medicines management programme: preferred drugs · icgp irish college of general practitioners imb...

Medicines Management Programme: Preferred Drugs

Selective Serotonin Reuptake Inhibitors (SSRIs) & Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)

for the Treatment of Depression

Approved by Prof. Michael Barry, Clinical Lead, MMP.

7th March 2014 Date approved

Version 1

Table of Contents 1. Background .................................................................................................................. 1 2. Aim ............................................................................................................................... 1 2.1 Definitions .............................................................................................................. 2

3. Preferred Drugs............................................................................................................ 2 3.1 Preferred SSRI ........................................................................................................ 2 3.2 Preferred SNRI........................................................................................................ 2

4. Therapeutic Indications ............................................................................................... 2 4.1 Depression ............................................................................................................. 2 4.2 Generalised Anxiety Disorder ................................................................................ 3 4.3 Additional anxiety‐related disorders ..................................................................... 3

5. Selection Criteria.......................................................................................................... 4 5.1 Efficacy ................................................................................................................... 4 5.1.1 Comparative efficacy ‐ SSRIs ........................................................................... 5 5.1.2 Comparative efficacy – SNRIs ......................................................................... 7

5.2 Adverse Effect Profile............................................................................................. 8 5.2.1 Adverse Effect Profile – SSRIs ......................................................................... 8 5.2.2 Adverse Effect Profile – SNRIs......................................................................... 9 5.2.3 Safety .............................................................................................................. 9

5.3 Drug Interactions ................................................................................................. 11 5.3.1 Drug Interactions ‐ SSRIs............................................................................... 11 5.3.2 Drug Interactions ‐ SNRIs .............................................................................. 12

5.4 Cost ...................................................................................................................... 14 5.4.1 Cost ‐ SSRIs .................................................................................................... 14 5.4.2 Cost ‐ SNRIs ................................................................................................... 16 5.4.3 Cost ‐ Summary............................................................................................. 16

5.5 Prescribing trends in Ireland................................................................................ 16 5.5.1 Market share................................................................................................. 17 5.5.2 Dose .............................................................................................................. 18

5.6 Clinical Guidance................................................................................................. 19 6. Summary .................................................................................................................... 20 7. Conclusion.................................................................................................................. 23 8. References ................................................................................................................. 24 9. Bibliography ............................................................................................................... 29 Appendix 1 Prescribing tips............................................................................................ 31 List of Tables Table 1 Pharmacokinetic properties of SSRIs & SNRIs................................................... 13 Table 2 Clinical Guidelines/Recommendations ............................................................. 19

Table of figures Figure 1 Cost of SSRIs & SNRIs per item dispensed (2013)............................................ 15 Figure 2 Reimbursement cost per month (defined daily dose)..................................... 15 Figure 3 SSRI market share (GMS 2012) ........................................................................ 17 Figure 4 Number of prescriptions dispensed for SSRIs and SNRIs on GMS in 2012...... 17 Figure 5 Average number of patients taking SSRIs and SNRIs during 2012 .................. 18

List of abbreviations

ACP American College of Physicians

APA American Psychiatric Association

BAP British Association of Psychopharmacology

CYP450 Cytochrome P450

DDD Defined daily dose

DPS Drug Payment Scheme

EMA European Medicines Agency

GAD Generalised Anxiety Disorder

GDP Gross Domestic Product

GMS General Medical Service

GP General Practitioner

HAM‐D Hamilton Rating Scale for Depression

HSE Health Service Executive

ICGP Irish College of General Practitioners

IMB Irish Medicines Board

MADRS Montgomery‐Asberg Depression Rating Scale

MAOI Monoamine oxidase inhibitor

MCID Minimum Clinically Important Difference

MHRA Medicines and Healthcare products Regulatory Agency

MMP Medicines Management Programme

NICE National Institute for Health and Care Excellence

OCD Obsessive Compulsive Disorder

OECD Organisation for Economic Co‐operation and Development

PCRS Primary Care Reimbursement Service

PTSD Post‐traumatic stress disorder

RCT Randomised controlled trial

SNRI Serotonin noradrenaline reuptake inhibitor

SSRI Selective serotonin reuptake inhibitor

TCA Tricyclic antidepressant

TdP Torsade de pointes

- 1 -

1. Background

Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake

inhibitors (SNRIs) are routinely prescribed in the community to treat a range of mental

health disorders including depression, generalised anxiety disorder (GAD), obsessive

compulsive disorder (OCD), social anxiety disorder, panic disorder, post‐traumatic

stress disorder (PTSD) and bulimia nervosa.

These conditions vary considerably in complexity and severity but in many cases are

managed in the community by general practitioners (GPs). Antidepressant drugs such

as SSRIs and SNRIs are frequently prescribed as part of a broader treatment plan

involving psychological therapy.

There are currently six SSRIs and two SNRIs authorised in Ireland.1 In 2013 there were

in excess of 1.6 million prescriptions for SSRIs and approximately 700,000

prescriptions for SNRIs dispensed on the community drug schemes, the General

Medical Service (GMS) and the Drug Payment Scheme (DPS).2 In any month, over

110,000 patients are expected to be treated with an SSRI and over 40,000 patients

treated with an SNRI. These drug classes represent a considerable cost to the health

system, in excess of €55 million in 2013.2

2. Aim

The Medicines Management Programme (MMP) conducted a review of SSRIs and

SNRIs as part of the Preferred Drugs initiative. The selection of a preferred SSRI and

SNRI under the MMP is designed to support prescribers in choosing a medicine of

proven safety, efficacy and cost effectiveness in the management of patients with

depression.

As with previous MMP Preferred Drugs initiatives, prescribers are encouraged to

consider these preferred drugs when initiating SSRI and SNRI therapy, and when

switching from another antidepressant when a change in drug treatment is indicated.

This guidance is not applicable to all patient populations, e.g. adolescents or patients

with resistant depression, in which cases specialist advice may be sought.

- 2 -

2.1 Definitions

For the purposes of this report, major depressive disorder, depressive disorder and

unipolar depression are hence referred to as depression.

3. Preferred Drugs

3.1 Preferred SSRI

Under the MMP, the preferred SSRI is CITALOPRAM.

3.2 Preferred SNRI

Under the MMP, the preferred SNRI is VENLAFAXINE.

4. Therapeutic Indications

4.1 Depression

The focus of this guidance is the pharmacological treatment of depression, which is

commonly treated in primary care.3 The six SSRIs and two SNRIs reviewed as part of

this evaluation are licensed in the treatment of depression.4‐11

The severity of depression at which antidepressants show consistent benefits over

placebo is poorly defined.12 Antidepressants are generally recommended as first‐line

treatment in patients whose depression is of at least moderate severity.12, 13 Of this

group, approximately 50% will respond to antidepressant drug treatment.12

SSRIs are well tolerated compared to older classes of antidepressants, i.e. tricyclic

antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), and are usually

recommended as first‐line pharmacological treatment for depression.12‐14 There is

evidence that SNRIs are less well tolerated than SSRIs but better tolerated than

TCAs.12

- 3 -

4.2 Generalised Anxiety Disorder

SSRIs are considered the first line treatment for GAD, 13, 15 however, the treatment of

GAD is not the focus of this evaluation. In patients with GAD, co‐existing depressive

symptoms are common and many patients simultaneously fulfil diagnostic criteria for

anxiety and depressive disorders.16

Where anxiety symptoms are present within the context of a depressive disorder,

drug treatment of the depression is effective in improving anxiety. Clinical practice has

been to direct treatment towards the depressive disorder in the first instance,

choosing treatments that also have action against the symptoms of the anxiety

disorder.16

Where GAD occurs without co‐existing depression, prescribers should consider a

suitable, licensed SSRI for its treatment.

