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

Summary of Treatments Summary of Treatments

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 - Cholestatis - Hematologic (iron deficiency, lymphoma, hemochromatosis, polycythemia vera) - Neurologic (stroke, MS, brain tumor/abscess, post-herpetic) - Solid tumors - Psychiatric disorder (OCD, substance abuse) - HIV - Drug induced65,66: opioids, ACE inhibitors, SSRIs, contrast media, drug hypersensitivity, anti-neoplastic agents

(epidermal growth factor inhibitors, tyrosine kinase inhibitors, BRAF inhibitors, and MEK inhibitors)

- 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 ointment [Vaseline®]) NIHB only covers: Barriere cream®

50g, 100g, 450g, Prevex cream®

(60g)

- 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] -

Localized Itchiness - Pramoxine HCL 1% cream BID (e.g. Aveeno® or Gold

Bond® Medicated Anti-Itch cream) [OTC,X NIHB, X MRP]

- *Topical steroids - apply BID PRN (ointment for thick,

lichenified lesions; low potency agents preferred on face

and intertriginous areas) [ PC, NIHB]

▪ Low potency – hydrocortisone 1% cream[OTC, MRP]

▪ Medium potency – betamethasone valerate 0.1% cream [Betaderm®]

- *Camphor 0.5%, menthol 0.5% in 1%

hydrocortisone cream [ PC, NIHB, X MRP]

- Topical capsaicin 0.025% cream applied sparingly

BID-QID [OTC, NIHB. X MRP]

Check: - Liver Enzymes - TSH - Ferritin

Generalized Itchiness Gabapentin 100-300 mg po 3x/wk to qHS,

titrate as tolerated. [ PC, NIHB, X MRP] (Consider pregabalin 25-75 mg qHS if no response

to gabapentin – X PC, X MRP, NIHB limited use for neuropathic pain)

Oral antihistamines [limited benefit] - Diphenhydramine 25 mg PO QID PRN, titrate

as tolerated. May prolong QT with excessive

doses [> 400 mg per day] – (Conditional risk) [OTC, NIHB, MRP]

INADEQUATE

CONTROL

Other

If no contraindication 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]

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)

Consult Dermatology for differential diagnosis/UVB light

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

*Lack of controlled studies, used anecdotally.

INADEQUATE

CONTROL

Consider acupuncture for those interested

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 applied sparingly BID-QID

2 RCTs15,16 - Placebo controlled - Cross-over design

-No serious adverse reactions -OTC -Covered by NIHB

- Initial burning on application - Onset 2-4 wks - Do not apply to open sores

Pramoxine HCL 1% BID (Aveeno Anti-Itch cream®, Gold Bond Medicated Anti-Itch cream®)

1 RCT17 - Placebo controlled - Double blinded

-Well tolerated -OTC

- Not covered by NIHB

Systemic

Gabapentin 100 to 300 mg po 3x/wk to qHS (6)

4 RCTs18–21 - Placebo controlled - 2 were cross-over design

- May be useful 2nd line agent -Covered by NIHB and Pharmacare (Part 1)

- Somnolence, dizziness, and fatigue - Onset 3 -8 weeks

Pregabalin 75 mg twice weekly or 25-75 mg qHS

1 RCT22 - Placebo controlled - Double blinded

- For those who don’t respond or tolerate gabapentin

- Not covered by pharmacare

- NIHB – limited use for neuropathic pain

Doxepin 10-50 mg po hs; titrate by 10-25 mg weekly

1 RCT23 - Placebo controlled - Cross-over design - Double blinded 1 RCT vs pregabalin24 - Single blinded

- Strong anti-H1 histaminic activity

- Possible 3rd line agent - Covered by NIHB and

Pharmacare (Part 1)

- Anticholinergic side effects are common (e.g. drowsiness, constipation)

- TCA – conditional risk 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 may prolong QT with excessive doses (> 400 mg per day) – conditional TdP risk.4

- Acupuncture/Acupressure

o A Cochrane review30 found that manual acupressure may provide short-term relief of CKD symptoms such as pruritus, however studies were of low quality. No conclusion could be made for acupuncture due to low quality evidence with high risk of bias. Safety of acupuncture was not assessed due to incomplete reporting of acupuncture-related harm.

o In the only RCT with a placebo control group, acupuncture was performed by inserting a 1-inch, 34-gauge acupuncture needle at Quchi (LI11) which was left in place for 1 hour, 3 times weekly.31 Mean pruritus scores (via 45 point questionnaire) in the active intervention group decreased by 56% at three months.

o Possible option for those who are interested in acupuncture.

