1

Zopiclone

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is zopiclone effective and safe in treating insomnia?

Literature search

Pubmed/Medline: zopiclone AND (insomnia OR Sleep Initiation and Maintenance Disorders); zopiclone AND

(insomnia OR Sleep Initiation and Maintenance Disorders) AND efficacy

e-CPS: Insomnia

Cochrane: Zopiclone

Jennifer Glass, Krista L Lanctot, Nathan Herrmann, Beth A Sproule, and Usoa E Busto. “Sedative hypnotics

in older people with insomnia: meta-analysis of risks and benefits.” BMJ (2005): 1-7

Quality of sleep. Reported sleep quality was significantly better with sedative use (mean effect size 0.14, 0.05 to

0.23; P<0.005). This effect size indicates a difference in mean scores on sleep quality for sedative versus placebo

groups of 0.11. In the most heavily weighted study in the analysis, this would correspond to mean scores of 3.8 in

the placebo group and 3.7 in the sedative group on a seven point scale. Three studies (339 participants) comparing

benzodiazepines with benzodiazepine receptor agonists (zaleplon, zolpidem, and zopiclone) found no significant

difference in sleep quality (mean effect size 0.04, -1.11 to 1.19; test for heterogeneity P=1.0). Two studies (116

participants) that reported sleep quality data for zopiclone versus placebo had a magnitude of effect of 0.41 (-0.76 to

1.58; test for heterogeneity P=0.98).

Amount of sleep. In eight studies (601 participants) with extractable data, the increase in total sleep time with any

sedatives compared with placebo was 25.2 minutes (12.8 to 37.8 minutes; P=0.001; test for heterogeneity P=0.10).

In eight studies (524 participants) that compared benzodiazepines with placebo, the increase in total sleep time was

34.2 minutes (16.2 to 52.8 minutes, P<0.01; test for heterogeneity P=0.13).

Number of awakenings. In six studies (441 participants) with extractable data, the mean number of awakenings

decreased by 0.63 (-0.48 to -0.77, P<0.0001; test for heterogeneity P=0.71). in six studies with benzodiazepines

versus placebo (296 participants) the mean number of awakenings decreased by 0.60 (-0.41 to -0.78, P<0.0001; test

for heterogeneity P=0.58).

Adverse events. The risk of adverse events was higher with sedative treatment. Most adverse events were reported to

be reversible and not severe. Patients who took sedatives had a higher incidence of falls and motor vehicle crashes.

Numbers needed to treat versus numbers needed to harm. The number needed to treat for improved sleep quality

was 13 and the number needed to harm for any adverse event was 6. This ratio indicates that an adverse event is

more than twice as likely as enhanced quality of sleep. This ratio can be used as a rough indicator only, as more than

double the number of participants contributed to the “harm” data than to the “effectiveness” data.

Nina Buscemi, Ben Vandermeer, Carol Friesen, Liza Bialy, Michelle Tubman, Maria Ospina, Terry Klassen,

and Manisha Witmans. “The Efficacy and Safety of Drug Treatments for Chronic Insomnia in Adults: A

Meta-analysis of RCTs.” Journal of General Internal Medicine 22 (2007): 1335-1350

Efficacy. The combined weighted mean difference (WMD) showed that benzodiazepine (BDZ), non-benzodiazepine

(non-BDZ), and anti-depressant (ADP) had significantly shorter sleep onset latency times compared to placebo

when measured by polysomnography (WMD: −10.0 minutes; 95% CI: −16.6, −3.4; WMD: −12.8 minutes; 95% CI:

−16.9, −8.8; WMD: −7.0 minutes; 95% CI: −10.7, −3.3, respectively) or sleep diary (WMD: −19.6 minutes; 95% CI:

−23.9, −15.3; WMD −17.0 minutes; 95% CI: −20.0, −14.0; WMD: −12.2 minutes; 95% CI: −22.3, −2.2, respectively)

(Table 4). The improvements measured by sleep diary were more prominent for all three drug groups. There was

heterogeneity among studies on BDZ and non-BDZ for both measures of sleep onset latency times, but the direction

2

of the estimate was fairly consistent for BDZ. Nine out of 11 comparisons had point estimates that favored BDZ for

polysomnography, while all 26 sleep diary trials had point estimates that favored BDZ (Fig. 2). For non-BDZ, all 12

studies for polysomnography and all 34 studies for sleep diary showed a point estimate that favored non-BDZ (Fig.

3). For ADP, there was moderate heterogeneity among studies in the polysomnography group and negligible

heterogeneity in the sleep diary group (Fig. 4). We conducted meta-analyses for wakefulness after sleep onset, sleep

efficiency, total sleep time, and sleep quality, subcategorized by polysomnography and sleep diary for BDZ, non-

BDZ, and ADP. All results were statistically significant and favored BDZ and non-BDZ with the exception of the

polysomnography studies measuring wakefulness after sleep onset and total sleep time, which were marginally

nonsignificant (Table 4). In contrast, for ADP, polysomnography results significantly favored ADP, but sleep diary

results were fewer and nonsignificantly favored ADP for wakefulness after sleep onset and nonsignificantly favored

placebo for total sleep time (Table 4).

Safety. To analyze the safety of BDZ, non-BDZ, and ADP, there were 34, 27, and 3 studies included, respectively.

The combined risk difference showed that all drug groups had significantly more adverse events than the placebo

group (Table 4). There was substantial heterogeneity among studies in the BDZ and non-BDZ groups, but it was

negligible in the ADP group. The most commonly reported adverse events in studies were somnolence (n=27),

headache (n=18), dizziness (n=16), nausea (n=11), and fatigue (n=11) in the BDZ group. There were no reports of

falls, injury, or death. In the non-BDZ group, the most commonly reported adverse events were headache (n=16),

dizziness (n=14), nausea (n=13), and somnolence (n=13). Accidental injury was reported in one study; however,

there was no significant difference in the frequency of this event between non-BDZ and placebo groups. Finally, for

ADP, the most commonly reported adverse events were somnolence (n=4), headache (n=3), dizziness (n=3), and

nausea (n=3). There were no reports of falls, injury, or death.

Indirect Comparisons of the Three Interventions. Compared to non-BDZ, BDZ showed a larger benefit on sleep

diary measures of sleep onset latency, but non-BDZ was favored when measured by polysomnography – neither

value was statistically significant. Non-BDZ was significantly safer than BDZ. Compared to ADP, the only

significant result was that non-BDZ was significantly more efficacious in terms of sleep onset latency when

measured by polysomnography – the result when measured by sleep diary still favored non-BDZ; but it was not

significant.

Alexander Winkler, Charlotte Auer, Bettina K. Doering, and Winfried Rief. “Drug Treatment of Primary

Insomnia: A Meta-Analysis of Polysomnographic Randomized Controlled Trials.” CNS Drugs 28 (2014): 799-

816.

Efficacy of Different Subgroups of Pharmacotherapy for Primary Insomnia. Comparisons for benzodiazepines

versus placebo were significant for all outcome variables (with the exception of sTST). For comparisons between

benzodiazepine receptor agonists, all effect sizes (with the exception of sWASO and sSE) were significant. With the

exception of sSOL, all effect sizes for comparisons between antidepressants and placebo were significant.

Comparison of Different Drug Classes. The Q test for heterogeneity yielded significant results for the comparison

between benzodiazepines and benzodiazepine receptor agonists with regard to sSOL, and, in the case of SOL, for

the comparisons between benzodiazepine receptor agonists and antidepressants as well as between benzodiazepines

and antidepressants. For outcome variable SOL, benzodiazepines and benzodiazepine receptor agonists are

significantly more effective than antidepressants and, for sSOL, benzodiazepines are more effective than

benzodiazepine receptor agonists.

A principal finding of this meta-analysis is that benzodiazepines and benzodiazepine receptor agonists are

significantly more effective than antidepressants in reducing SOL in patients with primary insomnia. Moreover,

benzodiazepines are significantly more effective than benzodiazepine receptor agonists in reducing sSOL of these

patients. A second main finding is that SOL and TST (which are primary endpoints in most treatment studies

addressing primary insomnia) showed higher effect sizes for objective outcomes in the benzodiazepine subgroup.

3

Naren Gunja. “The Clinical and Forensic Toxicity of Z-drugs.” Journal of Medical Toxicology 9 (2013): 155-

162.

Traditional therapy for insomnia has predominantly involved the use of benzodiazepines for several decades. Since

the 1980s, development of non-benzodiazepine drugs for the management of insomnia has been driven by the

significant adverse effect profile of the former group of drugs. The Z-drugs (zolpidem, zopiclone, zaleplon) have

significant hypnotic effects by reducing sleep latency and improving sleep quality, though their ability to prolong

total sleep time is debatable. While hypnosis and sedation are adequately achieved from oral benzodiazepines, they

invariably alter sleep architecture, reduce deep (stage 3 and 4) sleep, and lead to dependence, tolerance, and

withdrawal. Furthermore, benzodiazepines carry the risk of residual daytime effects such as impairment of cognitive

and psychomotor function. The Z-drugs possess shorter duratioxn of action and half-life, do not disturb overall sleep

architecture, and cause less residual effects during daytime hours, making them more clinically attractive than

benzodiazepines.

Adverse Effects. The Z-drugs are well-tolerated and the most common adverse effects include headache,

gastrointestinal upset, and dizziness. For a given dose, adverse reactions appear to be worse in elderly patients;

hence, lower doses are recommended in this group. The daytime residual effects of hypnotic drugs on cognitive and

psychomotor performance are a major concern in patients regularly taking these medications. Z-drugs have the

potential to cause residual effects post-awakening that related to cognition, memory, parasomnia, and bizarre

behavior. They have a profound effect on nocturnal and next-day psychomotor performance including body balance,

reaction times, and the ability to multi-task. Tolerance, dependence, and withdrawal are all reported with Z-drugs,

though this appears to be less severe and with lower incidence than for traditional benzodiazepines in the treatment

of insomnia.

Insomnia; Jonathan A.E. Fleming, MB, FRCPC, FABPN. FABSM. e-CPS. Date of Revision: July 2015.

Benzodiazepine receptor agonists. Although not a benzodiazepine, the cyclopyrrolone zopiclone acts at the

benzodiazepine receptor and so has similar therapeutic and side effects. Zopliclone can have residual or hangover

effects that could impair morning driving when used with or without alcohol. Warn patients not to drive or operate

machinery until at least 12hours after a bedtime dose of zopiclone. Compared with benzodiazepines, tolerance to

zopiclone’s hypnotic effect may be delayed and rebound insomnia may be reduced. Zolpidem is an imidazopyrine

with preferential affinity to benzodiazepine type I receptors. Memory disturbances and complex sleep behaviours

have been reported in patients using zolpidem. Gender and age-based differences in metabolic clearance of zolpidem

and incidence of complex sleep behaviours have led to lower dosing recommendations for women and elderly

patients.

4

Class Drug Dosage Adverse

Effects

Drug

Interactions

Comments Cost

Benzodiazepine

Receptor

Agonists

Zopiclone

Imovane,

Rhovane,

generics

Initial: 3.75mg

PHS PRN po

Usual adult dose:

3.75-7.5mg QHS

PRN po

Maximum: 7.5mg

QHS PRN po

Elderly patients

(>65y): 5mg QHS

PRN po

Risk of

driving

impairment up

to 11 hours

after dose.

Impaired

cognitive

function and

rarely,

anterograde

amnesia and

transient

global

amnesia

Bitter/metallic

taste.

Minimal

additive effects

with low doses

of alcohol.