4.3 Additional anxiety‐related disorders

While SSRIs are considered the first line pharmacological treatment for a range of

other related illnesses, e.g. OCD, social anxiety disorder and PTSD, these conditions

are not the focus of this guidance.

- 4 -

5. Selection Criteria

Six key criteria were considered in the selection process:

1. Efficacy

2. Adverse Effect Profile

3. Drug Interactions

4. Cost

5. Prescribing trends

6. Clinical guidelines

Submissions from relevant stakeholders, including the pharmaceutical industry and

clinician groups, were sought and considered in the evaluation process.

5.1 Efficacy

All licensed SSRIs and SNRIs have been shown to be effective in relieving the

symptoms of depression in placebo‐controlled clinical trials of varying duration.

However, the selective nature of the study populations, differences in clinical trial

design, including patient characteristics, make meaningful comparisons between

clinical trial results difficult.17 Systematic reviews and meta‐analyses utilise pooled

data from clinical trials and provide an additional means of assessing the general and

comparative efficacy of SSRIs and SNRIs.

Randomised controlled trials (RCTs) in depression generally use a 50% reduction in

depression rating scale scores, e.g. the Montgomery‐Asberg Depression Rating Scale

(MADRS), the Hamilton Rating Scale for Depression (HAM‐D), as the primary outcome

measure.12 When discussing the results of clinical trials in depression, the issue of

clinically meaningful differences becomes essential: a statistically significant difference

in outcome does not necessarily correspond to a clinically important difference in

outcome.

The issue of clinically important differences was addressed by Duro et al (2008), who

sought to determine the clinical relevance of changes in the MADRS using the

Minimum Clinically Important Difference (MCID) approach.

- 5 -

The MCID of the MADRS was estimated using data from three RCTs, and cross‐

validated using data from an observational study. From these analyses, estimates of

the MCID threshold for MADRS were found to range from 1.6 to 1.9.18 The MMP

considered the MCID threshold of 1.6 to 1.9 when reviewing comparative studies of

SSRIs and SNRIs that used a change in the MADRS as the primary outcome measure.

Similarly, where a change in the HAM‐D scale is used as the primary outcome

measure, it has been proposed that a 2‐point difference on this scale represents a

clinically meaningful difference in short‐term clinical trials.19

Where available, the less frequently used outcome measures response rate and

remission rate were also considered in the context of clinical efficacy. Response rate

refers to the proportion of patients achieving a ≥ 50% reduction in depression rating

score from baseline.16 Remission rate refers to the proportion of patients experiencing

minimal or an absence of major depressive symptoms, or a depression score within

normal, ‘non‐depressed’ range, e.g. MADRS 11‐13.16

5.1.1 Comparative efficacy ‐ SSRIs

A meta‐analysis of 234 studies of 2nd generation antidepressants (including the SSRIs

and SNRIs) conducted on behalf of the Agency for Healthcare Research and Quality in

the USA, determined that overall, treatment effects were similar among the SSRIs and

SNRIs.20 Meta‐analyses of head‐to‐head trials showed statistically greater response

rates for escitalopram than citalopram, and sertraline than fluoxetine. However, the

report concluded that absolute differences were modest and probably not clinically

relevant. For example, the pooled difference between escitalopram and citalopram in

the reduction of points on the MADRS was 1.52 in favour of escitalopram,20 which is

below that which the MMP considers to be the lower limit of clinical importance in

depression, i.e. 1.6‐1.9 MADRS points.18 These findings support the results of an

earlier review of 46 RCTs which evaluated the efficacy, effectiveness and tolerability of

commonly prescribed 2nd generation antidepressants and concluded that overall,

these antidepressants do not differ substantially for the treatment of depression.21

- 6 -

The MANGA study, a meta‐analysis of 117 comparative RCTs of antidepressants for

the acute treatment of depression in adults, concluded that escitalopram and

sertraline are statistically more efficacious than fluoxetine, fluvoxamine and

paroxetine.22 The main outcome measures were the proportion of patients who

responded to or withdrew from treatment. Reductions in MADRS/HAM‐D for

individual drugs are not reported.22 It assumed that a response on the HAM‐D equals a

response on MADRS.20, 23

The MANGA study has been criticised in some quarters on the basis that it included

studies with a high risk for bias and open‐label designs, and excluded placebo‐

controlled trials.20, 24 It has been advised that these results should be interpreted with

caution.12

A number of analyses of escitalopram versus other SSRIs for the treatment of

depression were reviewed.

An analysis of the comparative efficacy of escitalopram and citalopram showed a

difference in favour of escitalopram.25 The difference was modest, however, with

weighted mean differences ranging from 1.13 to 1.73 MADRS points. The MMP’s

view is that this difference is, at most, borderline for clinical importance in the

treatment of depression.

In a meta‐analysis of 16 RCTs the mean treatment difference was 0.9 MADRS

points for patients treated with escitalopram compared to other SSRIs.26 This is

below that which the MMP considers clinically important. With regard to specific

SSRIs, the difference was statistically significant only versus citalopram (1.2

MADRS points) but was below that which the MMP considers to be the limit of

clinical importance.

- 7 -

A series of Cochrane reviews explored the efficacy and tolerability of several SSRIs vs.

other antidepressants.27‐31 Efficacy was measured in terms of acute response and

remission. While there were differences between SSRIs in terms of clinical

outcomes/benefit, these differences were modest and in most cases, were only

statistically significant during specific phases of treatment, e.g. in the period from 6 to

12 weeks of treatment. As the treatment of a first episode of depression with an SSRI

is recommended to continue for at least 6 months, 12, 14, 32 the MMP takes the view

that these differences are of little importance clinically.

Following a comprehensive review of the literature and submissions from

stakeholders, the MMP has concluded that the clinical efficacy of individual SSRIs in

treating adults with depression does not differ substantially. Therefore,

recommending a particular SSRI on the basis of clinical efficacy is not warranted.

