sitagliptin addition to the list

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1 sitagliptin addition to the list Explanation for addition Ontario Public Drug Program (OPDP) data- financial year 2015/2016: the number of recipients was 6, and cumulative total number of claims was 8. Relevant medications on CLEAN Meds Essential Medication List gliclazide metformin short acting insulin long acting insulin Literature review question Is the (sitagliptin effective and safe when it is prescribed for children with 2 diabetes? Utilized electronic databases PubMed and Cochrane Brief Search strategies (systematic review OR RCT filter) AND (sitagliptin OR dipeptidyl peptidase 4 inhibitors[mesh Terms]) AND ((metformin) OR biguanides[mesh Terms])) No evidence in children found. Wu D, Li L, Liu C. Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes, obesity & metabolism. 2014;16(1):30-7. AIMS: This meta-analysis was performed to provide an update on the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a search on MEDLINE, Embase and Cochrane Collaborative database for randomized controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words 'alogliptin', 'dutogliptin', 'linagliptin', 'saxagliptin', 'sitagliptin', 'vildagliptin' and 'metformin'. RCTs were selected for meta-analysis if (1) they were RCTs comparing DPP-4 inhibitors plus metformin as initial combination therapy or DPP-4 inhibitor monotherapy to metformin monotherapy, (2) duration of treatment was 12 weeks and (3) reported data on haemoglobin A1c (HbA1c) change, fasting plasma glucose (FPG) change, weight change, adverse cardiovascular (CV) events, hypoglycaemia or gastrointestinal adverse events (AEs). RESULTS: A total of eight RCTs were included. Compared with metformin monotherapy, DPP-4 inhibitors monotherapy was associated with lower reduction in HbA1c level [weighted mean differences (MD) = 0.28, 95% confidence intervals (CIs) (0.17, 0.40), p < ], lower reduction in FPG level [MD = 0.81, 95% CI(0.60, 1.02), p < ], lower weight loss [MD = 1.51, 95% CI (0.89, 2.13), p < ], but lower risk of adverse CV events [risk ratio (RR) = 0.36, 95% CI (0.15, 0.85), p = 0.02], 1

2 lower risk of hypoglycaemia [RR = 0.44, 95% CI (0.27, 0.72), p = 0.001] and lower risk of gastrointestinal AEs [RR = 0.63, 95% CI(0.55, 0.70), p < ]. Compared with metformin monotherapy, DPP-4 inhibitors plus metformin as initial combination therapy was associated with higher reduction in HbA1c level [MD = -0.49, 95% CI (-0.57, -0.40), p < ], higher reduction in FPG level [MD = -0.80, 95% CI (-0.87, -0.74), p < ], lower weight loss [MD = 0.44, 95% CI (0.22, 0.67), p = ]; but was not associated with a further reduction in adverse CV events [RR=0.54, 95% CI (0.25, 1.19), p = 0.13], nor the higher risk of hypoglycaemia [RR = 1.04, 95% CI (0.72, 1.50), p = 0.82], nor the prolonged risk of gastrointestinal AEs [RR = 0.98, 95% CI (0.88, 1.10), p = 0.77]. 2

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4 Complete search strategy PubMed (n=96), using systematic review filter (((((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta synthesis [ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt]))))) AND ((((sitagliptin) OR dipeptidyl peptidase 4 inhibitors[mesh Terms])) AND ((metformin) OR biguanides[mesh Terms])) Pubmed (n=44), using RCT filter ((((((sitagliptin) OR dipeptidyl peptidase 4 inhibitors[mesh Terms])) AND ((metformin) OR biguanides[mesh Terms])))) AND ((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh])) Filters: Child: birth-18 years; Newborn: birth-1 month; Infant: birth-23 months; Infant: 1-23 months; Preschool Child: 2-5 years; Child: 6-12 years; Adolescent: years Cochrane (n=95) #1 MeSH descriptor: [Biguanides] explode all trees 3897 #2 MeSH descriptor: [Metformin] explode all trees 2064 #4 MeSH descriptor: [Sitagliptin Phosphate] explode all trees 244 #6 (#1 or #2) and (#4) 95 #7 MeSH descriptor: [Sitagliptin Phosphate, Metformin Hydrochloride Drug Combination] explode all trees 1 #8 #6 or #7 95 4

5 Tacrolimus Addition to the list Explanation for the addition: The Ontario Public Drug Program (OPDP) data-financial year 2015/2016: the number of recipients was 503, and total number of claims was 455. Relevant medications on CLEAN Meds Essential Medication List None Literature Review Question Is Tacrolimus safe and effective when used for treatment of atopic dermatitis in children? Utilized electronic databases: PubMed Clinical Queries Brief search strategies: Tacrolimus AND atopic dermatitis AND children Siegfried EC, Jaworski JC, Kaiser JD, Hebert AA. Systematic review of published trials: long-term safety of topical corticosteroids and topical calcineurin inhibitors in pediatric patients with atopic dermatitis. BMC Pediatr Jun 7;16:75. Background Atopic Dermatitis (AD) is a chronic, pruritic inflammatory skin disease that occurs most frequently in children. It is the most common chronic pediatric inflammatory skin disease, affecting 12.5 % of US children (aged 0 17 years) from 2009 to 2011, an increase of 5.1 % from 1997 to Methods A comparative systematic search of PubMed was done for long-term ( 12 week) clinical trials of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCIs) treatment in patients <12 years with AD. Citations were reviewed for inclusion based on MeSH terms, abstracts, and relevant article text. Studies were excluded if they did not encompass subjects <12 years, or were <12 weeks duration, retrospective, meta-analyses, or limited to anecdotal case reports. Results Of 27 trials meeting criteria, 21 included 5825 pediatric patients treated with TCIs, and 6 included 1999 patients treated with TCS. TCS studies were limited to low- to mid-potency products, and all but one study lacked a vehicle control. Eight TCI studies were vehicle-controlled, and safety data were well reported, with 5 % of patients reporting discontinuation due to adverse effects (DAEs). Cutaneous and systemic adverse events (AEs) were similar in TCI and vehicle groups, with no reports of lymphoma. Safety data in TCS trials were less well reported. DAE incidence was addressed in just 2 trials, and systemic and cutaneous AEs were mostly Conclusions This comprehensive literature review supports the long-term safety of TCI and low- to mid-potency TCS therapy in children with AD, with no evidence of cutaneous atrophy or cumulative systemic exposure and 5

6 no reports of lymphoma. We found comparatively limited data on the long-term safety of mid- to highpotency TCS. Our findings are not reflected by the current TCI labelling and Boxed Warning; therefore we hope our review facilitates the rescindment of the Boxed Warning. Cury Martins J, Martins C, Aoki V, Gois AFT, Ishii HA, da Silva EMK. Topical tacrolimus for atopic dermatitis. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD DOI: / CD pub2. Background Atopic dermatitis (AD) (or atopic eczema) is a chronic inflammatory skin condition that affects children and adults and has an important impact on quality of life. Topical corticosteroids (TCS) are the first-line therapy for this condition; however, they can be associated with significant adverse effects when used chronically. Tacrolimus ointment (in its 2 manufactured strengths of 0.1% and 0.03%) might be an alternative treatment. Tacrolimus, together with pimecrolimus, are drugs called topical calcineurin inhibitors (TCIs). Objectives To assess the efficacy and safety of topical tacrolimus for moderate and severe atopic dermatitis compared with other active treatments. Results We included 20 studies, with 5885 participants. The variability of drug doses, outcomes, and follow-up periods made it difficult to carry out meta-analyses. A single trial showed that tacrolimus 0.1% was better than low-potency TCS by the physician's assessment (risk ratio (RR) 3.09, 95% confidence interval (CI) 2.14 to 4.45, 1 study, n = 371, moderate-quality evidence). It was also marginally better than low-potency TCS on face and neck areas and moderate-potency TCS on the trunk and extremities by the physician's assessment (RR 1.32, 95% CI 1.17 to 1.49, 1 study, n = 972, moderate level of evidence) and for some of the secondary outcomes. Compared with pimecrolimus 1%, people treated with tacrolimus were almost twice as likely to improve by the physician's assessment (RR 1.80, 95% CI 1.34 to 2.42, 2 studies, n = 506, moderate quality of evidence). Compared with the lower concentration of 0.03%, the tacrolimus 0.1% formulation reduced the risk of not having an improvement by 18% as evaluated by the physician's assessment (RR 0.82, 95% CI 0.72 to 0.92, 6 studies, n = 1640, high-quality evidence). Tacrolimus 0.1% compared with moderate-to-potent TCS showed no difference by the physician's assessment, and 2 secondary outcomes (1 study, 377 participants) and a marginal benefit favouring tacrolimus 0.1% was found by the participant's assessment (RR 1.21, 95% CI 1.13 to 1.29, 1 study, n = 974, low quality of evidence) and SCORAD. Based on data from 2 trials, tacrolimus 0.03% was superior to mild TCS for the physician's assessment (RR 2.58, 95% CI 1.96 to 3.38, 2 studies, n = 790, moderate-quality evidence) and the participant's self-assessment (RR 1.64, 95% CI 1.41 to 1.90, 1 study, n = 416, moderate quality of evidence). One trial showed moderate benefit of tacrolimus 0.03% compared with pimecrolimus 1% on the physician's assessment (RR 1.42, 95% CI 1.02 to 1.98, 1 study, n = 139, low-quality evidence), but the effects were equivocal when evaluating BSA. In the comparison of tacrolimus 0.03% with moderateto-potent corticosteroids, no difference was found in most of the outcomes measured (including physician's and participant's assessment and also for the secondary outcomes), but in two studies, a marginal benefit favouring the corticosteroid group was found for the EASI and BSA scores. 6