CYP3A4

inhibitors (e.g.,

clarithromycin,

itraconazole,

ritonavir) may

increase plasma

levels of

zopiclone.

CYP3A4

inducers (e.g.,

carbamazepine,

phenytoin, St.

John’s wort)

may decrease

zopiclone

plasma levels.

Monitor patient

for increase or

reduced

response and

adjust dose

accordingly.

Use lowest

effective

dose.

Use only

when full

night’s sleep

is possible.

Advise

patients to

wait >12

hours before

driving or

operating

machinery.

Does not

accumulate;

may cause

less rebound

on

withdrawal.

$$

5

Varenicline

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is varenicline effective and safe for smoking cessation?

Literature search

Medline: Varenicline AND smoking cessation AND limit to (meta-analysis or review)

e-CPS: Varenicline; smoking cessation

Cochrane: Varenicline AND efficacy

Cahill K, Stevens S, Perera R, and Lancaster T. “Pharmacological interventions for smoking cessation: an

overview and network meta-analysis.” The Cochrane Library (2013).

Summary of main results. This overview identified 12 Cochrane reviews of pharmacotherapies used to assist

smoking cessation. Three treatments (NRT, bupropion and varenicline) are licensed as aids for smoking cessation

in high-income countries and recommended by many national guidelines, and we have concentrated on these

interventions for this overview. Both NRT and bupropion are similarly effective compared with placebo in helping

people to quit. Varenicline is more effective than NRT or bupropion, when compared with placebo. Direct and

indirect comparisons between the three treatments demonstrate no advantage for NRT over bupropion. Varenicline

is shown to be superior to any single type of NRT and to bupropion. Different types of NRT are generally equally

effective. Combinations of NRT outperform single formulations, and may be as effective as varenicline. None of the

network meta-analysis findings show evidence of inconsistency. Varenicline’s superior efficacy must be tempered

by current questions about its safety. Meta-analysis of any SAE while on varenicline compared with placebo finds

no difference between them, and subgroup analyses detect no significant excess of neuropsychiatric or

cardiovascular events. While this finding is supported by a number of observational studies and challenged by

others, the evidence is inconclusive at present, and long-term post-marketing surveillance will continue to inform the

debate.

6

Henri-Jean Aubin, Amandine Luquiens, and Ivan Berlin. “Pharmacotherapy for smoking cessation:

pharmacological principles and clinical practice.” British Journal of Clinical Pharmacology 77 (2013): 324-

336.

Therapeutic efficacy of varenicline. The recommended dosage is 1mg twice daily following a 1 week up-titration.

However, it has been shown that a self-regulated, flexible dosing regimen of varenicline is well tolerated, with

superior effectiveness vs. placebo [64]. Smokers treated with varenicline should normally aim to quit approximately

1 week after the start of the treatment. It has been shown, however, that using a flexible quit-date paradigm had

efficacy and safety similar to those in the previous fixed quit-date paradigm [65]. Meta-analyses have confirmed the

increased efficacy of varenicline on smoking quit rates at the dosage of 2mg day-1 during a 12 week treatment

compared with placebo and also to bupropion (see Table 1) [3, 66, 67]. For instance, the Cochrane review has shown

a risk ratio over placebo of 2.27 (95% CI 2.02, 2.55). Only two published studies have compared varenicline with

NRT [68, 69]. In an open but randomized study, varenicline performed better than the transdermal nicotine patch

[68]. Varenicline has been shown to result in higher abstinence rates than combined or high dose NRT in some [35],

but not all [1], meta-analyses. A 12 week treatment extension yields better cessation rates for smokers who quit

successfully for at least 1 week at the end of the first 12 weeks of treatment [70].The combination of varenicline

with NRT or bupropion seems to be safe [71, 72], but no published, randomized controlled data exist as to the

superiority of this co-administration over one or the other alone. Like NRT and bupropion, varenicline has been

shown to limit post-cessation weight gain during the active treatment phase, an effect that does not persist after

treatment has ended [43]. In addition, some data suggest that varenicline may help reduce alcohol consumption in

smokers who drink heavily [73, 74].

Safety and tolerability of varenicline. Phase I reports have shown that varenicline is tolerated after single doses up to

3mg in smokers and 1mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1mg in non-

smokers are dose limiting [75]. Recent reviews of the safety profile of varenicline concluded that the most frequent

adverse event was nausea, occurring in 30–40% of users [76–78].The nausea was generally reported as mild to

moderate and diminishing over time, and it was associated with low attributable discontinuation rates. Other

common adverse effects included insomnia, abnormal dreams and headaches. In the randomized, controlled phase

III studies, serious adverse events were rare, with no treatment-related deaths during the treatment or follow-up

phases. There are currently no known contraindications to varenicline [79]. Post-marketing surveillance reports have

suggested an increased risk of reported depression and suicidal/self-injurious behaviour with varenicline (and

bupropion) compared with NRT [58, 80–82]. However, a pooled analysis of more than 5000 smokers without

current psychiatric history who participated in one of 10 randomized, placebo controlled clinical trials found that

there was no significant increase in overall psychiatric adverse events aside from sleep disorders [83]. A study that

assessed neuropsychiatric adverse effects failed to find any difference in measurements of depressive symptoms,

anxiety, or aggression/ hostility between varenicline and placebo among smokers without psychiatric disorders [84].

Furthermore, a retrospective analysis of 80 600 adults prescribed varenicline, using records from the UK General

Practice Research Database, found that the incidence of depression and suicide was not greater with varenicline than

with NRT or bupropion [85].The post-marketing reports led the US Food and Drug Administration (FDA) and the

European Medicine Agency to add a ‘black box warning’ to the product labeling for both varenicline and bupropion

SR. Recently, two FDA-sponsored epidemiological studies that evaluated the risk of neuropsychiatric adverse events

associated with smoking cessation drugs found no difference in risk of neuropsychiatric hospitalizations between

varenicline and NRT [86]. Smoking and/or smoking cessation are frequently associated with neuropsychiatric

symptoms and suicide-related outcomes [87]. Therefore, drug regulatory agencies acknowledge that distinguishing

between drug-related adverse effects/events and the neuropsychiatric effects related to smoking and/or smoking

cessation is difficult, and they strongly recommend that patients be closely monitored for neuropsychiatric

symptoms [88]. A meta-analysis suggested an increased rate of cardiovascular events with varenicline [89].

However, a more recent meta-analysis that accounted for the major biases not taken into account in the previous

work concluded that treatment with varenicline is not associated with increased rates of cardiovascular events

compared with placebo [90].

7

Smoking Cessation; Peter Selby, MBBS, FRCPC, FCFP. e-CPS. Date of Revision: October 2014.

Class Drug Dosage Adverse Effects Drug

Interactions

Comments Cost

Nicotine

Receptor

Partial

Agonists

Varenicline,

Champix

0.5mg daily po

for 3 days then

BID for 4 days

then 0.5-1mg

BID po for 12

weeks. Patient

should quit

smoking 1-2

weeks after

starting

varenicline. If

patient is still

smoking 4 weeks

after starting,

reassess therapy;

can be continued

for an additional

12 weeks if

patient has

benefited. If 1mg

BID not

tolerated, can

reduce to 0.5mg

BID. No tapering

necessary when

discontinuing

Nausea (30%);

may be mitigated

by taking on a full

stomach,

increasing water

intake or reducing

dose.

May cause

insomnia; take

second daily dose

at suppertime.

Neuropsychiatric

side effects such

as

suicidal/homicidal

ideation have

been reported;

monitor closely

for changes in

mood/behavior.

Close monitoring

by health

professional for

those with pre-

existing

psychiatric

disorders.

Should not be

combined with

nicotine

replacement

therapy due to

increased risk

of adverse

effects.

Does not

induce

cytochrome

P450

enzymes;

excreted

renally

unchanged.

Efficacy is

dose-related.

$$$$$

8

Vitamin B12

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is vitamin B12 effective and safe?

Literature search

Medline: Vitamin B12 deficiency AND limit to (meta-analysis or review)

e-CPS: Vitamin B12; Nutritional Supplements

Cochrane: Vitamin B12 deficiency

We found no trials comparing B12 to placebo.

Vidal-Alaball J, Butler C, Cannings-John R, Coringe A, Hood K, McCaddon A, McDowell I, and

Papaioannou A. “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency (Review).”

The Cochrane Library (2009).

Two studies compared oral and intramuscular vitamin B12: Kuzminski and colleagues (Kuzminski 1998) reported

neurologic and haematologic responses. Four of the eighteen participants randomized to receive oral vitamin B12

and four of the fifteen randomized to receive intramuscular vitamin B12 had a neurological response with a marked

improvement or clearing of paresthesias, ataxia, or memory loss. Serum vitamin B12 levels were significantly

higher in the oral (643 +/- 328 pg/mL) compared to the intramuscular group (306 +/- 118 pg/mL) at 2 months

P<0.001). The difference was even greater at four months (1,005 +/- 595 vs. 325 +/- 165 pg/mL; P< 0.0005). Serum

methylmalonic acid concentrations decreased to < 3 SD above the normal range in all participants except one in the

oral and two in the intramuscular group. Mean concentrations of the metabolites were not significantly different

between the oral and the intramuscular groups, except at four months, when the value was higher in the

intramuscular group (P< 0.05). Elevated serum total homocysteine decreased to 3 SD above the normal range in

most participants, but the decrease was over four months in the oral group and during the first month in the

intramuscular group. However, in two patients in each group the response was not optimal. Bolaman and colleagues

(Bolaman 2003) reported neurologic and haematologic responses. Both groups receiving oral or intramuscular

vitamin B12 reported improvements of cognitive function, sensory neuropathy and vibration sense but the difference

between both groups was not statistically significant. Serum vitamin B12 levels increased in those receiving oral and

those receiving intramuscular vitamin B12 for 90 days. The authors reported a statistically significant difference

between day 0 and day 90 within both groups (P< 0.001) but did not analyse differences between both groups.

Vitamin B12 – Dietary Supplement Fact Sheet. National Institutes of Health – Office of Dietary Supplements.

Cardiovascular disease. Elevated homocysteine levels have been identified as an independent risk factor for

cardiovascular disease. Evidence from retrospective, cross-sectional, and prospective studies links elevated

homocysteine levels with coronary heart disease and stroke. Vitamin B12, folate and vitamin B6 are involved in

homocysteine metabolism. In the presence of insufficient vitamin B12, homocysteine levels can rise due to

inadequate function of methionine synthase. Results from several randomized controlled trials indicate that

combinations of vitamin B12 and folic acid supplements with or without vitamin B6 decrease homocysteine levels

in people with vascular disease or diabetes and in young adult women. In another study, older men and women who

took a multivitamin/multimineral supplement for 8 weeks experienced a significant decrease in homocysteine levels.

Evidence supports a role for folic acid and vitamin B12 supplements in lowering homocysteine levels, but results

from several large prospective studies have not shown that these supplements decrease the risk of cardiovascular

disease. In the Women’s Antioxidant and Folic Acid Cardiovascular Study, women at high risk of cardiovascular

disease who took daily supplements containing 1mg vitamin B12, 2.5mg folic acid, and 50mg vitamin B6 for

7.3years did not have a reduced risk of major cardiovascular events, despite lowered homocysteine levels. The Heart

Outcomes Prevention Evaluation (HOPE) 2 trial, which included 5,522 patients older than 54years with vascular

disease or diabetes, found that daily treatment with 2.5mg folic acid, 50mg vitamin B6, and 1mg vitamin B12 for an

average of 5 years reduced homocysteine levels and the risk of stroke, but did not reduce the risk of major

9

cardiovascular events. In the Western Normal B Vitamin Intervention Trial, which included 3,096 patients

undergoing coronary angiography, daily supplements of 0.4mg vitamin B12 and a 0.8mg folic acid with or without

40mg vitamin B6 for 1year reduced homocysteine levels by 30%, but did not affect total mortality or the risk of

major cardiovascular events during 38 months of follow-up. The Norwegian Vitamin (NORVIT) trial and the

Vitamin Intervention for Stroke Prevention trial had similar results. The American Heart Association has concluded

that the available evidence is inadequate to support a role for B vitamins in reducing cardiovascular risk.