5.1.2 Comparative efficacy – SNRIs

The balance of evidence suggests that venlafaxine and duloxetine have similar efficacy

in the treatment of depression, though information is limited. Pooled data from two

virtually identical head‐to‐head RCTs (n=667) found similar response and remission

rates between the two treatments.33

A systematic review and meta‐analysis to explore the general and comparative

efficacy and safety of duloxetine in depression determined that the only available

evidence is that which is referred to above.34

A Cochrane review found no difference between venlafaxine and duloxetine in terms

of clinical efficacy.35

Favoured SNRI ‐ Clinical Efficacy: No preference

Favoured SSRI ‐ Clinical Efficacy: No preference

- 8 -

5.2 Adverse Effect Profile

5.2.1 Adverse Effect Profile – SSRIs

SSRIs share a number of common side‐effects, most notably gastrointestinal (GI) and

sleep disturbances.32 Overall, the SSRIs are broadly similar in terms of adverse effects

though these effects may occur to a lesser or greater extent with certain SSRIs.24

Differences may arise between individual drugs, e.g. diarrhoea, nausea. A large meta‐

analysis found that paroxetine was less well tolerated than escitalopram and

sertraline22 and there is evidence that paroxetine may be associated with more weight

gain and sexual side effects compared to other SSRIs.12

Some SSRIs are associated with particular side effects that may not arise as frequently

with others, e.g. escitalopram/citalopram and a dose‐dependent risk of QT interval

prolongation. A recent review of QT interval prolongation potential among the SSRIs

points to numerous limitations in interpreting available data, not least that most trials

are not designed to examine QT interval changes.36 However, it concludes that current

evidence indicates that QT interval prolongation or the cardiac arrhythmia Torsade de

Pointes (TdP) is reported more frequently with citalopram and escitalopram. Where

the other SSRIs are concerned, QT prolongation and TdP are largely limited to case

reports, though there is evidence that paroxetine has the lowest risk for QT

prolongation of the SSRIs.36

The tolerability of a particular drug is a subjective parameter and can depend very

much on individual patients’ experiences. Furthermore, the inter‐individual variation

in tolerability is not easily predicted by knowledge of a drug’s adverse effect profile.12

In order to determine the tolerability of individual drugs, the MMP considered rates of

withdrawal from clinical trials due to adverse effects, while recognising that such

outcomes are a ‘crude measure of tolerability’.34 Published evidence suggests that

rates of discontinuation due to adverse effects are broadly similar among the

SSRIs.20, 21 Furthermore, analysis of the GMS database confirms little difference in the

discontinuation rate for currently marketed SSRIs in the Irish healthcare setting.2

- 9 -

Discontinuation symptoms were also considered in the review process. Where

possible, SSRIs and SNRIs should be not stopped abruptly but should be withdrawn

following a gradual dose reduction over a period of at least 4 weeks.32, 27 Paroxetine is

associated with a greater risk of discontinuation effects relative to other SSRIs.12, 32

5.2.2 Adverse Effect Profile – SNRIs

The evidence suggests that SNRIs are less well tolerated than SSRIs.12, 32, 38 In clinical

trials, more patients withdrew from duloxetine than venlafaxine because of adverse

effects.39 A Cochrane review comparing duloxetine to other antidepressants for the

treatment of depression found that duloxetine was less acceptable and less well

tolerated than venlafaxine.35

Evidence comparing venlafaxine and duloxetine in terms of discontinuation symptoms

is limited. However, venlafaxine is generally regarded as having a higher relative risk of

discontinuation symptoms. 12, 32

5.2.3 Safety

The use of antidepressants has been linked with suicidal thoughts and behaviour.

Younger adults (<25 years) with a history of suicidal behaviour are at particular risk.

Where necessary, patients should be monitored for suicidal behaviour, self‐harm or

hostility, particularly in the early stages of treatment and following dose changes.32

Over the last number of years the Irish Medicines Board (IMB), the UK Medicines and

Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency

(EMA) have issued warnings about the safety of some antidepressants, including SSRIs

and SNRIs.40‐42 While undertaking this review, we remained cognisant of these safety

warnings.

- 10 -

5.2.3.1 Citalopram & Escitalopram and risk of QT interval prolongation (IMB, 2011):

Dose dependent prolongation of the QT interval.

Co‐administration with other drugs known to prolong the QT interval is

contraindicated.

Contraindicated in patients with known QT interval prolongation.

Maximum daily dosages now apply to patients > 65 years.

5.2.3.2 Dose related toxicity of venlafaxine (UK MHRA, 2006):

Retrospective analysis of UK data found that the rate of overdose‐related

death for venlafaxine is higher than that for SSRIs.

Caution is advised in patients with pre‐existing cardiac abnormalities that

may increase the risk of ventricular arrhythmias.

The SmPCs of venlafaxine preparations authorised in Ireland contain

warnings in relation to cardiac arrhythmias and suicidal behaviour.

5.2.3.3 Paroxetine & increased risk of suicide in children/adolescents & risk of

withdrawal symptoms (EMA, 2004):

Paroxetine is not to be used in children/adolescents

Monitoring required for patients at risk of suicide

Withdrawal effects are usually mild‐moderate and self‐limiting but in some

cases can be severe and/or prolonged.

Favoured SSRI – Adverse Effect Profile: No preference

Favoured SNRI – Adverse Effect Profile: Venlafaxine

- 11 -

5.3 Drug Interactions

There is a reciprocal relationship between physical and mental health.3 Chronic or

numerous physical illnesses have an increased association with poor mental health.43

Patients with conditions requiring drug treatment, e.g. diabetes and heart failure, are

more likely to suffer chronic depression compared to their healthier counterparts.43, 44

Consequently, the potential for drug‐drug interactions must be borne in mind when

selecting a preferred drug. Antidepressant drugs with less potential for drug‐drug

interactions are preferred.

Particular focus was placed on the potential for pharmacokinetic interaction with

other drugs. Drugs with cytochrome P450 (CYP450)‐inhibiting or inducing properties

have greater potential for drug interactions and are, therefore, less favoured with

regard to drug interactions (Table 1).

5.3.1 Drug Interactions ‐ SSRIs

SSRIs have a common mechanism of action and generally, therefore,

pharmacodynamic interactions with other drugs are likely to occur with all SSRIs, e.g.

all SSRIs are contraindicated in combination with monoamine oxidase inhibitors

(MAOIs) due to a risk of serotonin syndrome, and there is an increased risk of upper GI

bleeding when aspirin is administered with SSRIs.32 However, fluoxetine, fluvoxamine,

and paroxetine have a higher propensity for pharmacokinetic drug interactions than

other SSRIs (Table 1).14

There is potential for QT interval prolongation when citalopram or escitalopram is

administered with drugs that prolong the QT interval.40 While this potential exists for

the other SSRIs, cases of QT interval prolongation and TdP are largely limited to case

reports,36 as discussed in section 5.2.1.

- 12 -

An analysis of all citalopram and escitalopram prescriptions reimbursed on the GMS

and DPS for a 12‐month period determined that the rate of co‐prescribing of

citalopram or escitalopram with drugs that have potential to prolong the QT interval(a)

is currently low.2

Approximately 6% of patients on citalopram received at least one prescription

for a QT‐interacting drug.

Approximately 5% of patients on escitalopram received at least one

prescription for a QT‐interacting drug.

In both cases, tricyclic antidepressants (TCAs) accounted for the majority (3‐3.5%

overall) of these prescriptions. Quinine accounted for 1% overall in both cases.2

5.3.2 Drug Interactions ‐ SNRIs

Available evidence suggests that there is little difference between venlafaxine and

duloxetine in terms of potential for drug interactions.

Table 1. Pharmacokinetic properties of SSRIs & SNRIs

Effect on cytochrome P450 (potential for drug‐drug interactions) Elimination half‐life (hr) SSRI

Minimal effect4 36 Citalopram

Minimal effect5 30 Escitalopram

Fluoxetine Norfluoxetine (active metabolite)

Potent inhibitor of CYP2D66 4‐6 days. Norfluoxetine: 4‐16 days.