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8 Adverse Effects Burning was more frequent in those using calcineurin inhibitors than those using corticosteroid tacrolimus 0.03% (RR 2.48, 95% CI 1.96 to 3.14, 5 studies, 1883 participants, high-quality evidence), but no difference was found for skin infections. Symptoms observed were mild and transient. The comparison between the two calcineurin inhibitors (pimecrolimus and tacrolimus) showed the same overall incidence of adverse events, but with a small difference in the frequency of local effects. Serious adverse events were rare; occurred in both the tacrolimus and corticosteroid groups; and in most cases, were considered to be unrelated to the treatment. No cases of lymphoma were noted in the included studies nor in the non-comparative studies. Cases were only noted in spontaneous reports, cohorts, and case-control studies. Systemic absorption was rarely detectable, only in low levels, and this decreased with time. Exception is made for diseases with severe barrier defects, such as Netherton's syndrome, lamellar ichthyosis, and a few others, with case reports of a higher absorption. We evaluated clinical trials; case reports; and in vivo, in vitro, and animal studies; and didn't find any evidence that topical tacrolimus could cause skin atrophy. Conclusions Tacrolimus 0.1% was better than low-potency corticosteroids, pimecrolimus 1%, and tacrolimus 0.03%. Results were equivocal when comparing both dose formulations to moderate-to-potent corticosteroids. Tacrolimus 0.03% was superior to mild corticosteroids and pimecrolimus. Both tacrolimus formulations seemed to be safe, and no evidence was found to support the possible increased risk of malignancies or skin atrophy with their use. The reliability and strength of the evidence was limited by the lack of data; thus, findings of this review should be interpreted with caution. We did not evaluate costs. 8

9 Liquor Carbonis Detergens (Coal Tar) Addition to the list Explanation for addition: Ontario Public Drug Program (OPDP) data- financial year 2015/2016: the number of recipients was 240, and cumulative total number of claims was 290. Relevant medications on CLEAN Meds Essential Medication list: hydorcortisone clotrimazole Literature review question: Is Liquor Carbonis Detergen (coal tar) safe and effective for the treatment of eczema, psoriasis, and seborrheic dermatitis? Utilized electronic databases: PubMed & Cochrane Brief search strategies: (coal tar[mesh Terms]) OR liquor carbonis detergens[mesh Terms]) AND Children[MeSH Terms]) OR pediatrics[mesh Terms]) AND eczema[mesh Terms]) OR psoriasis[mesh Terms]) OR seborrheic dermatitis[mesh Terms]) OR Dermatitis[MeSH Terms]) AND (Systematic review filter) *Note: as the literature search results for use of Liquor Carbonis Detergens (Coal Tar) in children/pediatric populations did not yield many results - literature search for Liquor Carbonis Detergens (Coal Tar) was carried out for use in adult populations. Relevant research literature for both population groups is illustrated below* Mason AR, Mason J, Cork M, Dooley G, Hancock H. Topical treatments for chronic plaque psoriasis. Cochrane Database of Systematic Reviews. 2013(3):CD Background: Chronic plaque psoriasis is the most common type of psoriasis, and it is characterized by redness, thickness, and scaling. First-line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid, and topical retinoids. Objectives: To compare the effectiveness, tolerability, and safety of topical treatments for chronic plaque psoriasis, relative to placebo, and to similarly compare vitamin D analogues (used alone or in combination) with other topical treatments. Selection criteria: Randomized trials comparing active topical treatments against placebo or against vitamin D analogues (used alone or in combination) in people with chronic plaque psoriasis. Data collection and analysis: One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted trialists and companies for missing data. We also extracted data on withdrawals and on local and systemic adverse events. We defined long-term trials as those with a duration of at least 24 weeks. 9

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11 Slutsky J, Clark R, Remedios A, Klein P. An evidence-based review of the efficacy of coal tar preparations in the treatment of psoriasis and atopic dermatitis. Journal of drugs in dermatology. 2010; 9(10): Background: There is a long history of using topical coal tar for the treatment of psoriasis and atopic dermatitis (AD). Objectives: To review the literature on coal tar and its derivatives, without the use of ultraviolet light, for the treatment of psoriasis or AD. Methods: MEDLINE/PubMed and Cochrane Database of systematic reviews literature searches were performed to identify randomized controlled trials and clinical trials of topical coal tar for the treatment of psoriasis or AD. Studies were graded according to a modified version of Sackett s criteria for clinical evidence and evaluated to determine if they support or do not support the use of coal tar therapy. 11

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13 National institute for Health and Care Excellence (NICE) Guidance: Psoriasis: assessment and management. [Clinical guideline [CG153] Published date: October 2012] Aim for a break of 4 weeks between courses of treatment with potent or very potent corticosteroids. Consider topical treatments that are not steroid-based (such as vitamin D or vitamin D analogues or coal tar) as needed to maintain psoriasis disease control during this period If twice-daily application of vitamin D or a vitamin D analogue does not result in clearance, near clearance or satisfactory control of trunk or limb psoriasis in adults after 8-12 weeks[22], offer either: A potent corticosteroid applied twice daily for up to 4 weeks or A coal tar preparation applied once or twice daily If twice-daily potent corticosteroids or coal tar preparation cannot be used or once-daily preparation would improve adherence in adults offer a combined product containing calcipotriol monohydrate and betamethasone diproprionate applied once daily for up to 4 weeks If continuous treatment with either a combined product containing calcipotriol monohydrate and betamethasone dipropionate [26] applied once daily or vitamin D or a vitamin D analogue applied once daily for up to 8 weeks [25] does not result in clearance, near clearance or satisfactory control of scalp psoriasis offer: a very potent corticosteroid applied up to twice daily for 2 weeks for adults only or coal tar applied once or twice daily or referral to a specialist for additional support with topical applications and/or advice on other treatment options Do not offer coal tar-based shampoos alone for the treatment of severe scalp psoriasis. 13

14 National institute for Health and Care Excellence (NICE) Guidance: Atopic eczema in under 12s: Diagnosis and managment [Clinical guideline [CG57] Published date: December 2007] Stepped approach to management Healthcare professionals should use a stepped approach for managing atopic eczema in children. This means tailoring the treatment step to the severity of the atopic eczema. Emollients should form the basis of atopic eczema management and should always be used, even when the atopic eczema is clear. Management can then be stepped up or down, according to the severity of symptoms, with the addition of the other treatments listed in table 2. Table 2. Treatment options 14

15 UpToDate Recommendations: Feldman SR, MD, PhD. Treatment of psoriasis [Literature review current through: Feb This topic last updated: Mar 01, 2017] Tar The use of tar is a time honored modality for treating psoriasis, although newer (and less messy) treatment options have reduced its popularity. The precise mechanism of action of tar is not known; it has an apparent antiproliferative effect. Tar can be helpful as an adjunct to topical corticosteroids. There are no commercially available corticosteroid/tar combinations. Tar products are available without a prescription in the form of shampoos, creams, lotions, ointments, and oils. Newer products include a solution and a foam. Some patients may prefer the less messy formulations. Tar can also be compounded into creams and ointments. A commonly used compound is 2% or 3% crude coal tar in triamcinolone cream 0.1% applied twice daily to individual plaques. An alternative is 4 to 10% LCD (liquor carbonis detergens, a tar distillate) in triamcinolone cream or ointment, used similarly. A preparation of 1% tar in a fatty acid based lotion may be superior to conventional 5% tar products [39] and appears to have efficacy similar to that of calcipotriene [40]. Topical tar preparations, including shampoos, creams, and other preparations, can be used once daily. Patients should be warned that tar products have the potential to stain hair, skin, and clothing. It may help to use them at night and wear inexpensive night clothes (eg, old pajamas) as they tend to be messy. Patients may also find the odor of tar products unpleasant. For shampoos, the emphasis should be on making sure the product reaches the scalp. Tar shampoo should be left in place for 5 to 10 minutes before rinsing it out. UpToDate Recommendations: Sasseville D, MD, FRCPC. Cradle cap and sebhorrheic dermatitis in infants [Literature review current through: Feb This topic last updated: April 30, 2015] Treatment: Cradle cap In infants, seborrheic dermatitis has a self-limited course and resolves spontaneously in weeks to several months. Therefore, we suggest that initial treatment should be conservative, including education and reassurance of parents, and simple skin care measures. Conservative measures for scalp seborrheic dermatitis may include: Application of an emollient (white petrolatum, vegetable oil, mineral oil, baby oil) to the scalp (overnight, if necessary) to loosen the scales, followed by removal of scales with a soft brush (eg, a soft toothbrush) or fine-tooth comb Frequent shampooing with mild, non-medicated baby shampoo followed by removal of scales with a soft brush (eg, a soft toothbrush) or fine-tooth comb In more extensive or persistent cases, we suggest either a short course of low-potency topical corticosteroids (group seven (table 1)) applied once per day for one week or ketoconazole 2% cream or 15

16 shampoo twice per week for two weeks. Corticosteroids are preferred if there is a predominant inflammatory component; ketoconazole 2% cream or shampoo is an alternative in diffuse cases or if the use of topical corticosteroids is a concern for the parents. Non-scalp seborrheic dermatitis We suggest that seborrheic dermatitis involving body areas other than the scalp in infants be treated with ketoconazole 2% cream (once a day for one to two weeks) or a low potency topical corticosteroid (eg,hydrocortisone 1% cream once a day). The use of topical corticosteroids should be limited to the time needed to achieve the clearing of the lesions, but no longer than one week (see 'Response to therapy' below). Emollients can be used liberally. There are no randomized trials evaluating the treatment of non-scalp seborrheic dermatitis in infants. A single randomized trial in adults suggested that ketoconazole 2% cream and mid-potency corticosteroids are equally effective. We generally use only low potency topical corticosteroids for seborrheic dermatitis in infants given the natural history of spontaneous resolution and the potential for systemic absorption of topical corticosteroids. (See "General principles of dermatologic therapy and topical corticosteroid use", section on 'Use in children'.) 16