Dementia and cognitive function. Observational studies show positive associations between elevated homocysteine

level and the incidence of both Alzheimer’s disease and dementia. Low vitamin B12 status has also been positively

associated with cognitive decline. Despite evidence that vitamin B12 lowers homocysteine levels and correlations

between low vitamin B12 levels and cognitive decline, research has not shown that vitamin B12 has an independent

effect on cognition. In one randomized, double-blind, placebo-controlled trial, 195 subjects aged 70 years or older

with no or moderate cognitive impairment received 1,000mcg vitamin B12, 1,000mcg vitamin B12 plus 400mcg

folic acid, or placebo for 24 weeks. Treatment with vitamin B12 plus folic acid reduced homocysteine

concentrations by 36%, but neither vitamin B12 treatment nor vitamin B12 plus folic acid treatment improved

cognitive function.

Energy and endurance. Due to its role in energy metabolism, vitamin B12 is frequently promoted as an energy

enhancer and an athletic performance and endurance booster. These claims are based on the fact that correcting the

megaloblastic anemia caused by vitamin B12 deficiency should improve the associated symptoms of fatigue and

weakness. However, vitamin B12 supplementation appears to have no beneficial effect on performance in the

absence of a nutritional deficit.

Health Risks from Excessive Vitamin B12. The IOM did not establish a UL for vitamin B12 because of its low

potential for toxicity. In Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12,

Pantothenic Acid, Biotin, and Choline, the IO states that “no adverse effects have been associated with excess

vitamin B12 intake from food and supplements in healthy individuals”. Findings from intervention trials support

these conclusions. In the NORVIT and HOPE 2 trials, vitamin B12 supplementation (in combination with folic acid

and vitamin B6) did not cause any serious adverse events when administered at doses of 0.4mg for 40 months

(NORVIT trial) and 1.0mg for 5 years (HOPE 2 trial).

10

Tretinoin

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is tretinoin effective and safe?

We also briefly summarize evidence of efficacy in the treatment of other conditions (e.g. rosacea, actinic keratosis).

Literature search

Medline: Tretinoin AND acne AND limit to (meta-analysis or review); Tretinoin AND efficacy AND limit to (meta-

analysis or review)

e-CPS: Tretinoin; Acne

Cochrane: Tretinoin AND efficacy; topical retinoid AND acne AND efficacy

Harald PM Gollnick and Andrea Krautheim. “Topical Treatment in Acne: Current Status and Future

Aspects.” Dermatology 2003 (206): 29-36.

Tretinoin was the first topical retinoid described in the first reports by Stuttgen and by Beer. It significantly reduces

the number of comedones but also of inflammatory acne lesions. It has been shown in several trials that at least

during a 12-week course the reduction of lesion counts ranges between 32-81% for non-inflammatory lesions and

17-71% for inflammatory lesions, i.e. 22-83% for the total lesion count. Comparing tretinoin 0.025% gel or 0.025%

cream with its vehicle in a once daily application manner, tretinoin was significantly more effective than the vehicle

in reducing both inflammatory and non-inflammatory lesions. Currently tretinoin is available in different galenic

formulations: cream (0.025%, 0.1%, gel 0.1%, 0.025%) and as a solution (0.05%). In a topical gel formulation

containing polyolprepolymer-2, tretinoin penetration was shown to be significantly reduced while potentially

enhancing epidermal deposition compared to a commercially available gel preparation at the same concentration.

Polyolprepolymer-2 helps to retain drug molecules on the skin surface and in the upper layers of the skin [19, 20].

Another new formulation is a microsponge delivery system consisting of macroporous beads of 10-25µm in

diameter which are loaded with an active ingredient. After topical application this is gradually released depending

on rubbing, temperature, pH and other factors [21]. Tretinoin 0.1% gel microsponge compared with tretinoin

0.025% gel, tazarotene 0.1% gel or adapalene 0.1% gel in a split face study showed similar facial tolerability for all

retinoids [22]. A formulation of liposomally encapsulated tretinoin 0.01% was in a comparative study equipotent in

clearing acne lesions as tretinoin 0.025 or 0.05% gel after once daily topical application for 10 weeks, but showed a

much better cutaneous tolerability [23]. This was also reproducible on in vitro reconstructed epidermis [24]. With

regard to systemic absorption and risk of embryotoxicity after topical application, the detected fecal and plasma

tretinoin concentrations were much below the endogenous tretinoin levels [25, 26] and did not affect the endogenous

levels of tretinoin or its metabolites or alter the plasma vitamin A levels [27].

11

Sanjiv Jain. “Topical tretinoin or adapalene in acne vulgaris: an overview.” Journal of Dermatological

Treatment 2004 (15): 200-07.

A series of large-scale, multicentre, comparative trials of adapalene 0.1% gel versus tretinoin have been undertaken

(Table III). The outcome of individual primary trials were not completely homogeneous and demonstrated varying

results regarding efficacy. The inconclusive and equivocal outcomes necessitated a meta-analysis that concluded

that adapalene 0.1% gel was equally as efficacious as tretinoin 0.025% gel.32 As it is not rational to extrapolate the

conclusions derived from the comparison of adapalene 0.1% gel with tretinoin 0.025% gel to tretinoin 0.05% gel, it

prompted a scrutiny of the comparative efficacy of 0.1% adapalene gel and tretinoin 0.05% gel. A split-face clinical

and bioinstrumental comparison of 0.1% adapalene gel and 0.05% tretinoin gel in facial acne was undertaken. In

contrast to previous studies, the present trial revealed the greater efficacy of tretinoin 0.05% gel over adapalene

0.1% gel. This may be ascribed to the higher concentration of tretinoin,27 and its higher affinity for gamma

receptors.33 The adverse reactions to adapalene are of the same type, but of significantly lower frequency and lesser

severity than for tretinoin (Table IV). Most studies concluded that adverse effects such as erythema, scaling,

pruritus, and burning could occur in a significant percentage of patients. Overall, 45.7% of the tretinoin-treated

patients experienced some form of irritation, compared with 32.4% of those treated with adapalene.29

A Geng, MA Weinstock, R Hall, D Eilers, M Maylor, and J Kalivas. “Tolerability of high-dose topical

tretinoin: the Veterans Affairs Topical Tretinoin Chemoprevention Trial.” British Journal of Dermatology

2009 (161): 918-24.

This study assessed the long-term tolerability of tretinoin 0.1% cream, and found that while participants using

tretinoin were more likely to have side-effects than the controls, the frequency of these side-effects decreased over

time, and there was no remaining difference between the groups after 2 years. Burning was the most commonly

reported specified side-effect, followed by itching and other local cutaneous reactions. The majority (67%) of

participants on tretinoin tolerated cream application at least once daily (80% tolerated at least every other day), and

the use of tretinoin cream was not associated with an increased drop-out rate from the study. We expected and found

that participants using tretinoin were more likely to have side-effects; this was true even after using the study cream

for 6 months (the first follow-up assessment). While there is a widely held belief in clinical practice that tretinoin

cream at the 0.1% concentration is a poorly tolerated medication, in this study population almost 40% of the

tretinoin group reported no side-effects at 6 months. We expect that the frequency of side-effects would probably

have been higher had the participants been assessed at earlier time points (e.g. at 2 weeks). We also expected and

found that the frequency of side-effects decreased over time, supporting the clinical observation that participants

seem to tolerate tretinoin better with continued usage. Of note, side-effects continued to decrease over 2 years before

the difference between the two groups became non-significant. We examined the frequency of cream application as

a measure of tolerability, as the tretinoin group might have applied the cream less often in response to the known

side-effects. As predicted, participants using tretinoin were less likely to apply their cream twice daily or once daily,

and more likely to apply every other day or ‘not at all’. These frequencies of application persisted over time.

Gupta AK, Paquet M, Villanueva E, and Brintnell W. “Interventions for actinic keratoses (Review).” The

Cochrane Library (2012).

Prescription-based topical treatments – Ro 14-9706 versus 0.05% tretinoin. This intervention was addressed by

only 1 intraindividual study (Misiewicz 1991), which compared the efficacy of 0.05% Ro 14-9706 and 0.05%

tretinoin applied twice-daily for 16 weeks for the treatment of facial actinic keratoses. Assessment was performed at

the end of the 16-week treatment. There was no major source of possible bias. Areas treated with tretinoin cream

showed an initial increase in the number of lesions (weeks 3 to 9), which eventually decreased after week 10. Ro 14-

9706 showed no initial increase in number of actinic keratoses lesions, but a gradual decline over time. The resulting

mean percentage of reduction in lesion counts was significantly higher in the group treated with Ro 14-9706 than the

group treated with tretinoin (MD 7.50, 95% CI 6.57 to 8.43; Analysis 3.1). To summarise, Ro 14-9706 treatment

showed better overall reduction in lesion counts, whereas tretinoin treatment, which showed an initial increase in

lesions, resulted in more participants with complete response.

12

Van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MMD, and Charland L. “Interventions for rosacea

(Review).” The Cochrane Library (2015).

Topical clindamycin phosphate combined with tretinoin was not considered to be effective compared to placebo

(moderate quality of the evidence)

Acne; Duane Lichtenwald, MD, FRCPC. e-CPS. Date of Revision: June 2015.

Topical retinoids.Topical retinoids are the most powerful comedolytic agents, yet still take months to be effective.

They are also effective for inflammatory lesions. Tretinoin is the most cost effective, but also the most

photosensitizing. Adapalene is the least irritating, tazarotene is the most potent. Topical retinoids (except when

combined in a commercial product) are unstable in the presence of benzoyl peroxide and should be applied at a

different time: usually benzoyl peroxide in the morning and retinoid at bedtime.

Class Drug Dosage Adverse Effects Cost

Retinoids Tretinoin

0.01%,

0.025%,

0.05%, 0.1%

Retin-A,

Retin-A

Micro,

Stieva-A,

Vitamin A

Acid

Crea, gel; once

daily at HS to

limit

photosensitivity

Photosensitivity.

Irritating.

SS

13

Baclofen

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is baclofen effective and safe for the management of low back pain?

Literature search

Medline: : Baclofen AND low back pain AND limit to (meta-analysis or review); Baclofen AND spasticity AND

limit to (meta-analysis or review)

e-CPS: Baclofen; Low back pain

Cochrane: Baclofen AND low back pain; Baclofen AND spasticity AND efficacy

van Tulder MW, Touray T, Furlan AD, Solway S, and Bouter LM. “Muscle relaxants for non-specific low-

back pain (Review).” The Cochrane Library (2008).

Acute LBP. One study compared an antispasticity muscle relaxant (baclofen) with placebo and incorporated bed rest

in the therapeutic regimen (Dapas 1983). In comparison with placebo, there was significant relief of pain and

improvement in terms of global efficacy. Relief of spasm did not reach statistical significance.

Low Back Pain; Eldon Tunks, MD, FRCPC and Paul Stacey, MD, MSc. e-CPS. Date of Revision: February

2014.