Potent inhibitor of CYP1A2; lesser inhibitor of CYP2C2 & 3A47 17‐22 Fluvoxamine

Potent inhibitor of CYP2D68 24 Paroxetine

Mild‐moderate inhibitor of CYP2D69 26 Sertraline

Effect on cytochrome P450 (potential for drug‐drug interactions) Elimination half‐life (hr) SNRI

Moderate inhibitor of CYP2D6; metabolised by CYP1A210 12 Duloxetine

Metabolised by CYP2D6 & 3A411 5‐11 Venlafaxine

Favoured SSRIs – Drug Interactions: citalopram, escitalopram, sertraline

Favoured SNRI – Drug Interactions: No preference

(a): Drugs included in the analysis of citalopram and escitalopram prescriptions over a 12‐month period: 4, 5, 32 Lidocaine, flecainide, quinidine (class IA antiarrhythmics); amiodarone, dronedarone, sotalol (class III antiarrhythmics); pimozide, haloperidol (antipsychotics); amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, trimipramine (tricyclic antidepressants); moxifloxacin (quinolone); halofantrine (anti‐malarial); astemizole, mizolastine (antihistamines); amisulpiride, sertindole (antipsychotics, atypical); quinine (anti‐malarial/leg cramps).

- 13 -

- 14 -

5.4 Cost

The direct and indirect costs associated with depression are high. In 2008, the OECD

reported that 21 million people in 28 European countries had depression, with an

associated cost of more than €118 billion, 1% of the region’s GDP.45

Antidepressants are just one of the many direct costs associated with depression. The

cost of direct healthcare provision, e.g. hospitalisation, for those who require it

represents another direct cost.45

The personal cost of depression is significant and can severely impact on home and

family life, interpersonal relationships and employment. Indirect costs arising from

lost work productivity, absenteeism and disability allowances account for much of the

economic burden of depression.45

The MMP recognises the complex and multi‐faceted nature of the costs associated

with depression. However, in the absence of a mixed treatment cost‐effectiveness

analysis specific to the Irish healthcare setting, the MMP compared the drug

acquisition cost of individual agents.46 The position of the MMP is that in general, the

cheaper of two drugs is preferred unless the more expensive drug has a clear and

proven advantage in terms of clinical efficacy, adverse effect profile and potential for

drug interactions.

5.4.1 Cost ‐ SSRIs

There is a considerable cost differential between individual SSRIs (Figure 1, Figure 2).

The most expensive SSRI, escitalopram, is more than twice the price of the cheapest

SSRI, fluoxetine, based on the cost per item dispensed(b) 2, 47 and the reimbursement

price of the defined daily dose (DDD) 47 (February 2014 prices). With the exception of

escitalopram (Lexapro®), all SSRIs are now off patent and available in generic form.

The patent for Lexapro® will expire in 2014.2

(b): Cost per item dispensed: the average drug cost paid by the HSE per item per month, taking into account dose range, dispensing fees and, where applicable, mark‐up.

- 15 -

Cost per item dispensed

13.24

29.52

12.86

22.216.18

23.42

42.31

22.34

05

1015202530354045

Citalop

ram

Escita

lopr

am

Fluoxe

tine

Fluvox

amine

Paroxe

tine

Sertra

line

Duloxetin

e

Venlaf

axine

Eu

ro

Figure 1 Cost of SSRIs & SNRIs per item dispensed (2013)2

Reimbursement cost per month (Defined Daily Dose)

6.83

20.7

5.21

13.98

6.91

12.87

35.46

17.88

05

10152025303540

Citalop

ram

Escita

lopr

am

Fluoxe

tine

Fluvox

amine

Paroxe

tine

Sertra

line

Duloxetin

e

Venlaf

axine

Eu

ro

Figure 2 Reimbursement cost per month (DDD) of the cheapest available preparation (Feb 2014) (c) 46

A number of studies in depression have focused on the cost‐effectiveness of

escitalopram relative to other antidepressants.48‐50 A UK cost‐effectiveness study in

which escitalopram was compared to generic SSRIs for the treatment of severe

depression found no significant difference between the total annual healthcare costs

with escitalopram and generic SSRIs.50 A pharmacoeconomic study conducted in

France which found escitalopram to be a more cost‐effective treatment for severe

depression than citalopram (MADRS >30) assumed parity between drug treatment

costs,48 i.e. the cost of escitalopram was assumed to be the same as that of

citalopram. As this is not the case in Ireland, this conclusion cannot be applied to the

Irish healthcare setting.

(c): A preparation containing the DDD of venlafaxine (100 mg) is not available on the Irish market. The above figure relates to the cheapest available venlafaxine 150 mg XL preparation.

- 16 -

5.4.2 Cost ‐ SNRIs

Duloxetine (Cymbalta®) is still under patent protection whereas venlafaxine is

available in generic form. Therefore, a significant price difference exists. Duloxetine is

generally €15‐20 more expensive per month than venlafaxine.

5.4.3 Cost ‐ Summary

In the case of SSRIs and SNRIs, the MMP takes the view that where one drug is more

expensive than another, the increased cost should be justified in terms of clinical

efficacy and tolerability. Significantly increased cost should correspond to significantly

better clinical outcomes for more patients.

As discussed in section 5.1, the view of the MMP is that the evidence does not support

the existence of meaningful differences between the SSRIs in terms of clinical efficacy.

Therefore, choosing a medication of considerably higher acquisition cost, e.g.

sertraline and escitalopram, for the MMP Preferred Drugs initiative is not justified.

Equally, the superiority of duloxetine over venlafaxine has not been demonstrated in

clinical trials and consequently, choosing an SNRI with a relatively high acquisition cost

is not justified.

Favoured SSRIs ‐ Cost: Fluoxetine, citalopram

Favoured SNRI ‐ Cost: Venlafaxine

5.5 Prescribing trends in Ireland

Prescribing trends are an important criterion. The MMP recognises that clinical

experience is an important factor for prescribers when choosing a medication to

prescribe. A drug that is rarely prescribed is at a disadvantage as clinical experience

among prescribers may be lacking.

- 17 -

5.5.1 Market share

Escitalopram and venlafaxine are the most frequently prescribed SSRI and SNRI in

Ireland, respectively (figure 5). Citalopram is the second most frequently prescribed

SSRI.2

Market share (SSRIs)

Citalopram

21%

Escitalopram

42%

Fluoxetine

12%

Fluvoxamine

0%

Paroxetine

8%

Sertraline

17%

Figure 3 SSRI market share (percent) (GMS 2012)

Figure 3 and Figure 4 depict the overall prescribing figures for SSRIs and SNRIs on the

GMS in 2012.2 At the time of publication, complete 2013 data were not yet available

to the MMP. As indication‐specific data are not recorded by PCRS, a proportion of

these prescriptions may relate to the treatment of other licensed indications, e.g. GAD

in the cases of escitalopram, paroxetine and venlafaxine, and diabetic neuropathy in

the case of duloxetine.