17 Complete search strategy PubMed (n=6) March 3, 2:30 PM with search children/pediatrics (((((((((coal tar[mesh Terms]) OR liquor carbonis detergens[mesh Terms]) AND Children[MeSH Terms]) OR pediatrics[mesh Terms]) AND eczema[mesh Terms]) OR psoriasis[mesh Terms]) OR seborrheic dermatitis[mesh Terms]) OR Dermatitis[MeSH Terms]) AND ((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta-analy*[ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR umbrella review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt]))) AND liquor picis carbonis[mesh Terms] PubMed (n=123) March 6, 2:11 PM ((((((Coal tar[mesh Terms]) OR liquor carbonis detergens[mesh Terms]) AND eczema[mesh Terms]) OR psoriasis[mesh Terms]) OR seborrheic dermatitis[mesh Terms]) AND adults[mesh Terms]) AND ((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta-analy*[ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR umbrella review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] 17

18 OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt])) Cochrane (n=6) March 3, 2017 at 1:34pm w/ search for children/pediatrics 1 liquor carbonis detergens.mp. [mp=title, short title, abstract, full text, keywords, caption text] (0) 2 liquor picis carbonis.mp. [mp=title, short title, abstract, full text, keywords, caption text] (0) 3 coal tar.mp. [mp=title, short title, abstract, full text, keywords, caption text] (10) 4 1 or 2 or 3 (10) 5 Children.mp. [mp=title, short title, abstract, full text, keywords, caption text] (3339) 6 Pediatrics.mp. [mp=title, short title, abstract, full text, keywords, caption text] (331) 7 5 or 6 (3419) 8 4 and 7 (6) Cochrane (n=8) March 3, 3:18 pm 1 liquor carbonis detergens.mp. [mp=title, short title, abstract, full text, keywords, caption text] (0) 2 liquor picis carbonis.mp. [mp=title, short title, abstract, full text, keywords, caption text] (0) 3 Coal tar.mp. [mp=title, short title, abstract, full text, keywords, caption text] (10) 4 1 or 2 or 3 (10) 5 Eczema.mp. [mp=title, short title, abstract, full text, keywords, caption text] (156) 6 psoriasis.mp. [mp=title, short title, abstract, full text, keywords, caption text] (100) 7 seborrheic dermatitis.mp. [mp=title, short title, abstract, full text, keywords, caption text] (3) 8 5 or 6 or 7 (235) 9 4 and 8 (8) 18

19 filgrastim (recombinant granulocyte colony stimulating factor, G-CSF) addition to the list Explanation for addition Ontario Public Drug Program (OPDP) data- financial year 2015/2016: the number of recipients was 182, and cumulative total number of claims was 757. Relevant medications on CLEAN Meds Essential Medication List none Literature review question Is the filgrastim effective and safe when it is prescribed for children with neutropenia? Utilized electronic databases PubMed and Cochrane Brief search strategies (systematic review filter) AND (filgrastim* [all fields] OR (granulocyte colony stimulating factor [MeSH Terms])) Wittman B, Horan J, Lyman GH. Prophylactic colony-stimulating factors in children receiving myelosuppressive chemotherapy: a meta-analysis of randomized controlled trials. Cancer treatment reviews. 2006;32(4): BACKGROUND: The colony-stimulating factors (CSFs) are widely utilized to prevent neutropenic complications in both adults and children, but randomized controlled trials in the pediatric setting have reported varied results. A systematic review of the literature and meta-analysis were conducted to definitively assess the impact of prophylactic CSFs on the risk of febrile neutropenia (FN) in pediatric oncology patients. METHODS: MEDLINE was searched and references hand-searched through July 2004 for randomized controlled trials of prophylactic G-CSF or GM-CSF in pediatric oncology patients. Weighted summary estimates of relative risks (RR) were calculated for FN and documented infection (DI). Mean differences in hospitalization, antibiotic use, and duration of neutropenia were calculated. 19

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22 Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(28): Methods The American Society of Clinical Oncology convened an Update Committee and conducted a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September2014. Guideline recommendations were based on the review of the evidence by the Update Committee. CLINICAL QUESTION 9 How should CSFs be used in the pediatric population? Recommendation 9.1 The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, a CSF is reasonable as the primary prophylaxis for pediatric patients with a high likelihood of febrile neutropenia. Similarly, a CSF as secondary prophylaxis or therapy should be limited to high-risk patients.(type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.) 22

23 Complete search strategy PubMed (n=191) (((granulocyte colony stimulating factor[mesh Terms]) OR filgrastim*)) AND ((((((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta synthesis [ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt]))))))) Filters: Humans 23

24 Pancreatic enzyme addition to the list Explanation for addition Ontario Public Drug Program (OPDP) data- financial year 2015/2016: the number of recipients was 3, and cumulative total number of claims was 13. Relevant medications on CLEAN Meds Essential Medication List none Literature review question Is the pancreatic enzyme (amylase, lipase and protease) effective and safe when it is prescribed for children with pancreatic insufficiency? Utilized electronic databases PubMed and Cochrane Search strategies (systematic review) AND (pancreatic enzyme [all fields] OR pancreatic insufficiency OR cystic fibrosis) Giuliano CA, Dehoorne-Smith ML, Kale-Pradhan PB. Pancreatic enzyme products: digesting the changes. The Annals of pharmacotherapy. 2011;45(5): OBJECTIVE: To review the pharmacology, dosage regimens, efficacy, and safety of currently marketed pancreatic enzyme products (PEPs). DATA SOURCES: Studies were identified by PubMed (1966-January 2011), clinicaltrials.gov, fda.gov, and International Pharmaceutical Abstracts. Search terms included pancreatic enzyme, lipase, Creon, Zenpep, Pancreaze, and exocrine pancreatic insufficiency (EPI). DATA SYNTHESIS: PEPs are composed of porcine lipase, amylase, and protease and are used in patients with EPI secondary to cystic fibrosis, chronic pancreatitis, and pancreatectomy. In 1938, PEPs were exempted from the Food, Drug, and Cosmetic Act of 1938 and never underwent a formal Food and Drug Administration (FDA) review process. In response to reports of treatment failures during product interchange, the FDA conducted a review of available PEP products. This review found a large variability of response between the unapproved PEP products, which resulted in the FDA requiring approval of all PEP products by April The 3 delayed-release, enteric-coated PEPs currently approved by the FDA (Creon, Zenpep, and Pancreaze) have demonstrated efficacy and safety in EPI secondary to cystic fibrosis. Creon has also demonstrated safety and efficacy in EPI secondary to chronic pancreatitis and pancreatectomy. Cost difference between the 3 products is minimal. Treatment-related adverse events in clinical studies for all PEPs were less than or similar to those with placebo. 24

25 CONCLUSION The 3 delayed-release, enteric-coated PEPs currently ap- proved by the FDA (Creon, Zenpep, and Pancreaze) have demonstrated efficacy and safety in the treatment of EPI. New formulations are regulated by the FDA, which will al- low for consistent enzyme unit strength in new and future PEPS. At this time, Cmn appears to be the most appropriate first-line agent, as it has been approved for treatment of chronic pancreatitis, pancreatectomy, and cystic fibrosis. 25

26 Taylor JR, Gardner TB, Waljee AK, Dimagno MJ, Schoenfeld PS. Systematic review: efficacy and safety of pancreatic enzyme supplements for exocrine pancreatic insufficiency. Alimentary pharmacology & therapeutics. 2010;31(1): AIM: To determine if pancreatic enzyme supplements are: (i) superior to placebo for treating fat malabsorption and (ii) superior to other supplements based on randomized cross-over trials. METHODS: A computer-assisted search of MEDLINE and EMBASE was performed to identify relevant studies. Data extraction on study design, improvement in coefficient of fat absorption, diarrhoea and adverse events using prespecified forms. 26

27 Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association. 2008;108(5): Background The Subcommittee developed a series of questions related to energy intake and PERT for children and adults with CF and PI. A systematic review of evidence was conducted to inform the guideline development process. Four specific questions were addressed: What is the evidence of a relationship between energy intake and nutritional and growth status? For this report, nutritional and growth status included weight, stature, and weight-for-stature. What is the evidence that nutritional and growth status is associated with health outcomes? What is the evidence for an association between the dose of PERT and the coefficient of fat absorption (CFA), and nutritional and growth status? What is the evidence for the effect of using generic rather than name brand PERT on the CFA and on nutritional and growth status? Methods Investigators at Johns Hopkins University conducted a systematic review in spring 2005 to assist the Subcommittee in making recommendations. English-language articles published from January 1988 to February 2005 reporting studies addressing the questions were identified for review. Searches were conducted in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, PASCAL, Allied and Complementary Medicine, and Agricultural On-line Access. A total of 1,008 publications were reviewed and resulted in 57 eligible publications addressing questions pertaining to energy intake and 10 eligible publications for PERT. 27

28 [Randomized controlled trial] Stern RC, Eisenberg JD, Wagener JS, Ahrens R, Rock M, dopico G, et al. A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency. The American journal of gastroenterology. 2000;95(8): OBJECTIVE: The safety and efficacy of Minimicrospheres, which are enteric-coated, delayed-release pancrelipase capsules, on fat absorption in pediatric/adolescent and adult cystic fibrosis (CF) patients was assessed. Exocrine pancreatic insufficiency, common in CF patients, causes steatorrhea due to insufficient release of pancreatic enzymes. METHODS: In the open-label phase, 97 CF patients with pancreatic insufficiency and steatorrhea were stabilized on a high-fat diet and administered pancrelipase. Seventy-four patients with >80% coefficient of fat absorption received placebo or pancrelipase in the double-blind phase. Fat intake and excretion, stool frequency and consistency, and clinical global improvement were recorded. 28