- Phototherapy o Meta-analysis from 1991, which included 3 small RCTs, found that UVB phototherapy

was effective for treatment of uremic pruritus. 32 o More recent RCT of narrowband UVB phototherapy did not show significant benefit

compared to control (UVA phototherapy). Possibly underpowered, as it only included 18 patients.33

o Long-term effects unknown; possible increased risk of skin cancer.7,8 o Narrow band UVB light therapy - not covered by MB Health (cost is $17/treatment)

Limited Evidence

Drug Efficacy Comments

Sertraline 25-75 mg po daily Modest benefit in 1 small prospective, non-RCT34 and 1 small retrospective review.35

- Conditional risk of TdP 4 - May be useful for concomitant

depression/anxiety disorder

Desloratidine 5 mg po 3 times/week

Modest benefit (43% reduction in VAS score) in small open-label, cross-over trial versus gabapentin.36

- OTC - Covered by NIHB

Montelukast 10 mg po daily One small RCT (n=14) crossover study showed modest improvement in pruritus (35% reduction in VAS score).10,37

- Pharmacare Part II EDS for asthma only

- Limited use benefit (prior approval required) for use in asthma only

Mirtazapine 15 mg po daily qHS Case reports, mostly non-uremic/chronic pruritus11,38,39

- Possible risk of TdP 4

Cromolyn Sodium - Orally 135 mg TID - Topical cream 4%

Benefit found in 1 small RCT (DB, PC) using oral cromolyn sodium 40 and another small RCT (DB, PC) using topical cream.41

- Nalcrom® 100 mg capsule (Sanofi-Aventis) indicated for treatment of food allergy

- No marketed topical product

Omega-3 fatty acids 1 g po tid One small RCT crossover trial showed some benefit.42

Common side effects: burping, indigestion, altered taste.42

Turmeric 500 mg (22.1 mg curcumin) PO TID

1 small RCT vs placebo showed modest benefit (57% decrease in pruritus score vs 31% decrease with placebo).43

Generally well tolerated. Reported side effects: dyspepsia, diarrhea, gastroesophageal reflux, nausea, and vomiting44

Not Recommended

Drug Comments

Hydroxyzine - Small (n=23) randomized crossover trial comparing hydroxyzine 10-mg po HS to Avena sativa (oatmeal) lotion and diluted vinegar.45 There was no statistically significant difference in uremic pruritus intensity between treatments. There was a 30% reduction in VAS score from baseline with hydroxyzine and diluted vinegar and a 40% reduction with Avena sativa.

Gamma-Linolenic acid8,10 (Topical)

- No product found

Tacrolimus ointment - 3 small single center studies with conflicting results7,10 - Case reports and animal studies reporting rare associations with

malignancies (lymphoma, skin cancer). FDA black box warning that use be limited to those who have failed other therapies and to treatment periods of less than 6 weeks.7,10

Naltrexone (mu-receptor agonist)

- 2 studies with conflicting results.46,47

Nalfurafine (kappa-opioid receptor agonist)

- Preliminary data with positive results although insomnia and constipation were common, studies ongoing with kappa-receptor agonists. 7

- Not available in Canada.

Activated Charcoal9,10 - Limited evidence suggesting efficacy but not practical. Would need to give 23 x 260 mg capsules to make up a 6 g daily dose.

- May bind to and needs to be spaced apart from other medications.

Pentoxifylline 600 mg IV 3x/wk - Possibly effective in patients refractory to gabapentin and UVB phototherapy but poorly tolerated.48

Thalidomide - One small RCT in refractory uremic pruritus showed moderate improvement. 49

- Common side effects include sedation, peripheral neuropathy and thromboembolism.50

- Peripheral neuropathy has occurred in approximately 20% of patients, at doses of 25 mg per day or more, within the first year of treatment. Symptoms may progress to muscle weakness, hypotonia, cramps and/or tendon reflex decline. It can be detected early using nerve conduction studies.50

Ondansetron - 2 small prospective studies showing no benefit.8–10 - Known risk of TdP4

Zinc sulfate - 1 small RCT (TB, PC) using zinc sulfate 220 mg po daily in 36 HD pts x 4 wks. Benefit reported but not statistically significant.51 Another small RCT (DB, PC) using 220 mg po BID showed modest benefit (52% reduction in VAS score) vs. placebo.52

Nicotinamide - 1 RCT (DB, PC)53 found to be ineffective

Evidence for Treatment of Uremic Pruritus

Study (y) UP treatment No. of pts

Level of Evidence

Design Efficacy Mean worst VAS score/10 (% response itch reduction)

Topical Treatments

Okada and Matsumoto et al (2004)12

Emollients 20 2 NR with control group

Yes 3.5 (85)

Morton et al (1996)13

Emollients 21 2 Prospective Cohort

Yes 5.0 (48)

Szepietowski et al (2005)14

Emollients 19 2 Prospective cohort

Yes 6.2 (80)