Number of Prescriptions Dispensed

0

100000

200000

300000

400000

500000

600000

700000

Citalop

ram

Escita

lopr

am

Fluoxe

tine

Fluvox

amine

Paroxe

tine

Sertra

line

Venlaf

axine

Duloxetin

e

Figure 4 Number of prescriptions dispensed for SSRIs and SNRIs on the GMS in 2012

- 18 -

Average Number of Patients taking SSRI/SNRI

05000

1000015000200002500030000350004000045000

Citalop

ram

Escita

lopr

am

Fluoxe

tine

Fluvox

amine

Paroxe

tine

Sertra

line

Venlaf

axine

Duloxetin

e

Figure 5 Average number of patients taking SSRIs and SNRIs during 2012

5.5.2 Dose

Adequate doses are needed for clinical effect in depression.12, 37 However,

antidepressant therapy is dosed according to clinical response and the patient’s ability

to tolerate a drug rather than to target.12 It is not necessary to increase doses

maximally in order to achieve maximal therapeutic benefit, as may be the case with

other drug classes. The lowest effective dose of an SSRI is recommended. 12, 51 For

these reasons, the MMP’s view is that prescribed doses of SSRIs and SNRIs are not an

indicator of prescribing quality.

Favoured SSRIs – Prescribing Trends: Escitalopram & citalopram

Favoured SNRI – Prescribing Trends: Venlafaxine

5.6 Clinical Guidance

Table 2. Clinical Guidelines/Recommendations

Clinical Guidelines

Group Guideline Recommended Drug (if applicable)

Excerpt/Comment

Irish College of General Practitioners (in collaboration with the HSE)

Guidelines for the Management of Depression and Anxiety Disorders in Primary Care (2006)13

SSRI: No preference SNRI: No preference

‘Consider generic form of SSRI’. ‘Sertraline is the treatment of choice when initiating treatment in a patient with ischaemic heart disease’.

National Institute for Health &Care Excellence (NICE) (UK)

Clinical Guideline No. 90: Treatment and Management of Depression in Adults (2009)52


‘While escitalopram has been found to be more effective than citalopram, the difference, though statistically significant, is unlikely to be clinically important’.

British Association for Psychopharmacology

Treating Depressive Disorders with Anti‐depressants (2008)16


‘Systematic reviews and meta‐analyses suggest that the commonly available antidepressants have comparable efficacy in the majority of patients seen in primary care’. ‘……at a dose of 20 mg escitalopram appears to be [marginally more effective] for severely ill patients’.

American College of Physicians

Using 2nd‐Generation Antidepressants to Treat Depressive Disorders (2008)53


‘The available evidence does not support clinically significant differences in efficacy, effectiveness, or quality of life among SSRIs, SNRIs for the treatment of acute‐phase major depressive disorder’.

American Psychiatric Association

Practice Guideline for the Treatment of Patients With Major Depressive Disorder,Third Edition (2011)54


‘For most patients, the effectiveness of antidepressant medications is generally comparable between classes and within classes of medications”’.

Practice Guidelines

NICE Clinical Knowledge Summaries (CKS)

Depression (August 2013)14 SSRI: Citalopram, fluoxetine, paroxetine, sertraline. SNRI: No preference

If it is the first episode, prescribe one of listed the SSRIs. In the case of a recurrent episode consider what worked/did not work in the past.

Maudsley Prescribing Guidelines 11th edition

Depression (2012)12 SSRI: No preference SNRI: No preference

- 19 -

- 20 -

6. Summary

The following summaries are based on the evidence reviewed and represent the

views of the MMP. Further details and references may be found in the relevant

sections of the evaluation.

Citalopram

Citalopram has comparable efficacy to the other SSRIs. Citalopram is well tolerated and has a favourable pharmacokinetic profile, with limited potential for drug‐drug interactions. Citalopram is the second least expensive SSRI on the Irish market, but is marginally more expensive than fluoxetine. The MMP Preferred Drugs Initiative takes the view that of the available SSRIs, citalopram achieves the best balance between efficacy, adverse effect profile, potential for drug interactions, cost, and other important criteria considered

Citalopram has comparable efficacy to the other SSRIs.

Citalopram is well tolerated and has a favourable pharmacokinetic profile, with limited potential for drug‐drug interactions.

Citalopram is the second least expensive SSRI on the Irish market, but is marginally more expensive than fluoxetine.

The MMP Preferred Drugs Initiative takes the view that of the available SSRIs, citalopram achieves the best balance between efficacy, adverse effect profile, potential for drug interactions, cost, and other important criteria considered as part of the evaluation

On this basis, citalopram has been selected as the preferred SSRI.

Escitalopram

Escitalopram has comparable efficacy to the other SSRIs. While limited evidence suggests that it may be marginally more effective than some SSRIs, differences in efficacy are modest and below that which the MMP considers clinically relevant. Furthermore, statistically superior efficacy was demonstrated for the most part in RCTs of short duration, usually 8 weeks. Antidepressant treatment is generally recommended to continue for at least 6 months. The clinical superiority of esc

italopram over these longer treatment periods has not been demonstrated. Escitalopram is well tolerated and has a favourable pharmacokinetic profile, with limited potential for drug interactions. Escitalopram is the most expensive SSRI in Ireland. The MMP takes the view that the increased cost of escitalopram relative to other SSRIs is not justified

file

in terms of increased clinical efficacy, more favourable adverse effect pro

Escitalopram has comparable efficacy to the other SSRIs.

While limited evidence suggests that it may be marginally more effective than some SSRIs, differences in efficacy are modest and below that which the MMP considers clinically relevant. Furthermore, statistically superior efficacy was demonstrated for the most part in RCTs of short duration, usually 8 weeks. Antidepressant treatment is generally recommended to continue for at least 6 months. The clinical superiority of escitalopram over these longer treatment periods has not been demonstrated.

Escitalopram is well tolerated and has a favourable pharmacokinetic profile, with limited potential for drug interactions.

Escitalopram is the most expensive SSRI in Ireland. The MMP takes the view that the increased cost of escitalopram relative to other SSRIs is not justified in terms of increased clinical efficacy, more favourable adverse effect profile or potential for drug interactions.

On this basis, escitalopram has not been selected as the preferred SSRI.

- 21 -

Fluoxetine

Fluoxetine has comparable efficacy to the other SSRIs in the treatment of depression.

It is the least expensive SSRI & the 4th most frequently prescribed SSRI.

Its CYP2D6‐inhibiting effect makes drug interactions more likely and its long half‐life (and the long half‐life of its active metabolite, norfluoxetine) may necessitate longer ‘wash out’ periods when changing antidepressant treatments, due to the continued potential for drug interactions following fluoxetine withdrawal.

On this basis, fluoxetine has not been selected as the preferred SSRI.

Fluvoxamine

Despite evidence of comparable efficacy to other SSRIs, there is limited clinical experience with fluvoxamine in Ireland and it is rarely prescribed. It is among the more expensive SSRIs. Like fluoxetine, fluvoxamine has considerable potential for drug interactions due to its CYP2D6‐inhibiting effect.

On this basis, fluvoxamine has not been selected as the preferred SSRI.

Paroxetine

On this basis, paroxetine has not been selected as the preferred SSRI.

Paroxetine has comparable efficacy to the other SSRIs and compares favourably to escitalopram, fluvoxamine and sertraline on the basis of cost. Paroxetine is prescribed less frequently than the other SSRIs with the exception of fluvoxamine.

Its pharmacokinetic profile makes it more likely to interact with co‐prescribed medications and its short half‐life increases the risk of discontinuation effects.