29 Complete search strategy PubMed (n=856) (((pancreatic enzyme) OR ((cystic fibrosis[mesh Terms]) OR pancreatic insufficiencies[mesh Terms]))) AND (((((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta synthesis [ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt]))))) Filters: Humans Cochrane (n= 107) #1 MeSH descriptor: [Cystic Fibrosis] explode all trees 1207 #2 MeSH descriptor: [Exocrine Pancreatic Insufficiency] explode all trees 77 #3 pancreatic enzyme:ti,ab,kw (Word variations have been searched) 650 #4 (#1 or #2) and (#3)

30 Tolterodine Addition to the list Explanation for addition: Ontario Public Drug Program (OPDP) data- financial year 2015/2016: the number of recipients was 9, and cumulative total number of claims was 17. Relevant medications on CLEAN Meds Essential Medication List: None Literature review question: Is Tolterodine effective and safe for treatment of urinary incontinence? Utilized electronic databases PubMed and Cochrane Brief search strategies - (Tolterodine[MeSH Terms]) OR Detrol[MeSH Terms]) OR Detrusitol[MeSH Terms]) AND Children[MeSH Terms]) OR Pediatrics[MeSH Terms]) AND urinary incontinence[mesh Terms]) AND [(systematic review filter)] *Note: as the literature search results for use of Tolterodine in children/pediatric populations was lacking, literature search for Tolterodine use in adult populations was carried out. Relevant information for both population groups is illustrated below* Deshpande AV, Caldwell PHY, Sureshkumar P. Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics). Cochrane Database of Systematic Reviews. 2012(12): CD Background: Enuresis (bedwetting) is a socially stigmatizing and stressful condition which affects around 15% to 20% of five-year olds and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs to the children can be great. Drugs (including desmopressin, tricyclics and other drugs) have often been tried to treat nocturnal enuresis. Objectives: To assess the effects of drugs other than desmopressin and tricyclics on nocturnal enuresis in children and to compare them with other interventions. Selection Criteria: All randomized trials of drugs (excluding desmopressin or tricyclics) for treating nocturnal enuresis in children up to the age of 16 years were included in the review. Trials were eligible for inclusion if children were randomized to receive drugs compared with placebo, other drugs or behavioral interventions for nocturnal enuresis. Studies which included children with daytime urinary incontinence or children with organic conditions were also included in this review if the focus of the study was on nocturnal enuresis. Trials focused solely on daytime wetting and trials of adults with nocturnal enuresis were excluded. Data collection and analysis: Two review authors independently assessed the quality of the eligible trials and extracted data. Differences between review authors were settled by discussion with a third review author. 30

31 Analysis 1.1. Comparison 1 Drugs versus placebo, Outcome 1 number of wet nights per week. Analysis 1.3. Comparison 1 Drugs versus placebo, Outcome 3 Number not achieving 14 consecutive dry nights. 31

32 Analysis 2.3. Comparison 2 Drug drug comparisons, Outcome 3 Number not achieving 14 consecutive dry nights. Analysis 5.1. Comparison 5 Combination therapy versus monotherapy, Outcome 1 Number not achieving 14 dry nights. 32

33 Rai BP, Cody JD, Alhasso A, Stewart L. Anticholinergic drugs versus non-drug active therapies for non-neurogenic overactive bladder syndrome in adults. Cochrane Database of Systematic Reviews 2012(12):CD Background: Overactive bladder syndrome is defined as urgency with or without urgency incontinence, usually with frequency and nocturia. Pharmacotherapy with anticholinergic drugs is often the first line medical therapy, either alone or as an adjunct to various nonpharmacological therapies after conservative options such as reducing intake of caffeine drinks have been tried. Non-pharmacologic therapies consist of bladder training, pelvic floor muscle training with or without biofeedback, behavioral modification, electrical stimulation and surgical interventions. Objectives: To compare the effects of anticholinergic drugs with various non-pharmacologic therapies for non-neurogenic overactive bladder syndrome in adults. Selection Criteria: All randomized or quasi-randomized, controlled trials of treatment with anticholinergic drugs for overactive bladder syndrome or urgency urinary incontinence in adults in which at least one management arm involved a non-drug therapy. Trials amongst patients with neurogenic bladder dysfunction were excluded. Data Collection and analysis: Two authors evaluated the trials for appropriateness for inclusion and risk of bias. Two authors were involved in the data extraction. Data extraction was based on predetermined criteria. Data analysis was based on standard statistical approaches used in Cochrane reviews. Analysis 1.3. Comparison 1 Anticholinergic drugs versus bladder training, Outcome 3 Numbers not improved at end of treatment (subjective). 33

34 Analysis Comparison 1 Anticholinergic drugs versus bladder training, Outcome 10 Number of micturition s per 24 hours. Analysis Comparison 1 Anticholinergic drugs versus bladder training, Outcome 20 Numbers withdrawing from treatment. 34

35 Analysis 5.2. Comparison 5 Anticholinergic drugs in combination with non-drug therapies versus non-drug therapies alone, Outcome 2 Numbers not improved end of treatment (subjective). Analysis 6.2. Comparison 6 Anticholinergic drugs in combination with non-drug therapies versus anticholinergic drugs alone, Outcome 2 Numbers not improved end of treatment (subjective). 35

36 Madhuvrata P, Cody JD, Ellis G, Herbison GP, Hay-Smith EJC. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database of Systematic Reviews 2012(1):CD Background: Around 16% to 45% of adults have overactive bladder symptoms, urgency with frequency or urgency urinary incontinence, or both, termed overactive bladder syndrome. Anticholinergic drugs are common treatments. Objectives: To compare the effects of different anticholinergic drugs for overactive bladder symptoms. Search methods We searched the Cochrane Incontinence Group Specialized Trials Register (searched 8 March 2011) and reference lists of relevant articles. Selection criteria: Randomized trials in adults with overactive bladder symptoms or detrusor over activity that compared one anticholinergic drug with another or two doses of the same drug. Data collection and analysis: Two authors independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions. Analysis 1.1. Comparison I One anticholinergic versus another, Outcome 1 Condition specific QoL. 36

37 Analysis 1.3. Comparison 1 One anticholinergic versus another, Outcome 3 Cure/improvement. 37

38 Analysis 1.4. Comparison 1 One anticholinergic versus another, Outcome 4 Leakage episodes in 24 hrs (End of tx and change from baseline). 38

39 National institute for Health and Care Excellence (NICE) Guidance: Urinary incontinence in neurological disease: assessment and management [Clinical Guideline [CG148] Published date: August 2012] This guideline covers assessing and managing urinary incontinence in children, young people and adults with neurological disease. It aims to improve care by recommending specific treatments based on what symptoms and neurological conditions people have. 1.3 Treatment to improve bladder storage Behavioral treatments 1.3.1Consider a behavioral management program (for example, timed voiding, bladder retraining or habit retraining) for people with neurogenic lower urinary tract dysfunction: only after assessment by a healthcare professional trained in the assessment of people with neurogenic lower urinary tract dysfunction and in conjunction with education about lower urinary tract function for the person and/or their family members and carers When choosing a behavioral management program, take into account that prompted voiding and habit retraining are particularly suitable for people with cognitive impairment. Antimuscarinics Offer antimuscarinic [2] drugs to people with: spinal cord disease (for example, spinal cord injury or multiple sclerosis) and symptoms of an overactive bladder such as increased frequency, urgency and incontinence Consider antimuscarinic [2] drug treatment in people with: conditions affecting the brain (for example, cerebral palsy, head injury or stroke) and symptoms of an overactive bladder Consider antimuscarinic [2] drug treatment in people with urodynamic investigations showing impaired bladder storage Monitor residual urine volume in people who are not using intermittent or indwelling catheterization after starting antimuscarinic treatment When prescribing antimuscarinics, take into account that: antimuscarinics known to cross the blood-brain barrier (for example, oxybutynin) have the potential to cause central nervous system-related side effects (such as confusion) antimuscarinic treatment can reduce bladder emptying, which may increase the risk of urinary tract infections antimuscarinic treatment may precipitate or exacerbate constipation. 39

40 1.4 Treatment for stress incontinence Pelvic floor muscle training 1.4.1Consider pelvic floor muscle training for people with: lower urinary tract dysfunction due to multiple sclerosis or stroke or other neurological conditions where the potential to voluntarily contract the pelvic floor is preserved. Select patients for this training after specialist pelvic floor assessment and consider combining treatment with biofeedback and/or electrical stimulation of the pelvic floor. UpToDate Recommendations: Management of bladder dysfunction in children. [Kenneth G Nepple, MD, Christopher S Cooper, MD, FACS, FAAP Literature review current through: Feb This topic last updated: Nov 19, 2015] Other anticholinergic agents Tolterodine is a selective competitive muscarinic receptor antagonist that has not been FDA approved for use in children. It has been shown to improve detrusor compliance and bladder capacity in patients with OAB [34]. In a placebo-controlled trial of 711 children ranging from 5 to 10 years of age, patients were randomly selected to receive tolterodine (2 mg per day) for 12 weeks [35]. There was no overall difference in the number of incontinent episodes. However, a subset analysis demonstrated a decrease in the frequency of incontinence in children with a weight at or below 35 kg, suggesting a possible under dosage effect in heavier children. A retrospective study of 200 children with OAB reported that tolterodine therapy resulted in complete continence or significantly reduced frequency of incontinent episodes (greater than a 50 percent reduction) in approximately one-half of the patients [36]. Other smaller observational studies suggest that tolterodine was effective in patients who failed oxybutynin therapy [19,37]. Other selective antimuscarinic agents including darifenacin, solifenacin, and trospium, have been developed and approved for use in adults. However these agents have not been studied extensively in the pediatric populations. As a result, these agents cannot be recommended to treat children with OAB. There are few studies that compare different anticholinergic agents. In one retrospective study of 132 children with daytime incontinence and symptoms of OAB, oxybutynin compared with either short or long-acting tolterodine was more effective in controlling daytime urinary incontinence and frequency [38]. Complete search strategies 40

