis, lichen planus, scabies, bed bugs) - Hyperthyroidism Check: - Cholestatis - Liver Enzymes - Hematologic (iron deficiency, lymphoma, hemochromatosis, polycythemia vera) - TSH - Neurologic (stroke, MS, brain tumor/abscess, post-herpetic) - Ferritin - Solid tumors - Psychiatric disorder (OCD, substance abuse) - HIV 65,66 - Drug induced : opioids, ACE inhibitors, SSRIs, contrast media, drug hypersensitivity, anti-neoplastic agents (epidermal growth factor inhibitors, tyrosine kinase inhibitors, BRAF inhibitors, and MEK inhibitors) Non -Pharmacologic Measures: - Patient education on importance of avoiding or minimizing scratching - Keep finger nails trimmed - Use gentle soap (e.g. Dove®, Cetaphil®) - Apply soap only to underarms and groin/perineum (except if other areas visibly dirty) - Avoid excessive bathing or bathing in hot water – use only lukewarm water. Gently pat skin dry. - Eliminate wool or irritating clothing - Aggressive skin moisturization with topical emollient cream (NOT lotion) BID and after bathing (e.g. Glaxal base® [MRP], Urea cream[MRP], Eucerin Complete Repair™, CeraVe®, Lac-Hydrin®, Cetaphil®, Petrolatum 50g, 100g, 450g (60g) ointment [Vaseline®]) NIHB only covers: Barriere cream® , Prevex cream® - Baby oil (chilled to 10–15°C/un-chilled) applied to affected area for 15-20 min at least once daily.[OTC,X NIHB, X MRP] - Generalized Itchiness Localized Itchiness Gabapentin 100-300 mg po 3x/wk to qHS, - Pramoxine HCL 1% cream BID (e.g. Aveeno® or Gold [OTC,X NIHB, X MRP] titrate as tolerated. [ PC, NIHB, X MRP] Bond® Medicated Anti-Itch cream) (Consider pregabalin 25-75 mg qHS if no response - *Topical steroids - apply BID PRN (ointment for thick, X PC, X MRP, NIHB limited use for neuropathic pain) lichenified lesions; low potency agents preferred on face to gabapentin – and intertriginous areas) [ PC, NIHB] INADEQUATE [OTC, MRP] Oral antihistamines [limited benefit] CONTROL ▪ Low potency – hydrocortisone 1% cream - Diphenhydramine 25 mg PO QID PRN, titrate ▪ Medium potency – betamethasone valerate 0.1% as tolerated. May prolong QT with excessive cream [Betaderm®] doses [> 400 mg per day] – (Conditional risk) - *Camphor 0.5%, menthol 0.5% in 1% [OTC, NIHB, MRP] [ PC, NIHB, X MRP] hydrocortisone cream *Lack of controlled studies, used anecdotally. Consider acupuncture for those interested - Topical capsaicin 0.025% cream applied sparingly [OTC, NIHB. X MRP] INADEQUATE BID-QID CONTROL Other Consult Dermatology for differential diagnosis/UVB light If noSummary contraindication of Treatments consider : doxepin 10 mg PO HS; titrate by 10-25 mg weekly to a maximum of 50 mg PO HS as tolerated. N.B. Can prolong QT (Conditional Risk) [ NIHB, Pharmacare, X MRP] Summary of Treatments Trial of agent with limited/lower quality evidence: sertraline[ PC, NIHB, X MRP], desloratidine[OTC, NIHB, X PC/MRP], mirtazapine[ PC, NIHB, X MRP], etc.(Check TdP risk) Summary of Treatments - Aggressive skin moisturization with emollient cream considered first-line treatment as dry skin (xerosis) is common in this population. - Lotions have higher water to lipid content, which is not well absorbed therefore it evaporates and may dry skin further. Creams preferred as they provide a layer of oil to lock moisture in. Level -1 Evidence Advantages Disadvantages Topical (localized areas) Capsaicin 0.025% cream 2 RCTs15,16 -No serious adverse - Initial burning on applied sparingly BID- - Placebo controlled reactions application QID - Cross-over design -OTC - Onset 2-4 wks -Covered by NIHB - Do not apply to open sores Pramoxine HCL 1% BID 1 RCT17 -Well tolerated - Not covered by NIHB (Aveeno Anti-Itch - Placebo controlled -OTC cream®, Gold Bond - Double blinded Medicated Anti-Itch cream®) Systemic Gabapentin 100 to 300 4 RCTs18–21 - May be useful 2nd line - Somnolence, dizziness, mg po 3x/wk to qHS (6) - Placebo controlled agent and fatigue - 2 were cross-over -Covered by NIHB and - Onset 3 -8 weeks design Pharmacare (Part 1) Pregabalin 75 mg twice 1 RCT22 - For those who don’t - Not covered by weekly or 25-75 mg qHS - Placebo controlled respond or tolerate pharmacare - Double blinded gabapentin - NIHB – limited use for neuropathic pain 23 Doxepin 10-50 mg po hs; 1 RCT - Strong anti-H1 - Anticholinergic side titrate by 10-25 mg - Placebo controlled histaminic activity effects are common weekly - Cross-over design - Possible 3rd line agent (e.g. drowsiness, - Double blinded - Covered by NIHB and constipation) 1 RCT vs pregabalin24 Pharmacare (Part 1) - TCA – conditional risk - Single blinded of TdP 4 Other treatments - Chilled or un-chilled baby oil (10–15°C) applied to affected area for 15-20 min at least once daily.27,28 - Menthol +/- camphor added to topical emollients may relieve itch – lack of controlled studies.11 o E.g. Camphor 0.5%, menthol 0.5% in 1% hydrocortisone cream - Topical steroids (applied BID PRN)- used anecdotally for localized itchiness.10 Ointment for thick, lichenified lesions. Low potency agents preferred on face and intertriginous areas.10 o Low potency – hydrocortisone 1% cream29 o Medium potency – betamethasone valerate 0.1% cream – [Betaderm®] (suitable for intermittent long term use)29 - Hydroxyzine, doxepin and diphenhydramine are often used for treatment of all types of pruritus without supporting data from RCTs – other than urticaria. Efficacy likely due to sedative effect.7,9,11 Hydroxyzine should be avoided for reasons discussed previously. Doxepin can prolong QT (Conditional TdP Risk).4 Diphenhdramine
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