Sertraline

Sertraline is the 3rd most frequently prescribed SSRI in Ireland, and has comparable efficacy to the other SSRIs. Though limited evidence suggests that sertraline may be more effective than some SSRIs, the MMP takes the view that this increased efficacy is unlikely to be important clinically.

Sertraline has a favourable drug interaction profile and safety in cardiac disease. However, the acquisition cost of sertraline is considerably higher than most other SSRIs, e.g. fluoxetine, citalopram. It is the view of the MMP that this increased cost is not justified in terms of clinical efficacy, adverse effect profile or potential for drug interactions.

On this basis, sertraline has not been selected as the preferred SSRI.

- 22 -

Venlafaxine

Duloxetine

Venlafaxine is less expensive than duloxetine, which remains under patent protection.

On this basis, venlafaxine has been selected by the MMP as the preferred SNRI.

The evidence suggests duloxetine has comparable efficacy to venlafaxine in the treatment of depression. However, in RCTs and subsequent meta‐analyses, duloxetine was found to be less well tolerated than venlafaxine.

Duloxetine remains under patent protection and consequently, is considerably more expensive than venlafaxine.

On this basis, duloxetine has not been selected as the preferred SNRI.

Venlafaxine has comparable efficacy to duloxetine.

Venlafaxine is well tolerated though there is evidence that, in general, the SNRIs are less well tolerated than the SSRIs.

- 23 -

7. Conclusion

Citalopram has a favourable cost profile relative to most SSRIs.

Citalopram is the second most frequently prescribed SSRI,

suggesting considerable clinical experience with its use among

prescribers.

Preferred SSRI: CITALOPRAM

Citalopram has comparable efficacy to other SSRIs.

Citalopram has a comparable or favourable adverse effect

profile compared to other SSRIs.

Citalopram has a favourable drug interaction profile and

pharmacokinetic drug interactions are unlikely.

Venlafaxine is prescribed more frequently than duloxetine

suggesting greater clinical experience with its use.

Preferred SNRI: VENLAFAXINE

Venlafaxine has comparable efficacy to duloxetine.

Venlafaxine has a favourable adverse effect profile relative to

duloxetine, based on the evidence reviewed.

Venlafaxine and duloxetine have similar potential for drug

interactions

Venlafaxine is considerably cheaper than duloxetine

- 24 -

8. References

1. Irish Medicines Board (IMB) – Human Medicines listing. Accessed at www.imb.ie

on 20th February 2014.

2. Health Service Executive (HSE) Primary Care Reimbursement Service (PCRS).

3. Mental Health Reform. Guiding a Vision for Change – Manifesto. Accessed at

www.mentalhealthreform.ie on 20th February 2014.

4. Cipramil® (citalopram) 20 mg film‐coated tablets SmPC. Last revised December

2013. Accessed at www.imb.ie on 20th February 2014.

5. Lexapro® (escitalopram) 10 mg film‐coated tablets SmPC. Last revised October


6. Prozac® (fluoxetine) 20 mg hard capsules SmPC. Last revised April 2013. Accessed

at www.imb.ie on 20th February 2014.

7. Faverin® (fluvoxamine) 100 mg film‐coated tablets SmPC. Last revised December


8. Seroxat® (paroxetine) 20 mg film‐coated tablets SmPC. Last revised November


9. Lustral® (sertraline) 50 mg film‐coated tablets SmPC. Last revised December


10. Cymbalta® (duloxetine) SmPC. Last revised July 2013. Accessed at

www.ema.europa.eu on 20th February 2014.

11. Efexor® (venlafaxine) XL 150 mg capsules. Last revised September 2013. Accessed

at www.imb.ie on 19th 20th February 2014.

12. Taylor D, Paton C and Kapur S. The South London and Maudsley NHS Foundation

Trust Prescribing Guidelines in Psychiatry. 11th Edition. London: Wiley‐Blackwell,

2012.

13. Copty M on behalf of the Irish College of General Practitioners (ICGP) in

collaboration with the Health Service Executive (HSE). Guidelines for the

Management of Depression and Anxiety in Primary Care, 2006.

14. National Institute of Health and Care Excellence (NICE). Clinical Knowledge

Summary (CKS): Depression, August 2013. Accessed at http://cks.nice.org on 20th

February 2014.

http://www.imb.ie/

http://www.mentalhealthreform.ie/

http://www.imb.ie/

http://www.imb.ie/

http://www.imb.ie/

http://www.imb.ie/

http://www.imb.ie/

http://www.imb.ie/

http://www.ema.europa.eu/

http://www.imb.ie/

http://cks.nice.org/

- 25 -

15. National Institute of Health and Care Excellence (NICE). Clinical Knowledge

Summary (CKS): Generalised Anxiety Disorder, June 2013. Accessed at

http://cks.nice.org on 20th February 2014.

16. British Association for Psychopharmacology. Evidence‐based guidelines for

treating depressive disorders with antidepressants. Journal of

Psychopharmacology 2008; 22(4): 343–396

17. Citalopram for moderate to severe depression. Drugs and Therapeutics Bulletin

2013; 51(5):50.

18. Duro G and Fantino B. The clinical relevance of changes in the Montgomery‐

Asberg depression Rating Scale using the minimum clinically important difference

approach. Current Medical Research 2008; 24(5):1329‐1335.

19. Niklson IA and Reimitz PE. Baseline characteristics of major depressive disorder

patients in clinical trials in Europe and United States: is there a transatlantic

difference? Journal of Psychiatric Research 2001; 35: 71–81.

20. Gartlehner G et al. Comparative benefits and harms of second‐generation

antidepressants for treating major depressive disorder. Annals of Internal

Medicine 2011; 155:722‐785.

21. Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS. Efficacy and safety of

second‐generation antidepressants in the treatment of major depressive

disorder. Annals of Internal Medicine 2005;143(6):415‐426.

22. Cipriani A et al. Comparative efficacy and acceptability of 12 new‐generation

antidepressants: a multiple‐treatments meta‐analysis. Lancet 2009; 373: 746–58.

23. Gartlehner G, Thaler K, Hill S and Hansen RA. How should primary care doctors

select which antidepressants to administer? Current Psychiatry Reports 2012;

14:360‐369.

24. National Prescribing Centre (NPC) Rapid Review No. 283, 25/2/2009. Accessed at

www.evidence.nhs.uk on 20th February 2014.

25. Ali M, Lam RW. Comparative efficacy of escitalopram in the treatment of major

depressive disorder. Neuropsychiatric Disease and Treatment 2011:7 39–49.

26. Kennedy SH, Anderson FH, Thase ME. Escitalopram in the treatment of major

depressive disorder: a meta‐analysis. Current Medical Research and Opinion

2009; 25(1):161‐75.

http://cks.nice.org/

http://www.evidence.nhs.uk/

- 26 -

27. Cipriani A, PurgatoM, Furukawa TA, Trespidi C, Imperadore G, Signoretti A,

Churchill R,Watanabe N, Barbui C. Citalopram versus other anti‐depressive

agents for depression. Cochrane Database of Systematic Reviews 2012, Issue 7.

Art. No.: CD006534. DOI: 10.1002/14651858.CD006534.pub2.