Tarng et al (1996)15

Capsaicin 0.025% 17 1 RCT PC Cross-over

Yes NA (39)

Makhlough et al. (2010)16

Capsaicin 0.03% 34 1 RCT DB PC Cross-over

Yes NA (84)

Weisshaar et al (2003)54

Capsaicin 0.05%

11 2 Case Control No NA

Breneman et al (1992)55

Capsaicin 0.025% 21 2 Open-Label Prospective

Yes NA

Breneman et al (1992)55

Capsaicin 0.025% 5 2 Prospective, DB Randomized Vehicle controlled

Yes NA

Young et al (2009)17

Pramoxine 1% 27 1 RCT DB PC Yes 5.5 (61)

Gabapentin/Pregabalin

Gunal et al (2004)18

Gabapentin 300 mg 3x/wk

25 1 RCT DB PC Cross-over

Yes 7.9 (85)

Naini et al (2007)19

Gabapentin 400 mg 2x/wk

34 1 RCT DB PC Yes 7.2 (79)

Tol et al (2010)20

Gabapentin 300 mg 3x/wk

14 1 RCT PC Cross-over

Yes 7.6 (83)

Nofal et al (2016)21

Gabapentin 100-300 mg 3x/wk

54 1 RCT PC Single blinded

Yes 7.63 (76)

Amirkhanlou et al (2016)56

Gabapentin 100 mg daily

52 1 RCT DB vs. Ketotifen

Yes NA (88)

Razeghi et al (2009)57

Gabapentin 100 mg 3x/wk

34 2 DB PC Single-arm Cross-over

Yes VAS 100 100 (94)

Marquez et al (2012)36

Gabapentin 300 mg 3x/wk to daily

19 2 Quasi-randomized, OL, Cross-over vs. desloratidine

No 5.95 (23)

Rayner et al (2012)58

Gabapentin 100 mg 3x/wk-daily, up to 900 mg daily

40 2 Step-wise OL ordered

Yes NA (77.5)

Hassan et al. (2015)59

Gabapentin 100 mg q 2 days

30 2 Retrospective Cohort

Yes NA

Manenti et al Gabapentin 6 3 Case series Yes 8.2 (83)

(2005)60 100 mg 3-4x/wk

Yue et al. (2015)22

Pregabalin 75 mg 2x/wk

179 1 RCT DB PC vs. ondansetron

Yes 8 (83)

Aperis et al. (2010)61

Pregabalin 25 mg/day

16 2 Open Label Yes 7.4 (77)

Shavit et al. (2013)62

Pregabalin 25 mg 3x/wk to 50 mg/day

12 2 Open Label Yes 9.7 (69)

Rayner et al. (2012)58

Gabapentin 100-900 mg/d or 100-400 mg per HD VS Pregabalin 25-150 mg/d or 25 mg per HD

79 2 Open Label Prospective Cohort

Yes NA

Solak et al. (2012)63

Gabapentin 300 mg per HD 3x/wk VS pregabalin 75 mg/d

29 1 RCT Cross-over

Yes No difference between groups

Antihistamines/Mast-cell Stabilizers

Pour-Reza-Gholi et al. (2007)23

Doxepin 10 mg po BID

24 1 RCT PC Cross-over

Yes NA Complete resolution in 58% of pts

Foroutan N et al. (2016)24

Doxepin 10 mg po daily to BID or Pregabalin 50 mg eod to daily

72 1 RCT vs pregabalin No Placebo arm Single blinded

Yes D 7.1 (41) Pr 7.5 (72)

Marquez et al (2012)36

Desloratidine 5 mg 3 x weekly

19 2 Quasi-randomized, open-label, cross-over vs. gabapentin

Yes 5.95 (43)

Nasrollahi A et al. (2007)37

Montelukast 10 mg daily

14 1 RCT PC Cross-over

Yes NA (35.7)

Vessal et al.40 (2010)

Cromolyn Sodium 135 mg po TID

40 1 RCT, DB, PC Yes 8.68 (89.6)

Feily et al.41

Cromolyn Sodium 4% (topical) BID

60 1 RCT, DB, PC Yes 2.5/5 (88)

Other

Chan et al (2013)35

Sertraline 25-75 mg daily

17 2 Retrospective review

Yes 7.47 (67)

Shakiba et al (2012)34

Sertraline 50 mg daily

19 2 Prospective, before/after

Yes NA

Ghanei E et al. (2012)42

Fish oil 1 g capsule (180 mg EPA/120 mg DHA) TID

22

1 RCT PC DB Cross-over

Yes NA (68)

Levels of evidence:

Level Evidence

1 One or more randomized, controlled clinical trials

2 Nonrandomized clinical trials, prospective observational studies, cohort studies, retrospective studies, case-control studies

3 One or more published case reports

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