Pharmacologic Choices. During the acute phase of low back pain, muscle relaxants may be effective for relief of

pain and spasm during short-term use, but are more likely to cause adverse effects such as drowsiness and

dizziness.5,15 Muscle relaxants might include benzodiazepines, cyclobenzaprine, nonprescription preparations

containing methocarbamol or orphenadrine, or the antispasticity drugs baclofen or tizanidine. A muscle relaxant

may also be combined with an NSAID or COX-2 inhibitor for relief of pain and spasm in acute back pain.

Taricco M, Adone R, Pagliacci C, Telaro E. “Pharmacological interventions for spasticity following spinal

cord injury (Review).” The Cochrane Library (2009).

Oral baclofen versus placebo. Brar 1991 reported significant improvement compared to placebo in angle of flexion

and subjective function report for participants treated with baclofen alone or in combination with stretching

exercises, but no significant added benefit from stretching exercises alone. Significantly more participants improved

Class Drug Dosage Adverse

Effects

Drug

Interactions

Comments Cost

Muscle

Relaxants

Baclofen

Lioresal

Oral,

generics

Start with

5mg TID po;

increase

gradually to

maximum of

20mg TID

Sedation,

weakness,

nausea,

dizziness.

Very rare:

hepatotoxicity

Potential additive

CNS depression

with tricyclic

antidepressants,

opioids,

benzodiazepines

and

antihypertensives

Adjust dose

gradually to

minimize

adverse

effects or

withdrawal

symptoms.

In acute pain,

short-term

use as muscle

relaxant.

Not

recommended

in the elderly.

$$

14

in Ashworth score only with baclofen combined with exercises compared with placebo. Feldman 1978 only reported

the numbers of participants who improved on each treatment. Significantly better improvement was suggested in

passive range of motion, painful spasms and clonus in participants taking baclofen.

Alessandro Dario and Giustino Tomei. “A Benefit-Risk Assessment of Baclofen in Severe Spinal Spasticity.”

Drug Safety 2004 (11): 799-818.

Benefit Evaluation. In open-label studies of oral administration of baclofen, the drug was demonstrated to improve

spasticity in 70-87% of patients; additionally, improvement in spasms was reported in the 75-96% of patients.[37-

40] However, it should be noted that the measures of symptom improvement used differed between the studies.

Spasticity and spasms following spinal cord injury seem to show better clinical improvement with baclofen

treatment than multiple sclerosis-associated symptoms.[39] Despite the reported symptomatic improvements,

baclofen has not yet been clearly shown to produce long-term functional improvement measured by appropriate

scale. [39] In double-blind crossover placebo-controlled trials, [41-44], baclofen was reported to be an effective drug

that produced a statistically significant improvement in symptoms (table II). However, in five patients with

traumatic spinal cord injuries the quantitative effects of baclofen versus placebo treatment failed to provide a

convincing effect of spasticity reduction; [45] of interest, baclofen did appear to have anxiolytic effects in these

patients. [46] The administration of oral baclofen demonstrated an improvement in gait in patients with spasticity

and an improvement in vertical unsteadiness in patients with multiple sclerosis; however, this study only lasted 11

days. [47] However, it should be noted that the clinical measure of improvement was not homogeneous between the

placebo controlled studies. The effective and well-tolerated dosage of oral baclofen lies in the range of 30-80mg

daily, [39] but in multiple sclerosis patients high-dose administration has been suggested. [51] The cost-

effectiveness of managing spasticity using baclofen was calculated as £10.50 per successfully treated day (year 2000

values) in one economic analysis.[22]

Benefit-Risk Evaluation. Oral baclofen appears to be effective in the treatment of spasticity. With regards to

increased tone and spasms, the drug is effective in 55-96% of patients; however, the long-term functional benefit for

patients is not yet certain. Considering the seriousness of the diseases affecting these patients (mainly spinal cord

injury or multiple sclerosis) and their clinical status, this result is favourable. The main risks of oral baclofen

administration are related to withdrawal (ie seizures, psychic symptoms and hyperthermia) [section 1.2]. These

symptoms have been reported to improve after the reintroduction of baclofen therapy, usually without sequelae.

When these symptoms are not related to drug withdrawal, they present mainly only in patients with brain damage

and in the elderly. The limited data available on baclofen toxicity in patients with renal disease suggest that

administration of the drug in these persons may carry an unnecessarily high risk. The interactions between tricyclic

drugs and baclofen are not clearly defined, so the contemporaneous administration of the two drugs should be

cautiously performed. Because the adverse consequences do not exceed the benefits of oral baclofen for the

treatment of patients with spinal spasticity the benefit-risk assessment is favourable.

15

Pramoxine/zinc

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is pramoxine effective and safe in the management of pruritus?

Literature search

Medline: Pramoxine AND (pruritus OR itch*) AND limit to (meta-analysis); (Pruritus OR itch*) AND zinc

Cochrane: Pramoxine AND limit to (meta-analysis or review); Zinc AND limit to (meta-analysis or review)

Trudye A Young, Tejesh S Patel, Fabian Camacho, Adele Clark, Barry I Freedman, Mandeep Kaur, Julie

Fountain, Lisa L Williams, Gil Yosipovitch, and Alan B Fleischer JR. “A pramoxine-based anti-itch lotion is

more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients.”

Journal of Dermatological Treatment 2009 (20): 76-81.

The present study shows that anti-itch lotion containing pramoxine reduces ESRD-associated pruritus to a greater

degree than the control lotion following 4 weeks of topical application. In addition, both the pramoxine lotion and

the control lotion resulted in overall improvements in disease severity, skin hydration and quality of life (in terms of

sleep disturbances and mood) at the end of the 4-week study period. No adverse effects were reported and only one

patient failed to complete the study (owing to death from an unrelated event). Treatment with anti-itch lotion

containing pramoxine was therefore well tolerated. Previous reports on the safety of pramoxine hydrochloride have

described this compound to be well tolerated by tissues in addition to displaying low systemic toxicity and

sensitizing potential (16). Pramoxine lotion and control lotion both resulted in improvements in individual reported

itch intensity. Although disease severity obtained by IGA (in terms of erythema, xerosis and lichenification) and

skin hydration improved following 4 weeks of topical application, because of the small size of this pilot study, the

results were not significant. Xerosis is the most frequent cutaneous manifestation of ESRD and has been suggested

as a cause of pruritus in such patients (17–21). The pramoxine lotion reduces ESRD-associated pruritus to a greater

degree than the control lotion, implying the active ingredients in this preparation independently augment the

reduction of this symptom. Pramoxine, a local anesthetic, has been suggested to affect itch sensation by interfering

with the transmission of impulses along the sensory nerve fibers (23).

Pongcharoen P and Fleischer AB. “An evidence-based review of systemic treatments for itch.” European

Journal of Pain 2016 (20): 24-31.

Zinc sulphate. One RCT (Najafabadi et al., 2012) investigated the effect of zinc sulphate in 40 haemodialysis

participants. Itch was significantly decreased in the treatment group compared with placebo. No severe side effects

were observed. However, due to the small number of sample size and small benefit, the effectiveness of zinc

sulphate cannot be assessed conclusively.

16

Benztropine

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is benztropine effective and safe?

Literature search

Medline: Benztropine AND efficacy AND limit to (meta-analysis)

Cochrane: Benztropine AND efficacy

Soares-Weiser K, Mobsy C, and Holliday E. “Anticholinergic medication for neuroleptic-induced tardive

dyskinesia (Review).” The Cochrane Library (2012).

Implications for practice. Based on the currently available data, this systematic review can provide no reliable

conclusions about the use of anticholinergics (benzhexol, benztropine, biperiden, orphenadrine, procyclidine,

scopolamine or trihexylphenidyl) for the treatment of neuroleptic-induced TD. In addition, there is no evidence to

support the suggestion that the withdrawal of these medications may benefit people with TD. In the absence of

evidence one way or another, the clinician must balance the possible benefits against the potential adverse effects of

the treatment.

Katzenschlager R, Sampaio C, Costa J, and Lees A. “Anticholinergics for symptomatic management of

Parkinson’s disease (Review).” The Cochrane Library (2009).

Main results. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8

to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25

mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs.

Outcome measures varied widely across studies and in many cases, the scales applied were the authors´ own and

were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study

designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and

other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a

combined analysis and results varied widely, from a significant improvement in tremor only to significant

improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant

improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between

placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to

show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse

events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently

reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial

anticholinergic treatment.

Powney MJ, Adams CE, and Jones H. “Haloperidol for psychosis-induced aggression or agitation (rapid

tranquillisation) (Review).” The Cochrane Library (2012).

Adverse events In terms of movement disorders and the emergence of ataxia (1 RCT, n = 66, RR 0.44 CI 0.04 to

4.65), dystonia (1 RCT, n = 66, RR 3.54 CI 0.42 to 30.03), speech disorder (1 RCT,n = 66, RR 1.77 CI 0.35 to 9.01),

rigidity (1 RCT, n = 66, RR 6.22 CI 0.33 to 115.91), tremor (1 RCT, n = 66, RR 1.77 CI 0.17 to 18.60) and the need

for benztropine (1 RCT, n = 66, RR 1.99 CI 0.68 to 5.83). One study (n = 60) reported that significantly more

participants experienced EPS in the haloperidol group compared with the lorazepam group (RR 15.00 CI 2.11 to

106.49, Analysis 13.7).

Walshe M, Smith M, and Pennington L. “Interventions for drooling in children with cerebral palsy

(Review).” The Cochrane Library (2012).

17

Pharmaceutical Interventions. Both studies on pharmaceutical interventions (Camp-Bruno 1989; Mier 2000)

compared intervention versus placebo. They differed in the medications given and outcome measures used. Camp-

Bruno 1989 examined reduction in salivary flow and found a statistically significant difference in salivary flow

between participants (age range 4-44 years) on placebo and those taking benztropine (p<.001) immediately after

intervention. Both studies examined the frequency and severity of drooling albeit using different outcome measures.

Camp-Bruno 1989 defined a ’responder’ as those participants who obtained a mean TDS rating of less than 3. They

also defined ’responsivity’ as a decrease of one baseline SD or greater. Mier 2000 defined an improvement of 4

points or greater in their 9 point scale as a standard for significant ’clinical improvement’. On the Teacher Drool

Scale, Camp-Bruno 1989 found a statistically significant difference between both placebo and intervention in the

frequency and severity of drooling immediately after intervention (p_0.001).Mier 2000 using an adaptation of

Thomas-Stonell and Greenberg Scale also found a statistically significant difference between the placebo and

intervention immediately after intervention (p<0.001). It is unknown how long the effects of these medications

lasted in terms of reducing the quantity of saliva produced and reducing the frequency and severity of drooling.

The adverse effects of benztropine reported were behavior changes such as irritability and listlessness. Medical side

effects reported were insomnia, vomiting, dilated pupils, disorientation, facial flushing, ’glassy eyes’ , stomachache,

and dry mouth. Three children of the 27 (11%) children in Camp-Bruno 1989 were excluded because of adverse

reactions to benztropine. Eight of the 39 (20.5%) children inMier 2000 study dropped out because of the adverse

side effects to glycopyrrolate. As with the trials on BoNT-A, it is difficult to determine whether all adverse effects

reported were directly related to the medication.

18

Fusidic Acid and Mupirocin

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is fusidic acid effective and safe?

Is mupirocin effective and safe?