41 PubMed (n=4) March 3, 2017 at 9:58AM w/ Children/peds query ((((((Tolterodine[MeSH Terms]) OR Detrol[MeSH Terms]) OR Detrusitol[MeSH Terms]) AND Children[MeSH Terms]) OR Pediatrics[MeSH Terms]) AND urinary incontinence[mesh Terms]) AND ((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta-analy*[ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR umbrella review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt])) Cochrane (n=3) March 6, 2:31 PM 1 Tolterodine.mp. [mp=title, short title, abstract, full text, keywords, caption text] (15) 2 Detrol.mp. [mp=title, short title, abstract, full text, keywords, caption text] (0) 3 Detrusitol.mp. [mp=title, short title, abstract, full text, keywords, caption text] (1) 4 1 or 2 or 3 (16) 5 Children.mp. [mp=title, short title, abstract, full text, keywords, caption text] (3339) 6 Pediatrics.mp. [mp=title, short title, abstract, full text, keywords, caption text] (331) 7 5 or 6 (3419) 8 4 and 7 (5) 9 urinary incontinence.mp. [mp=title, short title, abstract, full text, keywords, caption text] (191) 10 8 and 9 (3) PubMed (n=18) March 3, 2017 at 10:02 AM w/out search for Children/peds 41

42 ((((Tolterodine[MeSH Terms]) OR Detrol[MeSH Terms]) OR Detrusitol[MeSH Terms]) AND Urinary incontinence[mesh Terms]) AND ((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta-analy*[ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR umbrella review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt])) Cochrane (n=10) March 6, 2:46 PM 1 Tolterodine.mp. [mp=title, short title, abstract, full text, keywords, caption text] (15) 2 Detrol.mp. [mp=title, short title, abstract, full text, keywords, caption text] (0) 3 Detrusitol.mp. [mp=title, short title, abstract, full text, keywords, caption text] (1) 4 1 or 2 or 3 (16) 5 urinary incontinence.mp. [mp=title, short title, abstract, full text, keywords, caption text] (191) 6 4 and 5 (12) 7 adults.mp. [mp=title, short title, abstract, full text, keywords, caption text] (4668) 8 6 and 7 (10) 42

43 Ursodeoxycholic acid Addition to the list Explanation for addition Ontario Public Drug Program (OPDP) data- financial year 2015/2016: the number of recipients was 42 (42/594,392 = ), and cumulative total number of claims was 243. Relevant medications on CLEAN Meds Essential Medication list: None Literature review question Is Ursodeoxycholic acid effective and safe when used for cholestatic liver diseases? Utilized electronic database: Cochrane and PubMed Brief search strategies (with/without pediatric/children search query): (Ursodeoxycholic acid[mesh Terms]) OR Ursodiol[MeSH Terms]) AND cholestatic liver disease[mesh Terms]) AND [(systematic review filter)] *Note: as the literature search results for use of Ursodeoxycholic acid in children/pediatric populations for the treatment of cholestatic Liver disease did not yield many results; a literature search for Ursodeoxycholic acid use in adult populations was carried out. This search did not find articles for the treatment of cholestatic liver disease; hence the evidence package looks at specific causes of cholestatic liver disease and their treatment with ursodeoxycholic acid in both pediatric and adult populations. Relevant information for both population groups is illustrated below* Hempfling W., Dilger K., Beuers U. Systematic review: ursodeoxycholic acid adverse effects and drug interactions. Aliment Pharmacol Ther. 2003; 18: Background: Ursodeoxycholic acid is increasingly being used for the treatment of chronic cholestatic liver diseases. It appears to be generally well tolerated, but a systematic review on drug safety is lacking. Aim: As experimental data suggest a role of bile acids in the regulation of hepatic drug metabolism at both the transcriptional and post-transcriptional level, the literature was screened for adverse drug reactions and drug interactions related to ursodeoxycholic acid. Methods: A systematic review of the literature was performed using a refined search strategy to valuate the adverse effects of ursodeoxycholic acid and its interactions with other drugs. 43

44 Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosis-related liver disease (review). The Cochrane database of systematic reviews. 2014(12): CD Background: Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. Objectives: To analyze evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis. Selection Criteria: Randomized controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis. Data Collection and analysis: Two authors independently assessed trial eligibility and quality. 44

45 Comparison 1. UDCA versus placebo/no additional treatment (all groups given conventional care ) 45

46 Analysis 1.1. Comparison 1 UDCA versus placebo/no additional treatment (all groups given conventional care ), Outcome 1 lack of normalization of any liver enzyme reported in the study. Analysis 1.4. Comparison 1 UDCA versus placebo/no additional treatment (all groups given conventional care ), Outcome 4 Lack of normalization of aspartate transaminase. 46

47 Analysis 1.5. Comparison 1 UDCA versus placebo/no additional treatment (all groups given conventional care ), Outcome 5 Lack of normalization of alanine transferase. Analysis 1.6. Comparison 1 UDCA versus placebo/no additional treatment (all groups given conventional care ), Outcome 6 Lack of normalization of gammaglutamate transferase. 47

48 Analysis 1.7. Comparison 1 UDCA versus placebo/no additional treatment (all groups given conventional care ), Outcome 7 Need for Liver transplantation. Analysis Comparison 1 UDCA versus placebo/no additional treatment (all groups given conventional care ), Outcome 10 Change in weight (kg). 48

49 Poropat G, Giljaca V, Stimac D, Gluud C. Bile acids for primary sclerosing cholangitis. Cochrane Database of Systematic Reviews 2011(1): CD Background: Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients survival and disease outcome has yet been proven. Objectives: To assess the beneficial and harmful effects of bile acids for patients with primary sclerosing cholangitis. Search methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE and Science Citation Index Expanded generally from inception through to October Selection criteria: Randomized clinical trials comparing any dose of bile acids or duration of treatment versus placebo, no intervention, or another intervention were included irrespective of blinding, language, or publication status. Data collection and analysis: Two authors extracted data independently. We evaluated the risk of bias of the trials using pre-specified domains. We performed the meta-analysis according to the intention-to-treat principle. We presented outcomes as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI). Comparison 1. UDCA versus control (placebo or no treatment) 49

50 Comparison 2. Sensitivity analyses Analysis 1.1. Comparison 1 UDCA versus control (placebo or no treatment), Outcome 1 Mortality at the end of treatment. 50

51 Analysis 1.2. Comparison 1 UDCA versus control (placebo or no treatment), outcome 2 Number of treatment failures at the end of treatment. Analysis 1.3. Comparison 1 UDCA versus control (placebo or no treatment), Outcome 3 Adverse events. 51

52 Analysis 1.4. Comparison 1 UDCA versus control (placebo or no treatment), Outcome 4 Quality of life physical component. Analysis 1.5. Comparison 1 UDCA versus control (placebo or no treatment), Outcome 5 Quality of life mental component. Analysis 1.6. Comparison 1 UDCA versus control (placebo or no treatment), Outcome 6 Number of patients with liver histological deterioration at the end of treatment. 52

53 Analysis 1.8. Comparison 1 UDCA versus control (placebo or no treatment), Outcome 8 Number of patients with cholangiographic deterioration at the end of treatment. Analysis 1.9. Comparison 1 UDCA versus (placebo or no treatment), Outcome 9 Number of patients with worsening clinical symptoms (fatigue and/or pruritus) at the end of treatment. 53

54 Analysis Comparison 1 UDCA versus control (placebo or no treatment), Outcome 10 Serum bilirubin level (µmol/l) at the end of treatment. Analysis Comparison 1 UDCA versus control (placebo or no treatment), Outcome 11 Serum alkaline phosphatases activity (IU/L) at the end of treatment. 54

55 Analysis Comparison 1 UDCA versus control (placebo or no treatment), Outcome 12 Serum aspartate aminotransferase activity (IU/L) at the end of treatment. Analysis Comparison 1 UDCA versus control (placebo or no treatment), Outcome 13 Serum gamma-glutamyltranspeptidase activity (IU/L) at the end of treatment. 55

56 Analysis Comparison I UDCA versus control (placebo or no treatment), Outcome 14 Serum albumin concentration (g/l) at the end of treatment. Analysis 2.1. Comparison 2 Sensitivity analyses, Outcome 1 Mortality Duration of the treatment with UDCA. 56

57 Analysis 2.2. Comparison 2 Sensitivity analyses, Outcome 2 Mortality Dose of UDCA in the treatment. 57

58 Analysis 2.3. Comparison 2 Sensitivity analyses, Outcome 3 Mortality Different duration of the treatment with different doses of UDCA. 58