28. Magni LR, Purgato M, Gastaldon C, Papola D, Furukawa TA, Cipriani A, Barbui C.

Fluoxetine versus other types of pharmacotherapy for depression. Cochrane

Database of Systematic Reviews 2013, Issue 7. Art. No.: CD004185. DOI:

10.1002/14651858.CD004185.pub3.

29. Omori IM, Watanabe N, Nakagawa A, Cipriani A, Barbui C, McGuire H, Churchill R,

Furukawa TA. Fluvoxamine versus other anti‐depressive agents for depression.

Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD006114.

DOI: 10.1002/14651858.CD006114.pub2.

30. Cipriani A, La Ferla T, Furukawa TA, Signoretti A, Nakagawa A, Churchill R,

McGuire H, Barbui C. Sertraline versus other antidepressive agents for

depression. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.:

CD006117. DOI: 10.1002/14651858.CD006117.pub4.

31. Cipriani A, Santilli C, Furukawa TA, Signoretti A, Nakagawa A, McGuire H,

Churchill R, Barbui C. Escitalopram versus other antidepressive agents for

depression. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.:

CD006532. DOI: 10.1002/14651858.CD006532.pub2.

32. British National Formulary February 2014. Accessed at

www.medicinescomplete.com on 20th February 2014.

33. Perahia D et al. A randomized, double‐blind comparison of duloxetine and

venlafaxine in the treatment of patients with major depressive disorder. Journal

of Psychiatric Research 2008; 42 : 22–34.

34. Gartlehner G, Thaler K, Hansen RA and Gaynes BN. The general and comparative

efficacy and safety of duloxetine in major depressive disorder. Drug Safety 2009;

32(12):1159‐1173.

35. Cipriani A, Koesters M, Furukawa TA, Nosè M, Purgato M, Omori IM, Trespidi C,

Barbui C. Duloxetine versus other anti‐depressive agents for depression.

Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD006533.

DOI: 10.1002/14651858.CD006533.pub2.

http://www.medicinescomplete.com/

- 27 -

36. Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs.

Annals of Pharmacotherapy 2013; 47: 1330‐1341.

37. Bazire S. Psychotropic Drug Directory 2014. Lloyd‐Reinhold Communications,

Warwickshire, UK.

38. Machado M and Einarson TR. Comparison of SSRIs and SNRIs in major depressive

disorder: a meta‐analysis of head‐to‐head randomized clinical trials. Journal of

Clinical Pharmacy and Therapeutics 2010; 35: 177–188.

39. Schueler Y‐B, Koesters M, Wieseler B et al. (2011) A systematic review of

duloxetine and venlafaxine in major depression, including unpublished data. Acta

Psychiatrica Scandinavica 123: 247–65

40. Irish Medicines Board (IMB) Drug Safety Newsletter, 45th edition. Accessed at

www.imb.ie on 20th February 2014.

41. Medicines and Healthcare products Regulatory Agency (MHRA) – Updated

prescribing advice for venlafaxine, May 2006. Accessed at www.mhra.gov.uk on

20th February 2014.

42. European Medicines Agency (EMA). Questions and Answers on Paroxetine

(EMEA/192942/2004), 9th December 2004. Accessed at www.ema.europa.eu on

20th February 2014.

43. National Institute for Health and Care Excellence (NICE). Clinical Guideline No. 91.

Depression in Adults with a Chronic Physical Health Problem, 2009. Accessed at

www.nice.org.uk on 20th February 2014.

44. Prince M et al. No health without mental health. Lancet 2007; 370: 859‐77.

45. Boland M, Murphy J for the Working Group on Public Health Policy Framework.

The economic argument for the prevention of ill‐health at population level. May

2012. Accessed at www.dohc.ie on 20th February 2014.

46. Primary Care Reimbursement Service (PCRS): Reimbursable Items listing.

Accessed at www.sspcrs.ie on 20th February 2014.

47. World Health Organisation (WHO) Collaborating Centre for Drugs Statistics

Methodology. ATC/DDD Index 2014. Accessed at www.whocc.no on 20th

February 2014.

http://www.imb.ie/

http://www.mhra.gov.uk/

http://www.ema.europa.eu/

http://www.nice.org.uk/

http://www.dohc.ie/

http://www.sspcrs.ie/

http://www.whocc.no/

- 28 -

48. Fantino B et al. Cost‐effectiveness of escitalopram vs. citalopram in major

depressive disorder. International Clinical Psychopharmacology 2007;22:107–

115.

49. Lam RW and Annemans L. Efficacy, effectiveness and efficiency of escitalopram in

the treatment of major depression and anxiety disorders. Expert Review of

Pharmacoeconomics Outcomes Research 2007; 7(6):559–576.

50. Wade AG et al. Healthcare expenditure in severely depressed patients treated

with escitalopram, generic SSRIs or venlafaxine in the UK. Current Medical

Research & Opinion 2010; 26(5): 1161–1170.

51. Committee for the Safety of Medicines (CSM). Report of the CSM Expert Working

Group on the Safety of Selective Serotonin Reuptake Inhibitors (2004). Accessed

at www.mhra.gov.uk on 20th February 2014.

52. National Institute for Health and Care Excellence (NICE). Clinical Guideline No. 90.

Depression: The treatment and Management of Depression in Adults, 2009.

Accessed at www.nice.org.uk on 20th February 2014. in

53. Qaseem A, Snow V, Denberg TD, Forciea MA, Owens DK on behalf of the

American College of Physicians. Using Second‐Generation Antidepressants to

Treat Depressive Disorders: A Clinical Practice Guideline from the American

College of Physicians. Annals of Internal Medicine 2008; 149:725‐733.

54. American Psychiatric Association. Practice Guideline for the Treatment of

Patients with Major Depressive Disorder, 3rd edition (2010). Accessed at

www.psychiatryonline.org on 20th February 2014.

http://www.mhra.gov.uk/

http://www.nice.org.uk/

http://www.psychiatryonline.org/

- 29 -

9. Bibliography

1. Asberg‐Wistedt A et al. Sertraline versus paroxetine in major depression: Clinical

outcomes after six months of continuous therapy. Journal of Clinical

Psychopharmacology 2000;20(6): 645‐652.

2. Boulenger JP et al. A comparative study of the efficacy of long‐term treatment

with escitalopram and paroxetine in severely depressed patients. Current

Medical Research and Opinion 2006; 22(7):1331–1341.

3. Ekselius L et al. A double‐blind multi‐center trial comparing sertraline and

citalopram in patients with major depression treated in general practice.

International Clinical Psychopharmacology 1997; 12(6):323‐331.

4. Ely Lilly and Company (Ireland) Limited. Medicines Management Programme

Preferred Drugs Review: Cymbalta® (duloxetine). 29th November 2013. On file.

5. Fava M et al. Fluoxetine versus sertraline and paroxetine in major depression:

tolerability and efficacy in anxious depression. Journal of Affective Disorders

2000;59:119–126

6. Fieger AD et al. Sertraline versus fluoxetine in the treatment of major depression:

a combined analysis of five double‐blind comparator studies. International

Clinical Psychopharmacology 2003;18(4): 203‐210.

7. Fochtmann LJ, Gelenberg AJ. Guideline watch: Practice guidelines for the

treatment of patients with major depressive disorder, 2nd edition. The Journal of

Lifelong Learning in Psychiatry 2005; 3(1): 34‐42.