Literature search

Medline: Fusidic acid AND efficacy AND limit to (meta-analysis); Mupirocin AND efficacy AND limit to (meta-

analysis)

Cochrane: Fusidic acid AND efficacy; Mupirocin AND

Koning S, van der Sande R, Verhagen AP, van Suijlekom-Smit LWA, Morris AD, Butler CC, Berger M, van

der Wouden JC. “Interventions for impetigo (Review).” The Cochrane Library (2011).

Topical antibiotics versus placebo (six studies, four comparisons). Overall topical antibiotics showed better cure

rates or more improvement than placebo (pooled risk ratio (RR) 2.24, 95% CI 1.16 to 3.13 using a random-effects

model, I² = 53%) (see Analysis 1.1). This result was consistent for mupirocin (RR 2.21, 95% CI 1.59 to 3.05; 3

studies - Eells 1986; Gould 1984; Rojas 1985) (see Analysis 1.1), fusidic acid (RR 4.42, 95% CI 2.39 to 8.17; 1

study - Koning 2003) (see Analysis 1.1), and retapamulin (RR 1.64, 95% CI 1.30 to 2.07; 1 study - Koning 2008)

(see Analysis 1.1). In one small study (Ruby 1973), bacitracin did not show a significant difference in cure rate

compared with placebo (RR 3.71, 95% CI 0.16 to 85.29) (see Analysis 1.1).

Topical antibiotics versus oral (systemic) antibiotics (16 studies, 17 comparisons). Pooling 10 studies which

compared mupirocin with oral erythromycin showed significantly better cure rates, or more improvement, with

mupirocin (RR 1.07, 95% CI 1.01 to 1.13) (see Analysis 3.1). However, no significant differences were seen

between mupirocin and dicloxacillin (Arredondo 1987), cephalexin (Bass 1997), or ampicillin (Welsh 1987).

Bacitracin was significantly worse than oral cephalexin in one small study (Bass 1997), but no difference was seen

between bacitracin and erythromycin (Koranyi 1976), or penicillin (Ruby 1973). A sensitivity analysis on the

influence of blinding the outcome assessor on the comparison of mupirocin versus erythromycin (10 studies)

revealed that there was no clear relationship between blinding of the outcome assessor and the outcome. Pooling the

2 studies with observer blinding (Britton 1990;Dagan 1992) showed high heterogeneity (I² statistic = 79%) and

resulted in a non-significant difference between the 2 drugs (random-effects model, RR 1.12, 95% CI 0.86 to 1.46)

(see Analysis 3.2).

Secondary outcomes: Adverse Effects – Topical antibiotics. The trials included in this review usually reported few,

if any, side effects from topical antibiotics (see Table 1). The studies comparing mupirocin, bacitracin, and placebo

reported none (Eells 1986; Ruby 1973). The study that compared fusidic acid to placebo recorded more side-effects

in the placebo group (Koning 2003). Three of 4 studies comparing mupirocin with fusidic acid recorded side-effects:

minor skin side-effects were reported for mupirocin by 10 out of 368 participants (3%) and for fusidic acid by 4 out

of 242 participants (2%). The study that compared retapamulin to placebo found more itching in the group treated

with retapamulin (7%vs 1%; P = 0.17) (Koning 2008). In the other study of retapamulin, this side-effect was

reported in less than 1% of cases (Oranje 2007).Most other trials comparing topical antibiotics reported no side-

effects or reported minor skin side-effects in low numbers (less than 5% of participants).

19

20

George Ajay and Rubin Greg. “A systematic review and meta-analysis of treatments for impetigo.” British

Journal of General Practice 2003 (53): 480-487.

Mupirocin versus fusidic acid. The BNF advises use of mupirocin or fusidic acid as topical treatment for

impetigo.13 Of the four studies comparing these two treatments, one showed 100% cure or improvement in both

groups31 and one favoured fusidic acid,34 while the other two favoured mupirocin35,36 (with only one of these

showing mupirocin to be significantly better than fusidic acid). The three studies that showed differences in

treatment effects were all set in UK general practice. There was no strong evidence of statistical heterogeneity (χ2 =

5.94, df = 2, P = 0.051) and meta-analysis shows no difference between the two treatments, (OR = 1.76, 95% CI =

0.77 to 4.03) (Figure 4).

Kevin B Laupland and John M Conly. “Treatment of Staphylococcus aureus Colonization and Prophylaxis

for Infection with Topical Intranasal Mupirocin: An Evidence-Based Review.” Clinical Infectious Diseases

2003 (37): 933-38.

Several studies conducted with varied populations demonstrated that mupirocin was highly effective in eradicating

nasal colonization with S. aureus when compared with placebo in the short term. The efficacy of mupirocin was also

comparable to a systemic regimen and superior to other topical antibacterials in a few small trials. However, 2–14-

day therapeutic courses of mupirocin did not typically result in long-term clearance of S. aureus colonization.

Repeated application of mupirocin is a potential option for reducing colonization in the long term, but the evolution

of resistance is a risk. Several of the studies included in this review described resistance associated with mupirocin

therapy, but the rates were typically low. Ultimately, the most important goal of intranasal mupirocin application is

to reduce subsequent clinical infection. The body of literature currently does not support routine administration of

prophylactic intranasal mupirocin to patients in an attempt to decrease the rate of clinical infection. Although the

available literature does not support routine use of topical intranasal mupirocin to prevent subsequent infections,

there may be yet-identified patient populations that could benefit. For a significant effect to be seen, one may

speculate as to the characteristics of patients who would benefit the most. Ideally, mupirocin should be used for

patients when the period of risk for infection is acute. Chronic infection risk, such as with dialysis patients, has

demonstrated minimal clinical benefit but increased risk for resistance. Examples of patients with acute disease who

may be candidates for prophylactic mupirocin treatment include patients who have undergone cardiac surgery,

patients with multiple trauma (especially those with head injuries), and, possibly, other selected critically ill patients

[38–41]. The selection of patients with high rates of nasal colonization or documented carriers is also important for

mupirocin therapy to be effective.

21

Olopatadine

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is olopatadine effective and safe?

Literature search

Medline: Olopatadine AND efficacy AND limit to (meta-analysis or review)

e-CPS: Olopatadine

Cochrane: Olopatadine AND efficacy

Castillo M, Scott NW, Mustafa MZ, Mustafa MS, Azuara-Blanco A. “Topical antihistamines and mast cell

stabilisers for treating seasonal and perennial allergic conjunctivitis (Review).” The Cochrane Library (2015).

22

Olopatadine versus placebo or other control. The search identified two eligible studies comparing the antihistamine

olopatadine versus placebo, in Avunduk 2005, or other control, in Lanier 2001. The Avunduk 2005 study was a

three-arm trial comparing both olopatadine and ketotifen with placebo (Avunduk 2005). Duration of treatment was

four weeks, but two-week data were available. The sample size was relatively small, with 16 participants

randomised to olopatadine and 17 participants randomised to artificial tears (placebo). Mean and SD data were

available. Lanier 2001 compared the effect of topical olopatadine in people undergoing treatment with an oral

antihistamine (loratadine). Duration of treatment was one week. A total of 94 participants (49 versus 45) were

randomised but not masked. No SD data were available. Primary outcomes. Avunduk 2005 reported two of the four

symptoms prespecified as primary outcomes (participant-reported itching and watering eyes). Data on mean and SD

were available. Olopatadine had statistically significantly less severe itching (mean 0.76, SD 0.1) and tearing (mean

0.30, SD 0.1) than the placebo group (mean itching 1.85, SD 0.3; mean tearing 1.07, SD 0.2) after two weeks of

treatment. Lanier 2001 included participant-reported itching on a 4-point scale (from 1 to 4). After one week,

reported itching was less in the group treated with olopatadine (mean 2.21 versus 2.74, P = 0.044). Safety outcomes.

There were no adverse events or side effects associated with olopatadine in either study. Overall summary.

There was evidence from two small trials that olopatadine may be effective in improving some ocular symptoms.

Olopatadine versus ketotifen. The search identified four eligible studies comparing the antihistamines olopatadine

and ketotifen (Avunduk 2005; Höffling- Lima 2001; Sarker 2011; Varguez-Rodriguez 2009). One study was a three-

arm trial comparing both olopatadine and ketotifen with placebo (Avunduk 2005). Drug concentration was the same

in all studies (olopatadine 0.1% and ketotifen 0.025%), except Höffling-Lima 2001, which used ketotifen 0.05%.

Duration of treatment was four weeks in three studies, Avunduk 2005, Höffling-Lima 2001, and Varguez-Rodriguez

2009, and two weeks in one study (Sarker 2011). In all studies the sample size was relatively small. The number of

participants randomised to olopatadine and ketotifen were 16 versus 16 (Avunduk 2005), 20 versus 20 (Höffling-

Lima 2001), 46 versus 46 (Sarker 2011), and 20 versus 20 (Varguez-Rodriguez 2009), respectively. Primary

outcomes. Although four studies reported at least two of the four symptoms prespecified as primary outcomes

(itching and tearing), there was some variation in how these outcomes were reported. All four studies collected data

on participant-reported itching using a 0-3 scale. Two studies reported mean and SD values (Avunduk 2005; Sarker

2011). Two studies did not find any differences between olopatadine and ketotifen in itching reporting (Avunduk

2005;Höffling-Lima 2001), while two studies found a greater reduction in itching with olopatadine than with

ketotifen after two weeks of treatment (Sarker 2011; Varguez-Rodriguez 2009). Sarker 2011 reported two-week

mean scores of 1.09 (SD 0.53) with ketotifen and 0.33 (SD 0.60) with olopatadine. A random-effects meta-analysis

of these four studies showed evidence of a statistically significant difference in favour of olopatadine in the

reduction of itching at 14 days (mean difference (MD) -0.32, 95% confidence interval (CI) -0.59 to -0.06) (Figure

5). However, there was high statistical heterogeneity (I2 = 83%). Two studies presented data for participant-reported

ocular irritation (described in both studies as burning) Höffling-Lima 2001; Varguez-Rodriguez 2009). Höffling-

Lima 2001 did not find any differences between groups, while Varguez-Rodriguez 2009 reported a statistically

significant greater reduction in burning in the lopatadine group (P < 0.05). All four studies reported data on tearing.

Only one study reported differences between groups after two weeks (Sarker 2011),with the group treated with

olopatadine having less tearing (mean 0.03, SD 0.16) than the one treated with ketotifen (mean 0.40, SD 0.66).

Three studies assessed tearing at 14days (Avunduk 2005;Höffling- Lima 2001; Sarker 2011). A random-effects

meta-analysis of these studies found no evidence of a difference between lopatadine and ketotifen (MD -0.06, 95%

CI -0.35 to 0.22). There was no evidence of a difference in the reduction of tearing scores at 14 days between the 2

groups (Figure 6). Once again, there was high statistical heterogeneity between the studies (I2 = 90%).We knew of

two studies that collected data on photophobia (Höffling-Lima 2001; Sarker 2011). There were no differences

between groups. Safety outcomes. No serious adverse events were reported in the four papers. Three studies did not

report any side effects (Avunduk 2005; Höffling- Lima 2001; Varguez-Rodriguez 2009). In one study, ketotifen was

associated with a mild stinging sensation of short duration (less than 30 minutes) in 13 out of 43 participants; no

participants treated with olopatadine reported such discomfort (Sarker 2011). Overall summary. There was some

evidence from individual trials that olopatadine may be more effective than ketotifen in improving some ocular

symptoms such as itching. Both drugs are safe.

23

Atsuki Fukushima and Nobuyuki Ebihara. “Efficacy of Olopatadine versus Epinastine for Treating Allergic

Conjunctivitis Caused by Japanese Cedar Pollen: A Double-Blind Randomized Controlled Trial.” Advances

in Therapeutics 2014 (31): 1045-1058.