59 National institute for Health and Care Excellence (NICE) Guidance: Ursodeoxycholic acid for cystic fibrosis-related liver disease [The UK Cochrane Centre and NICE] Publication date: 31 Jan Evidence does not support the use of ursodeoxycholic acid (UDCA) for the prevention of cystic fibrosis (CF)-related liver disease. Many of the studies performed to date failed to include important outcomes (for example, number of liver transplants), and showed no significant improvement in the normalization of any single hepatocellular enzyme, increase in weight or improvement in biliary excretion with the use of UDCA. Therefore at present UDCA cannot be recommended. 1.2 Evidence of the effectiveness of UDCA is as yet inconclusive. Routine use of UDCA in people with CF cannot, therefore, be recommended. However, in view of these important preliminary results and because of the lack of any other effective intervention to prevent or treat CF-related liver disease, it is essential that a large multicentre RCT of UDCA in people with CF is undertaken. UpToDate Recommendations: Leung DH, MD, Borowitz D, MD. Cystic Fibrosis: Hepatobiliary disease. Literature review current through: Feb This topic last updated: Oct 12, 2015] Ursodeoxycholic acid The role of ursodeoxycholic acid (UDCA) in CFLD has not been established and is controversial. Limited clinical evidence suggests that UDCA at moderate doses may improve biochemical parameters in patients with CFLD. However, there is no good evidence that it improves other outcomes, and indirect evidence from other cholestatic liver diseases suggest that high doses may be detrimental. In view of these uncertainties, expert opinion differs as to whether UDCA should be used for all patients with CFLD, or only those with significant cholestasis and fibrosis [17,33]. Our practice is to give UDCA to children who have established cholestasis (eg, conjugated bilirubin >1 mg/dl [17.1 micromol/l]), particularly those on or recently weaned off total parenteral nutrition (TPN). We use a dose of 10 to 20 mg/kg body weight per day in two divided doses and continue for two months beyond resolution of hyperbilirubinemia. We do not use UDCA for children with subclinical or milder forms of CFLD. However, more liberal use of UDCA has been advocated in the past by an expert panel, including its use for children with early or mild CFLD (eg, persistently elevated aminotransferases), and escalating the dose if there is no improvement in aminotransferase concentrations after three months of treatment [3]. UDCA is a nontoxic bile acid, naturally occurring in humans, and is thought to reduce liver injury in cholestatic liver disease by replacing cytotoxic bile acids. It also may increase bicarbonate secretion, and may have a direct cytoprotective and antiinflammatory effect [20,34]. Despite these theoretical benefits, the clinical evidence supporting the use of UDCA is weak, and consists of low-quality or indirect clinical evidence [35], as outlined below: Several observational studies and two small randomized trials suggest that UDCA may delay the progression of CFLD [36-38]. One of the randomized trials included 55 children and adults with CFLD, and reported that those treated with UDCA for one year experienced improvements in gamma glutamyl transpeptidase (GGTP) and in a global measure of CF severity, as compared with placebo [37]. A separate trial in children who presented with meconium ileus (MI) at birth (and who were 59

60 therefore at increased risk for developing CFLD) reported that treatment with UDCA reduced the likelihood of developing chronic liver disease by nine years of age [39]. A Cochrane review found insufficient evidence to determine whether UDCA is effective for treatment or prevention of CFLD [35]. Three studies were included involving close to 120 subjects, two-thirds of whom had CFLD based on criteria similar to those outlined above (large liver, persistently elevated hepatic enzyme levels). The participants were treated with UDCA doses ranging from 10 to 20 mg/kg/day for up to 12 months. There was no significant difference in weight gain. No improvement in biliary excretion was found in the one trial that measured this outcome. There were no data available for analysis for long-term outcomes, such as death or need for liver transplantation. Indirect evidence suggests possible adverse effects of UDCA in high doses. In a randomized trial in adults with primary sclerosing cholangitis (PSC), chronic treatment with high-dose UDCA (20 to 30 mg/kg per day) was linked to improvement in liver biochemistry abnormalities, but also was associated with higher rates of serious adverse events and did not improve survival [40]. The trial was terminated at year six due to futility. The limited role for UDCA in the management of PSC is discussed in a separate topic review. (See "Primary sclerosing cholangitis in adults: Management", section on 'Ursodeoxycholic acid'.) Indirect evidence from studies in adults with primary biliary cholangitis (PBC) suggests possible benefit of UDCA on some measures of cholestasis. In a cohort of adult patients with PBC, UDCA seemed to have a beneficial effect on both liver biochemistry measures and on histological progression, but did not improve all-cause mortality or need for liver transplantation [41]. Similar conclusions were reached in a meta-analysis that included 16 randomized trials [42]. Individual trials and another meta-analysis have reached more optimistic conclusions [43]. (See "Trials of ursodeoxycholic acid for the treatment of primary biliary cholangitis (primary biliary cirrhosis)".) UpToDate Recommendations: Flamm S, MD, Poupon R, MD. Trials of ursodeoxycholic acid for the treatment of primary biliary cholangitis (primary biliar cirrhosis). Literature review current through: Feb This topic last updated: Oct 15, 2015] In aggregate, the data suggest that ursodeoxycholic acid (UDCA) for the treatment of primary biliary cholangitis (PBC) is associated with improvement in liver biochemical tests, a reduction in disease progression, and possibly transplant-free survival. However, they do not confirm initial reports that suggested relief of the troublesome systemic symptoms of fatigue and pruritus. Several additional conclusions can be made from these data: UDCA appears to be more effective in patients with early disease. Patients with advanced PBC and complications of portal hypertension (eg, ascites or variceal bleeding) do not benefit from UDCA. Such patients should be considered for liver transplantation. Additional therapy is probably needed in patients with florid bile duct lesions and severe lymphocytic piecemeal necrosis and lobular inflammation since these patients appear to be at increased risk for disease progression despite UDCA. (See "Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis)".) 60

61 Complete search strategies Cochrane (n=17) March 1, :46pm 2005 to February 22, Ursodeoxycholic acid.mp. [mp=title, short title, abstract, full text, keywords, caption text] (42) 2 Ursodiol.mp. [mp=title, short title, abstract, full text, keywords, caption text] (2) 3 bile acids.mp. [mp=title, short title, abstract, full text, keywords, caption text] (41) 4 1 or 2 or 3 (65) 5 children.mp. [mp=title, short title, abstract, full text, keywords, caption text] (3343) 6 pediatrics.mp. [mp=title, short title, abstract, full text, keywords, caption text] (331) 7 5 or 6 (3423) 8 4 and 7 (17) PubMed (n=6) March 7, 2017 at 3.00 pm (search results with children/pediatrics query provided 0 returns) ((((Ursodeoxycholic acid[mesh Terms]) OR Ursodiol[MeSH Terms]) OR bile acids[mesh Terms]) AND cholestatic liver disease[mesh Terms]) AND ((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta-analy*[ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR umbrella review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt])) 61

62 Deferasirox Addition to the list Explanation for addition Ontario Public Drug Program (OPDP) data financial year: 2015/2016: the number of recipients was 30 and cumulative total number of claims was 101. Relevant medications on CLEAN Meds Essential Medication List None Literature review question Is deferasirox effective and safe when it is prescribed for children with iron overload? Utilized electronic databases PubMed and Cochrane Brief search strategies (systematic review) AND (deferasirox OR iron chelator) AND (children or pediatrics); (deferasirox OR iron chelator) AND (efficacy OR safety). No evidence in children found. McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, Dickson R, Dundar Y, Greenhalgh J, Modell B, Olujohungbe A, Telfer P, Walley T. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation. Health Technology Assessment. 2009;13(1). Background Deferasirox is a new orally active iron-chelating agent that is given once daily as a suspension (usually in water or fruit juice). Deferasirox may be of particular value in treating patients with iron overload who cannot tolerate deferoxamine (DFO) and who are not suitable for, or who are intolerant of, deferiprone. The ease of administration of deferasirox (oral) compared with DFO (infusional) might improve patient adherence to therapy and, if effective, may also improve quality and quantity of life. Adverse effects The most common side effects reported are increased serum creatinine ( 1/10), headache ( 1/100 to <1/10), GI disorders including diarrhea, constipation, nausea, vomiting and abdominal pain ( 1/100 to <1/10), increased ALT ( 1/100 to <1/10) proteinuria ( 1/100 to <1/10) and rash ( 1/100 to <1/10). Results A total of 14 RCTs, making comparisons between deferasirox, deferoxamine (DFO), deferiprone and combination therapy (deferiprone and DFO) and involving a study population of 1480 (ranging from 13 to 586), met the inclusion criteria. Three RCTs comparing deferasirox with DFO were found although none contained data that could be included in the meta-analyses; there were no studies comparing deferasirox with deferiprone or combination therapy. Discussion Our review of the evidence from RCTs indicates that, in the short term, all of the chelators appear to be efficacious in reducing iron in the liver and blood as measured by mean changes in LIC and serum ferritin. Meta-analysis found combination therapy to be statistically superior to DFO monotherapy in reducing mean serum ferritin concentrations over 12 months. There is evidence that children and adults metabolise deferasirox differently and so efficacy may also differ by age. Unfortunately, none of the RCTs conducted subgroup analysis to address this issue. 62

63 Meerpohl JJ, Antes G, Rucker G, Fleeman N, Motschall E, Niemeyer CM, Bassler D. Deferasirox for managing iron overload in people with thalassaemia (Review). The Cochrane Library. 2012(2). Objectives To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and secondary iron overload. Main results Two studies compared deferasirox to placebo or standard therapy of deferoxamine (n=47). The placebocontrolled studies, a pharmacokinetic and a dose escalation study, showed that deferasirox leads to net iron excretion in transfusion-dependent thalassaemia patients. In these studies, safety was acceptable and further investigation in phase II and phase III trials was warranted. Two studies, one phase II study (n=71) and one phase III study (N=586) compared deferasirox to standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared; in the phase III trial, similar or superior efficacy for surrogate parameters of ferritin and liver iron concentration could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1mg of deferasirox to 1.8mg of deferoxamine corresponding to a mean dose of 28.2 mg/d and 51.6 mg/d respectively. Data on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was significantly better with deferasirox, while rate of discontinuations was similar for both drugs. Authors conclusions Deferasirox offers an important alternative line of treatment for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1mg of deferasirox to 2mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy in the long run and will translate to similar benefits as has been shown for deferoxamine, needs to be confirmed. Therefore, we think that deferasirox should be offered as an alternative to all patients with thalassaemia who either show intolerance to deferoxamine or poor compliance with deferoxamine. In our opinion, data are still too limited to support the general recommendation of deferasirox as first-line treatment instead of deferoxamine. If a strong preference for deferasirox is expressed, it could be offered as first-line option to individual patients after a detailed discussion of the potential benefits and risks. 63