8. GlaxoSmithKline (Ireland) Limited. Medicines Management Programme

submission: Seroxat® (paroxetine). 29th November 2013.

9. Haffmans et al. Efficacy and tolerability of citalopram in comparison with

fluvoxamine in depressed outpatients: a double‐blind, multicentre study.

International Clinical Psychopharmacology 1996; 11:157‐164.

10. Lin HL et al. Comparison of escitalopram and paroxetine in the treatment of

major depressive disorder. International Clinical Psychopharmacology 2013;

28(6):339–345.

11. Lundbeck Ireland Limited. Submission to the Medicines Management Programme

as part of the Preferred Drugs Initiative: Citalopram (Cipramil®). On file.

- 30 -

12. Lundbeck Ireland Limited. Submission to the Medicines Management Programme

as part of the Preferred Drugs Initiative: Escitalopram (Lexapro®). On file.

13. NHS Evidence. Depression: Evidence Update April 2012. A summary of selected

new evidence relevant to NICE clinical guideline No. 90 ‘The treatment and

management of depression in adults’ (2009). Accessed at www.evidence.nhs.uk

on 20th February 2014.

14. Ou et al. 2011 Efficacy and safety of escitalopram versus citalopram in major

depressive disorder: a 6‐week, multicentre, randomized, double‐blind, flexible‐

dose study. Psychopharmacology 2011; 213(2–3):639–646.

15. Patris et al. Citalopram vs. fluoxetine: a double‐blind, controlled, multicentre,

phase III trial in patients with unipolar major depression treated in general

practice. International Clinical Psychopharmacology 1996; 11:129‐136.

16. Pfizer Healthcare Ireland Limited. Manufacturer submission to Medicines

Management Programme Preferred Medicines: Efexor® (venlafaxine). 29th

November 2013. On file.

17. Pfizer Healthcare Ireland Limited. Manufacturer submission to Medicines

Management Programme Preferred Medicines: Lustral® (sertraline). 29th

November 2013. On file.

18. Stahl SM. Placebo‐Controlled Comparison of the Selective Serotonin Reuptake

Inhibitors Citalopram and Sertraline. Biological Psychiatry 2000; 48:894‐901.

19. Ventura D, Armstrong EP, Skrepnek GH and Erder MH. Escitalopram versus

sertraline in the treatment of major depressive disorder: a randomised clinical

trial. Current Medical Research and Opinion 2007; 23(2): 245–250.

20. Yevtushenko VY et al. Efficacy and tolerability of escitalopram versus citalopram

in major depressive disorder: a 6‐week, multicenter, prospective, randomised,

double blind, active‐controlled study in adult out‐patients. Clinical Therapeutics

2007; 229(11):2319‐2332.

http://www.evidence.nhs.uk/

Appendix 1 Prescribing tips

Prescribing tips for Citalopram There is a range of citalopram preparations available, including tablets and oral drops. An up‐to‐date listing is freely available on the Irish Medicines Board website at www.imb.ie

Depression: Dosing & Administration Full prescribing information is available in the Summary of Product Characteristics (SmPC), which may be accessed freely online at www.imb.ie and www.medicines.ie Please consult individual SmPCs for guidance on prescribing for other indications and in special patient populations, e.g. hepatic failure. Table 1a. Dosing and administration of citalopram

Starting Dose Maximum Daily Dose

Adults (18‐65 years) 20 mg daily 40 mg

Elderly (>65 years) 10 mg daily 20 mg

Comment: May be taken at any time of the day with or without food.

Important Prescribing Information

Duration of Treatment A single episode of depression should be treated for a minimum of 6 months after recovery. If antidepressant therapy is stopped immediately on recovery, 50% of patients may experience a return of their depressive symptoms.

QT Interval prolongation Citalopram is contraindicated in patients with known QT

interval prolongation or congenital long QT syndrome.

Citalopram is contraindicated with medicinal products that are known to prolong the QT interval.

Caution is advised in patients at higher risk of developing Torsade de Pointes, e.g. patients with congestive heart failure, myocardial infarction, bradyarrhythmias or a predisposition to hypokalaemia or hypomagnesaemia.

Medicines that prolong the QT interval – avoid with citalopram Antihistamines: Astemizole, mizolastine.

Anti‐malarials: Halofantrine, quinine.

Atypical antipsychotics: Amisulpiride, sertindole.

Antipsychotics: Pimozide, haloperidol.

Class IA antiarrhythmics: Flecainide, lidocaine, quinidine.

Class III antiarrhythmics: Amiodarone, dronedarone, sotalol.

Tricyclic antidepressants: Amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, trimipramine.

Quinolone: Moxifloxacin.

This list is not exhaustive and is intended to serve as guidance only. Prescribers should consult appropriate prescribing and drug interaction information for further guidance.

Onset of Action In clinical practice, an antidepressant effect in an individual is usually seen by 2 weeks. In individuals in whom no antidepressant effect is evident after 3‐4 weeks, a change in dose or drug is indicated.

31

http://www.imb.ie/

http://www.imb.ie/

http://www.medicines.ie/

Prescribing tips for Venlafaxine There is a range of venlafaxine preparations available, including modified‐release capsules and immediate‐release tablets. An up‐to‐date listing is freely available on the Irish Medicines Board website at www.imb.ie

Depression: Dosing & Administration Full prescribing information is available in the Summary of Product Characteristics (SmPC) which may be accessed freely online at www.imb.ie and www.medicines.ie.

Please consult the individual SmPCs for guidance on prescribing for other indications and in special patient populations, e.g. renal impairment. Table 2a. Dosing and administration of venlafaxine

Adults (≥18 years) Starting Dose Maximum Daily Dose

Modified Release (XL) 75 mg once daily 375 mg once daily

Immediate‐release tablets

75 mg in 2 divided doses

375 mg in 2 divided doses

Comment Should be taken with food at approximately the same time(s) each day.

Important Prescribing Information

Elderly Patients No specific dose adjustments required. However, elderly patients are at increased risk of renal impairment and sensitivity to drug effects. Use the lowest effective dose.

Dose Titration The dose may be increased at intervals of 2 weeks. In some instances, faster dose titration may be necessary. A minimum of 4 days should be allowed between dose increases.

Withdrawal symptoms Abrupt discontinuation of venlafaxine should be avoided.

When stopping treatment, reduce the dose gradually over a period of several weeks (minimum 2 weeks, longer if possible)

If intolerable symptoms occur on dose reduction or withdrawal, consider restarting venlafaxine at the previously prescribed dose. Subsequent attempts to withdraw venlafaxine should be made at a more gradual rate.

Onset of Action In clinical practice, an antidepressant effect in an individual is usually seen by 2 weeks. In individuals in whom no antidepressant effect is evident after 3‐4 weeks, a change in dose or drug is indicated.

Duration of Treatment A single episode of depression should be treated for a minimum of 6 months after recovery. If antidepressant therapy is stopped immediately on recovery, 50% of patients may experience a return of their depressive symptoms.

32

http://www.imb.ie/

http://www.imb.ie/

http://www.medicines.ie/

medicines management programme: preferred drugs · icgp irish college of general practitioners imb...

Documents