We found that administration of olopatadine significantly reduced self-assessed ocular itching at 7 min (the primary

endpoint) and investigator assessed conjunctival hyperemia at 20 min (the main secondary endpoint) compared with

epinastine without apparent safety concerns. These results support the use of olopatadine for the treatment of allergic

conjunctivitis caused by Japanese cedar pollen. In a similarly designed study, Abelson and Greiner [9] performed

CAC tests in 68 subjects and reported that olopatadine 0.1% significantly reduced itching and redness compared

with levocabastine 0.05%. The authors also reported that olopatadine was more tolerable than levocabastine in terms

of reduced discomfort following administration. In another study in which 32 subjects underwent CAC tests, Berdy

et al. [10] reported that olopatadine 0.1% was more effective in reducing ocular itching than ketotifen fumarate

0.025% while causing less ocular discomfort. They also found that olopatadine was preferred over ketotifen by

approximately three times as many patients. In addition, Lanier et al. [8] reported that olopatadine 0.1% was more

effective than epinastine 0.05% in controlling allergic symptoms induced by a CAC test. Taken together, the results

of these studies support the use of olopatadine 0.1% as an effective treatment for preventing allergic conjunctivitis

and other ocular allergic symptoms. However, data should be interpreted with caution because there was no negative

control group treated with physiological saline.

24

Cromolyn

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is cromolyn effective and safe?

Literature search

Medline: Cromolyn AND efficacy AND limit to (meta-analysis)

Cochrane: Cromolyn AND efficacy

Castillo M, Scott NW, Mustafa MZ, Mustafa MS, and Azuara-Blanco A. “Topical antihistamines and mast

cell stabilisers for treating seasonal and perennial allergic conjunctivitis (Review).” The Cochrane Library

(2015)

Nedocromil sodium/sodium cromoglycate versus placebo – Primary outcomes. There was some evidence from

individual trials that nedocromil sodium or sodium cromoglycate is more effective than placebo in improving ocular

symptoms. However, it was not possible to perform formal meta-analyses for this comparison due to variation in

how outcomes were reported and the lack of suitable data (especially standard deviations (SDs)).

Pacharn P and Vichyanond P. “Immunomodulators for conjunctivitis.” Current Opinion in Allergy and

Clinical Immunology. 2013 (13): 550-557

Cromolyn was found to be effective in treating seasonal allergic conjunctivitis [23]. Cromolyn 4% solution was

found to be more effective than 2% solution [24]. However, limitation of ophthalmic cromolyn is that it has to be

applied four times per day. In fact, nedocromil 2% solution applied twice daily was found to be as effective as

cromolyn 2% solution applied four times daily [25]. By increasing concentration of cromolyn to 4%, a satisfactory

effect was obtained with twice-daily application [26]. Both drugs were tried in patients with VKC with more

effective results attained with the use of nedocromil eye drops [27,28]. Moreover, at 22 weeks of treatment,

improvement of severe conjunctivitis sign of VKC such as pannus, papilla and keratitis was improved with

nedocromil treatment only [28]. In an extensive review of experience with nedocromil, it was found to be effective

in seasonal, perennial and VKC with four times daily application being more efficient than twice daily [29].

Surprisingly, the effect of nedocromil was noted to be as rapid as 15 min in this review.

van der Wouden JC, Uijen JHJM, Bernsen RMD, Tasche MJA, de Jongste JC, and Ducharme FM. “Inhaled

sodium cromoglycate for asthma in children (Review).” The Cochrane Library (2011)

25

Effect of interventions. Symptoms. Only four studies provided results for the percentage of symptom-free

days: our primary outcome measure (Figure 2; Table 3). In all but one of the studies (Cogswell 1985), the

confidence interval included the point of no difference. Pooling the results revealed no significant difference

between DSCG and placebo (WMD 6.76% favouring DSCG, 95%CI -2.18 to 15.70), random-effects model. Mean

overall symptom scores favoured DSCG in direction in six out of ten studies (Figure 5;Table 6).The 95%confidence

intervals of four of the studies included the point of no difference. Pooling the results (test of homogeneity rejected,

hence random-effects model) showed an overallmean difference of -0.22 symptom score points (WMD), favouring

the DSCG group (95%CI -0.34 to - 0.09), hence statistically significant.

Sodium Cromoglycate. e-CPS. Date of Revision: December 2011.

Nausea, vomiting, diarrhoea, abdominal discomfort, headache, insomnia, skin rashes sneezing, cough, unpleasant

taste in the mouth, and joint pains have been reported. Hypersensitivity reactions have been reported rarely.

Possible immunologic changes resulting in reactions such as polymyositis, pneumonitis and heart failure, urticaria

and anaphylaxis, have been reported.

Cases of erythema, urticaria or maculopapular rash have been reported and these have cleared within a few days on

withdrawal of the drug.

26

Montelukast

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is montelukast effective and safe?

Literature search

Medline: Montelukast or Leukotriene Antagonists AND efficacy AND limit to (meta-analysis)

Cochrane: Montelukast AND efficacy

Watts K and Chavasse RJPG. “Leukotriene receptor antagonists in addition to usual care for acute asthma

in adults and children (Review).” The Cochrane Library (2012).

27

Oral montelukast or zafirlukast in addition to usual care

Hospitalisation (primary outcome). There was no significant difference between oral leukotriene receptor

antagonists (LTRAs) and control in the risk of admission to hospital in three studies including 194 children

comparing oral montelukast to control in addition to usual care for acute asthma (RR 0.86; 95% CI 0.21 to 3.52;

Figure 3).

Lung function. There was a significant difference in FEV1 favouring LTRAs in the combined results of a single

study on 641 adults on different doses of zafirlukast (MD 0.08; 95% CI 0.01 to 0.14; Figure 4). In Silverman 2004a

20 mg of zafirlukast was administered orally and in Silverman 2004b the dose was 160 mg. Change in predicted

FEV1 did not show a significant effect of LTRAs in a single study ofmontelukast in 26 children (MD-3.10;

95% CI -12.70 to 6.50; Analysis 1.4).

IV montelukast in addition to usual care.

Hospitalisation (primary outcome). Three studies on 772 adults and one study on 276 children reported hospital

admission using intravenous montelukast. There was no statistically significant difference in the number of hospital

admissions in adults (RR 0.78; 95% CI 0.57 to 1.06) or children (RR 0.79; 95% CI 0.51 to 1.23). The pooled result

from all age groups approached statistical significance (RR 0.78; 95% CI 0.61 to 1.01; see Figure 5).

Nikolaos G Papadopoulos, George Philip, Hilde Giezek, Molly Watkins, Steven S Smugar, and Peter G Polos.

“The Efficacy of Montelukast during the Allergy Season In Pediatric Patients with Persistent Asthma and

Seasonal Aeroallergen Sensitivity.” Journal of Asthma 2009 (46): 413-20.

Efficacy. For the primary endpoint of percentage change from baseline FEV1, there was no significant difference

28

between montelukast and placebo (LS mean: 9.53% vs. 9.15%, respectively; difference: 0.38% [95% CI: −2.74,

3.50]; p = 0.810) (Table 2). There were no significant differences between treatment groups in the analyses of the

primary endpoint by prespecified subgroups (Figure 2); treatment difference was consistent among subgroups for

gender, age, race, concomitant inhaled steroid use, asthma severity, and pollen level. A somewhat higher treatment

difference was observed for the subgroup spring 2007 (treatment difference in LS means of 2.52%). Montelukast

was significantly more effective than placebo for the investigator’s global asthma evaluation (LS mean: 2.71 vs.

2.98;p <0.05) (Figure 3A) and parent/guardian global asthma evaluation (LS mean: 2.63 vs. 2.90;p <0.05) (Figure

3B).

Xun Chen, Ke Wang, Min Jiang, and Guang-Min Nong. “Leukotriene receptor antagonists for small-airway

abnormalities in asthmatics: a systematic review and meta-analysis.” Journal of Asthma 2013 (50): 695-704.

LTRAs versus placebo. HRCT One RCT (41) showed that an LTRA was more efficacious than placebo in reducing

regional air-trapping on HRCT (MD 61.00; 95% CI, 26.32–95.68; p50.001). FEF25–75% Three RCTs [41,46,47]

reported changes in FEF25–75% when comparing LTRAs with placebo. There was no heterogeneity among the 3

RCTs (p=0.40, I2=0%). The pooled MD for the treatment effect was 5.29 (95% CI, -4.05 to 14.62; p=0.27),

showing no improvement in the FEF25–75% in participants receiving LTR compared with patients receiving

placebo (Figure 2). RV Three RCTs [41,46,48] reported changes in RV when comparing LTRAs with placebo. One

RCT [48] showed its result for the parameter of residual volume as the percent predicted (RV% predicted), while

other RCTs [41,46] displayed their results as the ratio of the residual volume to the total lung capacity (RV/TLC).

Therefore, the SMD was used as a summary statistic. There was no heterogeneity among the 3 RCTs (p=0.58,

I2=0%). The pooled SMD for the treatment effect was -0.85 (95% CI, -1.29 to -0.42; p<0.001), showing a reduction

in RV in participants receiving LTRAs compared with patients receiving placebo (Figure 3).

29

Drugs Used for Maintenance Therapy for Asthma in Children; Mary Noseworth, MD, FRCPC, and Mark

Montgomery, MD, FRCPC. e-CPS. Date of Revision: April 2015.

Class Drug Dosage Adverse Effects Comments Cost

Leukotriene

Receptor

Antagonists

Montelukast

Singulair,

Montelukast,

generics

>15y: 10mg QHS po

6-14y: 5mg

(chewable tablet)

QHS po

2-5y: 4mg

(chewable tablet or

granules) QHS po

Headache, abdominal

pain, flu-like

symptoms,

hepatotoxicity (rare).

Reports of

neuropsychiatric

effects, e.g. depress,

agitation

Decreased

montelukast levels:

carbamazepine,

rifampin,

phenobarbital,

phenytoin

$$

30

Calcium

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is calcium effective and safe?

Literature search

Medline: Calcium, Dietary/ or Caclium/ or Dietary Supplements AND efficacy AND limit to (meta-analysis or

review)

e-CPS: Calcium supplementation; nutritional supplementation

Cochrane: Calcium supplementation AND efficacy

IR Reid, SM Bristow, and MJ Bolland. “Calcium supplements: benefits and risks.” Journal of Internal

Medicine 278 (2015): 354-369.

Benefits of calcium supplements.

Bone density. Ingestion of a calcium bolus, in the form of a supplement, acutely increases circulating calcium

concentrations and reduces parathyroid hormone levels and markers of bone resorption, with a decline in bone

formation markers 2–3 months later (Fig. 3). This produces a benefit to bone density of about 0.5–1% in the hip and

spine, mostly in the first year of treatment [52]. In most trials, no relationship was found between individuals’

baseline dietary calcium intake and their bone density response [25, 53]. In general, calcium doses ≥1000 mg day

31

have been used in supplement studies [54]. Doses of 250–600 mg day have been found to produce no or minimal

effects on BMD [55, 56], except in individuals with very low calcium intakes [12, 57]. Collectively, these findings

suggest that calcium supplements act as weak anti-resorptive agents, reducing bone turnover whatever the baseline

calcium intake, and producing a one-off gain in bone density as a result of filling-in of some of the osteoclastic

resorption sites. This, however, does not produce cumulative benefits in terms of bone mass.