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66 Fisher SA, Brunskill SJ, Doree C, Gooding S, Chowdhury O, Roberts DJ. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. The Cochrane Library (8). Objective To determine the effectiveness (dose and method of administration) of desferrioxamine in people with transfusion-dependent thalassaemia To summarise data from trials on the clinical efficacy and safety of desferrioxamine for thalassaemia and to compare these with deferiprone and deferasirox. Main results Desferrioxamine and the oral iron chelators deferiprone and deferasirox produce significant reductions in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomized controlled trials to suggest that any one of these has a greater reduction of clinically significant end organ damage, although in two trials, combination therapy with desferrioxamine and deferiprone showed a greater improvement in left ventricular ejection fraction than desferrioxamine used alone. Author s conclusions Desferrioxamine is the recommended first-line therapy for iron overload in people with thalassaemia major and deferiprone or deferasirox are indicated for treating iron overload when desferrioxamine is contraindicated or inadequate. Oral deferasirox has been licensed for use in children aged over six years 66

67 who receive frequent blood transfusions and in children aged two to five years who receive infrequent blood transfusions. 67

68 Complete search strategies Cochrane (n=15) 1 deferasirox. mp. [mp=title, short title, abstract, full text, keywords, caption text] (12) 2 iron chelator. mp. [mp=title, short title, abstract, full text, keywords, caption text] (11) 3 1 or 2 (15) 4 efficacy. mp. [mp=title, short title, abstract, full text, keywords, caption text] (5458) 5 safety. mp. [mp=title, short title, abstract, full text, keywords, caption text] (4382) 6 4 or 5 (6575) 8 3 and 6 (15) PubMed (n=7) ("review"[publication Type] OR "review literature as topic"[mesh Terms] OR "systematic review"[all Fields]) AND (("deferasirox"[supplementary Concept] OR "deferasirox"[all Fields]) OR (("iron"[mesh Terms] OR "iron"[all Fields]) AND ("chelating agents"[pharmacological Action] OR "chelating agents"[mesh Terms] OR ("chelating"[all Fields] AND "agents"[all Fields]) OR "chelating agents"[all Fields] OR "chelator"[all Fields]))) AND (("child"[mesh Terms] OR "child"[all Fields] OR "children"[all Fields]) OR ("paediatrics"[all Fields] OR "pediatrics"[mesh Terms] OR "pediatrics"[all Fields])) AND (("safety"[mesh Terms] OR "safety"[all Fields]) AND efficacy[all Fields]) 68

69 Aripiprazole Addition to the list Explanation for the addition The Ontario Public Drug Program (OPDP) data-financial year 2015/2016: the number of recipients was 2,700, and cumulative total number of claims was 15,216. Relevant medications on CLEAN Meds Essential Medication List Clozapine Literature Review Question Is Aripiprazole effective and safe when used for treatment of psychosis in children? Utilized electronic databases: PubMed, Cochrane Brief search strategies: (((aripiprazole OR atypical antipsychotic[mesh Terms])) AND psychosis[mesh Terms]) AND children Kumar A, Datta SS, Wright SD, Furtado VA, Russell PS. Atypical antipsychotics for psychosis in adolescents. Cochrane Database of Systematic Reviews 2013, Issue 10 Art.No.: CD Background Schizophrenia is a mental disorder that often presents in adolescence, but current treatment guidelines are based largely on studies of adults with psychosis. Over the past decade, the number of studies on treatment of adolescent-onset psychosis has increased. The current systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis. Objectives This review aimed to investigate the effects of atypical antipsychotic medications in adolescents with psychosis. Studies included This review included 13 RCTs involving 1112 participants that compared atypical antipsychotic medication with placebo or another pharmacological intervention or with psychosocial interventions, standard psychiatric treatment or no intervention in children and young people aged 13 to 18 years with a diagnosis of schizophrenia, schizoaffective disorder, acute and transient psychoses or unspecified psychosis. Two trials compared one atypical antipsychotic medication with placebo; Five trials compared atypical antipsychotic medications with a typical antipsychotic medication; Six studies compared one atypical antipsychotic vs another atypical antipsychotic; Three studies reported comparisons of lower doses of the atypical antipsychotic medication with standard/higher doses of the same medication Primary and Secondary Outcomes 1. Global state 2. Clinical response 3. Global functioning 4. Adverse effects 5. Social functioning 6. Service utilisation 7. Economic outcomes 8. Quality of life/satisfaction with care for recipients of care or carers 69

70 70

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73 Results 1. Atypical antipsychotic medications vs placebo (only short term) Two studies (reported comparative efficacy of atypical antipsychotic medications versus placebo. Mental State A study by Findling (2008) found that 46% of adolescents treated with Aripiprazole 10 mg did not achieve remission compared with 64% in the placebo group. Adverse Effects Increased weight gain and treatment-emergent high prolactin levels were reported in the olanzapine arm of the Kryzhanovskaya (2009) study. No significant weight gain was described with aripiprazole 30 mg as compared with placebo. 2. Atypical vs Typical antipsychotic medications (only short term) Five studies compared atypical antipsychotic medications with typical antipsychotic medications. Mental State One study, Kumra (1996), reported that participants treated with clozapine had a better outcome as measured on the Bunney-Hamburg Rating Scale. Adverse effects All side effects were not uniformly reported in the five studies making it difficult to make a headto-head comparison of side effects between studies. 3. Atypical antipsychotic vs atypical antipsychotic medications (only short term) Five studies compared two different antipsychotic medications for adolescents with psychosis. Mental State 73

74 No difference in the outcome of mental state was noted in the studies that compared one atypical antipsychotic medication with another. However, most participants improved as compared with baseline score. Adverse effects Similar and comparable side effects were reported by all studies. This included: Increased body weight (Olanzapine, Risperidone and Clozapine) De Hert 2011reported that ziprasidone was associated with the least weight gain, followed by aripiprazole, quetiapine, risperidone and olanzapine in ascending order. Olanzapine was associated with increased mean end point serum cholesterol concentration as compared with risperidone (Sikich 2008). More people had elevated serum prolactin when treated with risperidone as compared with quetiapine (Swadi 2010). 4. Atypical (higher-dose) vs atypical (lower-dose) antipsychotic medications (only short term) Three studies compared higher doses of an antipsychotic medication with lower doses of the same antipsychotic medication. Global State Some evidence shows that risperidone 1.5 to 6 mg is more likely to improve the global state when compared with the very low dose of 0.15 to 0.6 mg/d for adolescents with psychosis (Haas 2009). However, no difference has been noted between the final global state achieved by aripiprazole 30 mg/d and 10 mg/d (Findling 2008) and similarly between ziprasidone 160 mg/d and 80 mg/d (DelBello 2008). Mental State In most comparisons of mental state, the lower dose (< 150 mg chlorpromazine equivalent) was equally efficacious as the higher dose of the same antipsychotic medication (> 150 mg chlorpromazine equivalent). However, on the PANSS, the higher dose of risperidone fared better. Adverse effects Lower dose was associated with lesser side effects in general. However, the number of young people who had symptomatic hyperprolactinaemia was similar to the number who moved from being overweight to obese, even on lower doses of risperidone. In the study by Haas 2009, no difference was observed between groups receiving low-dose versus standard-dose risperidone with regard to treatment-emergent self-injury/aggression or worsening of any psychiatric symptoms. 74

75 The National Institute for Health and Care Excellence (NICE) Clinical Guidance: Psychosis and schizophrenia in children and young people: recognition and management 75

76 Glucagon Addition to Child Essential Meds List Explanation for the addition The Ontario Public Drug Program (OPDP) data-financial year 2015/2016: the number of recipients was 554, and cumulative total number of claims was 791. Relevant medications on CLEAN Meds Essential Medication List None Literature Review Question Is glucagon effective and safe when used for the treatment of severe hypoglycemia in children? Utilized electronic databases: PubMed Clinical Queries Brief search strategies: glucagon AND hypoglycemia AND children Sherr JL, Ruedy KJ, Foster NC, Piché CA, Dulude H, Rickels MR, et al. Glucagon Nasal Powder: A Promising Alternative to Intramuscular Glucagon in Youth with Type 1 Diabetes. Diabetes Care Apr;39(4): Objective The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years. Methods A total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dl (mean nadir ranged between 67 and 75 mg/dl). Results All 24 intramuscular and 58 of the 59 intranasal doses produced a 25 mg/dl rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts. Conclusions Results of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range. 76

77 Figure 2: Plasma Glucose and Glucagon Responses 77

78 Growth Hormone Addition to the list Explanation for Addition The Ontario Public Drug Program (OPDP) data-financial year 2015/2016: the number of recipients was 446, and total number of claims was Relevant medications on CLEAN Meds Essential Medication List None Literature Review Question Is growth hormone effective and safe when used for the treatment of growth failure in children? Utilized electronic databases: PubMed, Cochrane Brief search strategies: (systematic review filter) AND ("growth hormone"[mesh Terms]) AND ("failure to thrive"[mesh Terms]) Somatropin (Genotropin) for Subcutaneous Injection: Long-term Treatment of Children who have Growth Failure Due to an Inadequate Secretion of Endogenous Growth Hormone [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Objective The objective of this systematic review is to compare the benefits and harms of Genotropin with other available somatropin products in children with growth hormone deficiency (GHD). Results Efficacy Two head-to-head randomized controlled trials (RCTs) with parallel design that examined the efficacy and safety of Genotropin compared with other somatropin products were included in this review: one trial (Romer et al.) comparing Genotropin with Omnitrope was conducted in Europe; another trial was carried out in Taiwan and compared Genotropin with both Humatrope and Saizen (Shih et al.). The Romer et al. study (N = 89) was an open-label, phase 3 RCT with an equivalence trial design, to evaluate the clinical efficacy and safety of Omnitrope versus Genotropin over nine months in children with GHD. Thereafter, patients in the Genotropin group were switched to Omnitrope therapy. This CDR review reports results from the first nine months, during which Genotropin was compared with Omnitrope. The Shih et al. study (N = 15) was a head-to-head RCT designed to assess the clinical efficacy and safety of a one-year treatment of Genotropin versus Humatrope or Saizen in children with GHD. The study did not indicate whether patients or investigators were blind to treatment allocation. Height In the Romer et al. study, baseline height was similar in the Genotropin group and the Omnitrope groups. Increases in height over nine months were 8.4 cm and 8.6 cm for the Genotropin and Omnitrope groups respectively. The baseline-adjusted difference (by ANCOVA model) in mean change in height between Genotropin and Omnitrope was statistically non-significant: 0.23 cm (95% CI, 0.59 to 1.06). HtSDS was 78