Fractures. In the early 1990s, Chapuy et al. conducted the first study designed to test the anti-fracture efficacy of

calcium (with vitamin D in this case) [14]. At 18 months, there was a 43% decrease in hip fractures in a completers’

analysis, which equated to a 26% decline in fracture rate on an intention-to treat basis. The effect was similar at 36

months [58]. Non-vertebral fracture numbers were decreased by 25% and 17%, at 18 and 36 months, respectively

(intention-to-treat analysis). This led to the conclusion that calcium and vitamin D were an essential part of

osteoporosis management, because of their demonstrable anti-fracture efficacy and their presumed safety. Several

features of this study by Chapuy and colleagues should be mentioned. First, it was carried out in frail elderly women

living in institutions. Secondly, calcium intakes were ~500 mg day_1 and mean serum 25-hydroxyvitamin D

concentration was 25 nmol L_1 in placebo subjects 12 months into the study, equating to 13.7 nmol L_1 after

correction for inaccuracies in assay calibration [59]. Finally, calcium plus vitamin D produced a between-group

difference in total hip bone density of 7.3%, a response larger than reported with any anti-osteoporotic medication.

Such a large effect can only be explained as a response to the treatment of osteomalacia, which is highly likely to

have affected many of these women, considering their marked vitamin D deficiency. In the last 10 years, the results

of five large trials of calcium supplements have been reported; none showed beneficial effects on fractures in their

primary analyses [25, 60–63], although some found beneficial and adverse fracture effects in secondary analyses.

This is reflected in recent meta-analyses, which showed either no effect of calcium on fracture or small effects [54,

64]. The influential nature of the study by Chapuy and colleagues in the first of these meta-analyses, by Tang et al.

[54], is noteworthy. In the subgroup analyses, the group in which Chapuy lies usually is found to have the greatest

therapeutic effect. Thus, total fractures were only reduced by 6% in community- dwelling subjects. Fracture

prevention was reduced with trial duration, reaching no effect at 7 years, and with declining compliance [relative

risk 0_96, 95% confidence interval (CI) 0_91–1_01, with <80% compliance] (Fig. 4). Tang et al. did not consider

hip fracture as a separate endpoint, but at least three meta-analyses have shown upward trends in hip fracture from

the use of calcium alone [51, 64, 65]. The effects of calcium plus vitamin D on hip fracture are dominated by the

results of Chapuy et al., but analyses of community- dwelling subjects have shown no evidence of fracture

prevention. Recently, the investigators from the Women’s Health Initiative (WHI) demonstrated a significant

interaction between randomization to calcium plus vitamin D and to hormones on risk of hip fracture in their study

[66]. When results from the non-hormone-treated WHI subjects were used in the meta-analysis, there was a

trend towards an adverse effect on hip fracture risk from the use of calcium plus vitamin D [65] (Fig. 5).

In summary, calcium supplements clearly have small beneficial effects on bone density, but a cumulative density

benefit has not been demonstrated in most studies. As a result, the anti-fracture efficacy of calcium supplements

remains an open question; there is no evidence to support a role in hip fracture prevention (other than in a cohort

with severe vitamin D deficiency) and total fracture numbers are only reduced by 0–10%, depending on which meta-

analysis is considered. This has led to the US Preventive Services Task Force not recommending their use [67], a

view supported by some journal editorials [68].

32

Risks of calcium supplements

Gastrointestinal effects. From their earliest use, there has been an awareness that calcium supplements have

gastrointestinal side effects, mainly constipation but also, with the use of calcium carbonate, flatulence. However, it

has been assumed that such side effects are only of minor inconvenience. The frequency of minor gastrointestinal

symptoms with calcium supplements has been confirmed, and this appears to contribute to low compliance [25].

These adverse effects were summarized in the recent meta-analysis by Lewis et al. [69] (Fig. 6). The authors

described the symptoms as ‘constipation, excessive abdominal cramping, bloating, upper gastrointestinal events,

gastrointestinal disease, gastrointestinal symptoms and severe diarrhoea or abdominal pain’. However, of more

concern, was the finding by Lewis and colleagues of acute admissions to hospital with acute abdominal symptoms:

6.8% in the placebo group and 3.6% in the calcium-treatment group (over 5 years). In fact, they found that the

absolute excess of hospital admissions for acute abdominal problems was numerically greater than the decrease

in total fracture numbers. In contrast to the fracture results, the difference in hospital admissions for gastrointestinal

emergencies was statistically significant. This suggests that serious gastrointestinal side effects alone abrogate the

possible benefit of calcium supplements for fracture prevention.

Renal calculi. Calcium balance is maintained within tight limits to ensure that circulating levels are adequate to

facilitate skeletal mineralization, yet not elevated to levels that would cause mineralization of soft tissues.

Accordingly, the use of calcium supplements is associated with increases in urine calcium excretion [55]. This has

caused concern that calcium supplements would increase the risk of renal calculi, as was confirmed in the WHI

(hazard ratio for renal calculi 1.17, 95% CI 1.02–1.34). As for adverse gastrointestinal symptoms, the absolute

increase in renal stone events in the active treatment group in the WHI was statistically significant and numerically

greater than the decrease in fractures, whereas there was no statistically significant difference in fracture rates

between groups in the primary analyses. Again, the increase in incidence of renal calculi alone counter-balances

any possible fracture benefit from the use of calcium supplements.

33

Cardiovascular effects. We have recently reviewed the cardiovascular side effects of calcium supplements in detail

elsewhere [70]. Deposition of calcium into arterial walls is an integral part of the atherosclerotic process, so there

has been concern for some decades that calcium supplementation might increase the risk of cardiovascular disease.

However, this concern has principally been expressed by vascular biologists [71] and often not considered seriously

by those involved in the therapeutic management of osteoporosis. By contrast, there has been long-standing concern

about the use of calcium in patients with chronic renal failure. In pre-dialysis patients, calcium supplements increase

coronary artery calcification [72] and adversely impact on survival [73]. These patients have renal function

comparable to that seen in many older individuals at risk of osteoporosis [74]. This concern has resulted in ‘the

demise of calcium-based phosphate binders’ in many centres [75, 76]. More than a decade ago, we and others

observed that calcium supplements appeared to produce small benefits in terms of blood pressure [77, 78] and

circulating lipid levels [79], although the latter findings have not been consistent. On the basis of these possible

beneficial effects, a number of cardiovascular events were pre-specified as secondary endpoints in the Auckland

Calcium Study. We were surprised to discover that the incidence of myocardial infarction was significantly

increased in this study, and there was an upward trend in stroke incidence [80]. Subsequently, as part of an

international consortium, we conducted a meta-analysis of all trials in older adults randomly assigned to calcium or

placebo for ≥1 year [81]. This analysis confirmed a 27% increase in the incidence of myocardial infarction and again

suggested an adverse effect on the risk of stroke. A quarter of myocardial infarctions in this analysis were self-

reported; the hazard ratio was 1.44 (95% CI 1.08–1.91, P = 0.013) if these events were excluded [82]. A similar

numerical increase in myocardial infarction risk associated with calcium monotherapy has been found in two

subsequent meta-analyses [83, 84], although their statistical significance was marginal because of smaller numbers

in those analyses. Our findings with calcium monotherapy appeared to contradict those of the WHI, which

concluded that there was no adverse effect of calcium plus vitamin D on cardiovascular health [85]. However, their

analyses did demonstrate an interaction between body mass index and cardiovascular disease risk, such that the

incidence of myocardial infarction increased by 17% in non-obese subjects. In addition, an almost significant hazard

ratio of 1.08 (95% CI 0.99–1.19) was reported for a composite endpoint that included myocardial infarction and

coronary artery revascularization, which is not reassuring from a safety perspective. The WHI differed in several

important respects from those studies included in the first meta-analysis led by Bolland [80]. The subjects were, on

average, 10 years younger, the active treatment group received vitamin D in addition to calcium, and participants

were accepted into the trial even if they were already taking calcium supplements, and were permitted to continue

these self-administered calcium supplements throughout the trial. Thus, at randomization, 54% of subjects were self-

administering calcium, and this proportion rose to 69% at trial end. We hypothesized that contamination with self-

administration of calcium might have obscured an adverse effect of supplements on cardiovascular disease risk and

designed a protocol to address this issue. Following approval of the analysis plan by the NIH, we obtained the

publicly available WHI data set. We found a significant interaction between self-administration of calcium

supplements and the effect of the calcium/vitamin D intervention on cardiovascular disease risk [86]. There were no

adverse effects from the addition of further calcium in those already taking a supplement, but, in calcium-naive

subjects, an increase in risk very similar to that found in our first meta-analysis was demonstrated. The adverse

trends applied to both myocardial infarction and stroke. As shown in Fig. 7, the time courses of the effects of

calcium supplementation on myocardial infarction and stroke are very similar between our meta-analysis of calcium

monotherapy and the analysis of the calcium-naive subjects in the WHI. It is also noteworthy that the onset of

adverse effect is more rapid for myocardial infarction than for stroke and this difference is consistent between the

two separate data sets. Thus, there is no evidence that the addition of vitamin D abrogates the adverse effects

of calcium on cardiovascular disease risk, and this is consistent with the much larger body of clinical trial evidence

suggesting that vitamin D is not cardioprotective [87, 88]. Recently, Lewis et al. have performed another meta-

analysis of these data, but excluding men and self-reported events [89]. For calcium monotherapy and myocardial

infarction, their results were very similar to those of Bolland and colleagues [81] (relative risk 1.37, 95% CI 0.98–

1.92); the lack of statistical significance was accounted for by the smaller numbers they included (6333 vs. 10 210).

For their analysis of calcium plus vitamin D, Lewis and colleagues added two groups of women not included in the

meta-analysis by Bolland et al.: 20 000 participants from the WHI who were already taking calcium at the time of

randomization, and 6000 women from the study of Larsen et al. [90], which was not a randomized, controlled trial.

Because we have shown that self-administration of calcium significantly influenced the cardiovascular outcomes of

the WHI [86], the first of these additions is not appropriate. In the Larsen study [90], the authors divided the

residential area into district ‘clusters’, with one ‘cluster’ per intervention. Prospective participants knew what their

intervention would be before agreeing to participate, and there was a higher participation rate among those offered

calcium plus vitamin D. The use of cardiovascular medications, sedatives and analgesics was lower in this group

compared with those agreeing to act as controls, suggesting a difference in cardiovascular disease risk and other

34

comorbidities at baseline, which would bias the study against finding an adverse effect of calcium supplements.

Thus, this study does not qualify for inclusion in a meta-analysis of randomized, controlled trials. In the analysis by

Lewis et al., no effect of calcium plus vitamin D supplements on total coronary heart disease was found, but 82% of

the weight in this analysis was from the WHI, so it is essentially a re-publication of those data. As for

gastrointestinal and renal adverse effects, it is instructive to compare the absolute increase in numbers of

cardiovascular events with the absolute decrease in number of fractures. For calcium monotherapy, treatment of

1000 persons for 5 years will cause 14 myocardial infarctions, 10 strokes and 13 deaths, while preventing 26

fractures [81]. Thus, consideration of the cardiovascular adverse effects in isolation suggests that calcium

supplements produce no net benefit. When these cardiovascular adverse events are considered alongside

gastrointestinal events and renal calculi, it is apparent that a negative impact of calcium supplement use is likely.

Benjamin MP Tang, Guy D Eslick, Caryl Nowson, Caroline Smith, and Alan Bensoussan. “Use of calcium or

calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50

years and older: a meta-analysis.” The Lancet 2007 (370):657-66.

Discussion. Our meta-analysis has shown that calcium supplementation, alone or in combination with vitamin D, is

effective in the preventive treatment of osteoporotic fracture. Over an average treatment duration of 3・5 years,

the risk of fracture was reduced and was accompanied by a reduction of bone loss at the hip and spine. The fracture

risk reduction was greater in individuals who were elderly, lived in institutions, had a low bodyweight, had a low

calcium intake, or were at a high baseline risk than it was in others. The treatment effect was consistent irrespective

of sex, fracture sites, or history of previous fracture. Moreover, the treatment was similarly effective whether the

person used calcium or calcium in combination with vitamin D supplementation. However, the treatment was less

effective if compliance was poor. For calcium-only supplementation, a minimum dose of 1200 mg is needed for best

therapeutic effect. For calcium in combination of vitamin D supplementation, a minimum dose of 800 IU of vitamin

D is recommended. Although addition of vitamin D supplementation was not shown to offer additional risk

reduction over and above the use of calcium alone, a significant difference was observed between the effects of

different vitamin D doses. This discrepancy could be due to statistical artifact. However, we would like to point out

that our analysis was limited by the scarcity of data for vitamin D doses higher than 800 IU. It is possible that

vitamin D does have a beneficial effect when the dose is large enough (ie, >800 IU). In the absence of such data, we

recommend that if vitamin D is to be used as an adjunct supplementation to calcium, its dose should be at least

800 IU or more. Poor compliance is a major obstacle to obtaining the full benefit of calcium supplementation. When

we analysed trials with a compliance rate of at least 80% separately, the risk reduction was doubled. We noted a

greater treatment effect in individuals with low dietary calcium intake than in those whose dietary intake was high.

This result is important since inadequate dietary calcium is prevalent throughout the world, especially in elderly

people and women.47,48 It is also consistent with what is understood about the pathophysiology of osteoporosis.

After midlife there is an age-related yearly loss of bone in both sexes of about 1%,49 which is accelerated to 2% for

up to 14 years in women around the age of menopause.50 This bone loss is characterised by the loss of calcium from

bone. To keep bone loss to a minimum, increased dietary calcium is needed to offset the continuing loss. It is

possible that the role of supplementation might diminish with increased intake. It can be difficult, however, for

many elderly people to maintain a calcium intake above 1000 mg per day, especially when energy intake falls with

increasing age. Our study has implications for both clinicians and policymakers. The estimated number needed to

treat shows that 63 patients will need to be treated over 3・5 years to prevent one fracture. This result is comparable

to other preventive treatments such as statins, in which 40 people would need to be treated for 5 years to prevent one

major cardiovascular event,52 and it is substantially better than aspirin treatment, in which more than 270

participants would need to be treated for 6 years to prevent one cardiovascular event.53 Furthermore, the number

needed to treat decreased to 30 or fewer in individuals who were elderly, had low dietary calcium intake, or were

compliant with calcium supplementation. On the basis of our recommended minimum dose of 1200 mg of calcium

or 800 IU of vitamin D, many formulations of calcium or combined calcium with vitamin D tablets that are available

contain insufficient quantities of the active ingredients. In view of the large number of calcium supplementation

tablets sold worldwide, adequate dosage is an important issue to address if best possible public-health benefits are to

be realised. Our study also has implications for future studies of cost-effectiveness. Although our findings confirmed

that therapeutic effect generally increased with age, it also suggested that the effect becomes much greater and

clinically significant after the age of 70 years. The cost-effectiveness of selecting a specific age group, such as

people aged 70 years or older, will therefore need to be addressed in future studies. Our study has several strengths.

35

e-CPS – Calcium Salts: Oral

Serious Warnings and Precautions. A 2010 meta-analysis showed an association between high-dose calcium

supplementation (taken without supplemental vitamin D) and an increased risk of myocardial infarction [BMJ 2010;

341:c3691]. Since then, cohort studies, randomized controlled trials and systematic reviews have shown conflicting

results, ranging from positive, neutral and negative associations between calcium and increased cardio vascular

disease risk [JAMA 2013; 173(8):639-46]. Important factors to consider are the dietary versus supplemental sources

of calcium, low versus high dose and benefit versus risk in the particular patient. Further study is warranted to

clarify the effect of calcium on cardiovascular disease. Until further safety information is available, high doses of

calcium supplements should not be used in those who do not need extra calcium. Those who have inadequate

calcium intake should consider first increasing dietary intake before taking supplements. Health Canada

recommends that patients not exceed 1500 mg/day from supplements alone; some experts recommend a lower

maximum of 500 mg/day from supplements alone.

36

Vaginal ring eluting etonogestrel and ethinyl estradiol

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is the combined hormonal vaginal ring effective and safe?

Literature search

Medline: combined hormonal vaginal ring AND efficacy AND limit to (meta-analysis)

Cochrane: combined hormonal vaginal ring AND efficacy And limit to (meta-analysis or review)

Lopez LM, Grimes DA, Gallo MF, Stockton LL, and Schulz KF. “Skin patch and vaginal ring versus

combined oral contraceptives for contraception (Review).” The Cochrane Library (2013).

Vaginal ring versus COC. Effectiveness Contraceptive effectiveness was not significantly different for the vaginal

ring and comparison COCs in the eight trials that reported pregnancy. Compliance (adherence) Compliance results

varied across the four vaginal ring studies with those data. One found poorer compliance among the ring users, two

showed no difference, and one showed ‘perfect’ use was more common for the vaginal ring users compared to COC

users. Cycle control The ring trials with bleeding data generally showed fewer problems for the ring group

compared to the COC group. In three of seven trials with such data, the ring group had fewer episodes of

breakthrough bleeding and spotting. One study showed the ring group had a greater mean for breakthrough bleeding

and spotting days. Fewer problems may relate to steady-state hormone levels, in contrast to peaks and troughs with

oral contraceptives. The better bleeding patterns did not translate into less discontinuation, though. Adverse events

For adverse events, five patch trials and seven ring trials reported data. Ring users had more vaginal irritation and

discharge than COC users in several trials, but less nausea and acne. One trial showed ring users had fewer reports

of worsening body weight, headaches, or sex drive. Another found less irritability, depression, and vaginal dryness

among the ring users than the COC users. However, that trial investigated certain tolerability issues, presumably

actively, whereas other researchers usually summarized participants’ reports of adverse events. Participants may

report more problems if prompted, but the effect should be similar in both groups. Since these trials were not

blinded, the results could be biased. For the etonogestrel ring users, the risk of deep venous thrombosis was 149

(95% xCI 18 to 538) per 100,000 women, but one woman with deep venous thrombosis had an additional risk

factor. Because of the rarity of venous thromboembolism, these randomized controlled trials are not informative

concerning comparative risk.

37

Estrogen (conjugated estrogens & ethinyl estradiol)

Addition to the List

Note: Commonly prescribed medication.

Literature question

Is estrogen effective and safe?

Are conjugated estrogens effective and safe?

Literature search

Medline: Conjugated estrogens AND efficacy AND limit to (meta-analysis or review); Ethinyl estrogen AND

efficacy AND limit to (meta-analysis or review)

Cochrane: Conjugated estrogens AND efficacy And limit to (meta-analysis or review); Ethinyl estrogen AND

efficacy And limit to (meta-analysis or review)

Boardman HMP, Hartley L, Eisinga A, Main C, Roque I Figuls M, Bonfill Cosp X, Gabriel Sanchez R,

Knight B. “Hormone therapy for preventing cardiovascular disease in post-menopausal women (Review).”

The Cochrane Library (2015).

We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no

protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial infarction, angina, or re-

vascularisation. However, there was an increased risk of stroke in those in the hormone therapy arm for combined

primary and secondary prevention (RR 1.24, 95% CI 1.10 to 1.41). Venous thromboembolic events were increased

(RR 1.92, 95% CI 1.36 to 2.69), as were pulmonary emboli (RR 1.81, 95% CI 1.32 to 2.48) on hormone therapy

relative to placebo.

38

Heidi D Nelson. “Commonly Used Types of Postmenopausal Estrogen for Treatment of Hot Flashes.” JAMA

2004 (291): 1610-1620.

All 8 trials of oral CEE reported statistically significant improvements in hot flash frequency, severity, or both

compared with placebo (Table 1, Table 7, Table 8).20,42-48 Three trials included treatment groups with

concomitant progestin or progesterone use (cyclic and continuous medroxyprogesterone acetate, cyclic micronized

progesterone).42,47,48 One trial compared 3 doses of CEE alone (0.3, 0.45, and 0.625 mg/d) and reported bigger

treatment effects with 0.625mg than 0.45 mg or 0.3 mg (P_.05).48 Differences between estrogen doses were not

found in patients provided with CEE (0.3, 0.45, and 0.625 mg/d) and continuous medroxyprogesterone acetate

(1.5 or 2.5 mg/d) in this trial.48

Lethaby A, Hogervorst E, Richards M, Yesufu A, and Yaffe K. “Hormone replacement therapy for cognitive

function in postmenopausal women (Review).” The Cochrane Library (2015).

Meta-analyses showed no effects of either ERT or HRT on prevention of cognitive impairment after five and four

years of treatment, respectively (odds ratio 1.34, 95% CI 0.95 to 1.9; odds ratio 1.05, 95% CI 0.72 to 1.54

respectively) (trend favouring control in both instances). Analyses assessing the effects of treatment over time found

that both ERT and HRT did not maintain or improve cognitive function and may even adversely affect this outcome

(WMD = -0.45, 95% CI -0.99 to 0.09;WMD = -0.16, 95% CI -0.58 to 0.26, respectively at maximum follow up).

Negative effects were found for ERT after one year and HRT after three and four years of therapy. Results from

smaller trials assessing effects onindividual cognitive domains mostly reported no evidence of benefit.

Suckling JA, Kennedy R, Lethaby A, Roberts H. “Local oestrogen for vaginal atrophy in postmenopausal

women (Review).” The Cochrane Library (2010).

The vaginal oestrogen ring was significantly more effective than placebo in reducing the following symptoms of

vaginal atrophy: dyspareunia, pallor, friability, pruritis and dryness. The oestrogen vaginal tablets, when compared

to the ring and placebo, were significantly more effective for reducing the symptoms of dyspareunia, frequency,

dryness and burning and itching. Vaginal oestrogen cream was significantly effective for reducing vaginal dryness,

vaginal moisture, vaginal fluid volume and elasticity when compared to moisturizing gel. When the ring was

compared to the cream there were no noted significant differences. The cream (conjugated equine oestrogen), when

39

compared with the tablets (17B-oestradiol), was the only treatment with any reported significant adverse effects

(uterine bleeding, breast pain and perineal pain). These results should be viewed with caution as they are based on

the results of two trials. Although not statistically significant, there were cases of hyperplasia and endometrial

overstimulation with the ring, cream and tablets (17B-oestradiol). This raises the question of whether women need

progestogenic protection from possible vaginal absorption of oestrogen from the ring, cream or tablets when used

beyond six months.

Menopause; Amie J. Cullimore, Bed, MD, MSc, FRCSC. e-CPS. Date of Revision: July 2015.

Class Drug Dosage Adverse Effects Comments Cost

Estrogens, oral Conjugated estrogens

Premarin

0.3-1.25mg daily Bloating, headache,

nausea, chloasma,

breast tenderness,

breakthrough

bleeding/spotting.

Increased risk of VTE,

CVD, breast cancer

Administer with a

progestogen in

patients with

intact uterus to

prevent

endometrial

hyperplasia or

cancer.

Consider vaginal

estrogen for

patients with

vaginal

symptoms only.

$