79 another primary outcome in the Romer et al. study. Similar to height, the difference between Omnitrope and Genotropin in change in HtSDS from baseline to nine months was not statistically significant: 0.12 (95% CI, 0.06 to 0.30). Height Velocity (HV) In the Romer et al. study, the baseline-adjusted difference between Omnitrope and Genotropin for the change in HV was not statistically significant after nine months of treatment: 0.20 cm per year (95% CI, 1.34 to 0.94). Thus, the effect on HV of Genotropin and Omnitrope may be considered equivalent, given that the 95% CI did not exceed ± 2 cm per year. Similar results were observed for HVSDS. The baselineadjusted difference between Omnitrope and Genotropin for the change in HVSDS was not statistically significant after nine months of treatment: 0.76 (95% CI, 0.57 to 2.10). In the Shih et al. study, HV at 12 months was statistically higher than before treatment (P < 0.05 for all three treatment groups). The changes in HV from baseline to study end (calculated by CDR) were 7.9 cm per year, 5.4 cm per year, and 7.4 cm per year for the Genotropin, Humatrope, and Saizen groups respectively. The statistical significance of between-treatment differences was not reported. Table 1: Key Efficacy Outcomes 79

80 Adverse Events In the Romer et al. study, the overall frequency of AEs (based on all enrolled patients) was not reported; however, the frequency of individual AEs (experienced by at least 5% of the enrolled population), including eosinophilia, elevated glycosylated hemoglobin, hematoma, and headache, was comparable between Genotropin and Omnitrope groups. The majority of adverse reactions were reported to be mild in intensity. Complete search strategies ((systematic review [ti] OR meta-analysis [pt] OR meta-analysis [ti] OR systematic literature review [ti] OR this systematic review [tw] OR pooling project [tw] OR (systematic review [tiab] AND review [pt]) OR meta synthesis [ti] OR meta synthesis [ti] OR integrative review [tw] OR integrative research review [tw] OR rapid review [tw] OR consensus development conference [pt] OR practice guideline [pt] OR drug class reviews [ti] OR cochrane database syst rev [ta] OR acp journal club [ta] OR health technol assess [ta] OR evid rep technol assess summ [ta] OR jbi database system rev implement rep [ta]) OR (clinical guideline [tw] AND management [tw]) OR ((evidence based[ti] OR evidence-based medicine [mh] OR best practice* [ti] OR evidence synthesis [tiab]) AND (review [pt] OR diseases category[mh] OR behavior and behavior mechanisms [mh] OR therapeutics [mh] OR evaluation studies[pt] OR validation studies[pt] OR guideline [pt] OR pmcbook)) OR ((systematic [tw] OR systematically [tw] OR critical [tiab] OR (study selection [tw]) OR (predetermined [tw] OR inclusion [tw] AND criteri* [tw]) OR exclusion criteri* [tw] OR main outcome measures [tw] OR standard of care [tw] OR standards of care [tw]) AND (survey [tiab] OR surveys [tiab] OR overview* [tw] OR review [tiab] OR reviews [tiab] OR search* [tw] OR handsearch [tw] OR analysis [ti] OR critique [tiab] OR appraisal [tw] OR (reduction [tw]and (risk [mh] OR risk [tw]) AND (death OR recurrence))) AND (literature [tiab] OR articles [tiab] OR publications [tiab] OR publication [tiab] OR bibliography [tiab] OR bibliographies [tiab] OR published [tiab] OR pooled data [tw] OR unpublished [tw] OR citation [tw] OR citations [tw] OR database [tiab] OR internet [tiab] OR textbooks [tiab] OR references [tw] OR scales [tw] OR papers [tw] OR datasets [tw] OR trials [tiab] OR meta-analy* [tw] OR (clinical [tiab] AND studies [tiab]) OR treatment outcome [mh] OR treatment outcome [tw] OR pmcbook)) NOT (letter [pt] OR newspaper article [pt]))and (("growth hormone"[mesh Terms] OR ("growth"[all Fields] AND "hormone"[all Fields]) OR "growth hormone"[all Fields]) AND ("failure to thrive"[mesh Terms] OR ("failure"[all Fields] AND "thrive"[all Fields]) OR "failure to thrive"[all Fields] OR ("growth"[all Fields] AND "failure"[all Fields]) OR "growth failure"[all Fields]) AND ("child"[mesh Terms] OR "child"[all Fields] OR "children"[all Fields])) 80

81 Benzoyl Peroxide & Clindamycin Addition to the list Explanation for addition Ontario Public Drug Program (OPDP) data- financial year 2015/2016: the number of recipients was 3033, and cumulative total number of claims was Relevant medications on CLEAN Meds Essential Medication List Clindamycin (oral) Benzoyl Peroxide Fusidic acid Mupirocin Literature review question Is benzoyl peroxide & clindamycin safe and effective when prescribed to treat severe acne vulgaris? Utilized electronic databases PubMed and Cochrane Search Strategies (((benzoyl peroxide AND clindamycin) AND acne OR acne vulgaris) AND children) AND systematic[sb] Seidler E and Kimball A. Meta-analysis comparing efficacy of benzoyl peroxide, clindamycin, benzoyl peroxide with salicylic acid, and combination benzoyl peroxide/clindamycin in acne. JAm Acad Dermatol Jul;63(1):52-62 Objective: We compared the efficacy of topical 5% BPO, 1% to 1.2% CL, 5% BPO with salicylic acid (SA) preparation, and combination BPO/CL in acne lesion reduction. Studies Included: A total of 23 studies including 7309 patients were used in the meta-analysis. Studies had to have at least one treatment arm with 5%BPO (either with or without SA-based cleanser and toner), 1% to 1.2% CL, or combination BPO/CL as part of a randomized controlled trial for acne vulgaris. Studies that used a 5% BPO 1 SA cleanser and toner regimen were separated from the other 5% BPO groups. All studies had to have efficacy end points of actual lesion reduction and/or percent lesion reduction at 2 to 4 weeks and/or 10 to 12 weeks. Results: At 2 to 4 weeks, 5% BPO 1 SA had statistically greater percent lesion reductions over other groups (weighted mean inflammatory lesion reduction: BPO = 33.4%, CL = 21.5%, BPO 1 SA = 55.2%, BPO/CL = 40.7%, placebo =7.3%; weighted mean noninflammatory lesion reduction: BPO = 19.1%, CL = 10.0%, BPO 1 SA = 42.7%, BPO/CL = 26.2%, placebo = 6.7%). At 10- to 12-week end points, 5% BPO 1 SA and BPO/CL were similar, with overlapping confidence intervals (weighted mean inflammatory lesion reduction: BPO = 43.7%, CL =45.9%, BPO 1 SA = 51.8%, BPO/CL = 55.6%, placebo = 26.8%; weighted mean noninflammatory lesion reduction: BPO = 30.9%, CL = 32.6%, BPO 1 SA = 47.8%, BPO/CL = 40.3%, placebo = 17.0%). Conclusion: At early time points, 5% BPO 1 SA had the best profile. BPO/CL was only incrementally better than BPO alone but was superior to CL alone. At later time points, 5% BPO 1 SA was similar to BPO/CL. 81

82 Pariser D, Rich P, Cook-Bolden, F and Korotzer, A. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 3.75% for the once-daily treatment of moderate to severe acne vulgaris. Journal of Drugs in Dermatology. 2014; 13.9 Objective: To evaluate efficacy, safety, and tolerability of a fixed combination clindamycin phosphate 1.2% and benzoyl peroxide 3.75% (clindamycin-bp 3.75%) aqueous gel in moderate to severe acne vulgaris. Multicenter, randomized, double-blind, vehicle-controlled, parallel group study in 498 patients with moderate to severe acne vulgaris who met specific inclusion/exclusion criteria. Results: Clindamycin-BP 3.75% demonstrated statistical superiority to vehicle in reducing both inflammatory and noninflammatory lesions and acne severity. Clindamycin-BP 3.75% showed greater efficacy relative to vehicle in assessments of skin oiliness, SSA and PSS. No substantive differences were seen in cutaneous tolerability among treatment groups and no patients discontinued treatment with Clindamycin-BP 3.75% because of adverse events. 82

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85 American Acne and Rosacea Society. Evidence-based recommendations for the diagnosis and treatment of pediatric acne Consensus Recommendation: Fixed-dose combination topical therapies may be useful in regimens of care for all types and severities of acne. (SOR adolescents: A; preadolescents and younger: B). Severe Acne- Patients with severe acne are at significant risk for scarring. The panel recommends that the prompt initiation of appropriate treatment is essential to control the condition and prevent permanent skin changes. American Academy of Dermatology. Guidelines of care for the management of acne vulgaris Benzoyl peroxide or combinations with erythromycin or clindamycin are effective acne treatments and are recommended as monotherapy for mild acne, or in conjunction with a topical retinoid, or systemic antibiotic therapy for moderate to severe acne 85