Duloxetine (Cymbalta) for major depressive disorder

Published in NPS RADAR

Date published: About this date

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PBS listing | Reason for PBS listing | Place in therapy | Safety issues | Dosing issues | Information for patients | References

Key points

  • Duloxetine is a serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant, in the same class as venlafaxine.
  • Duloxetine has similar efficacy to that of other antidepressants, including SSRIs and venlafaxine.
  • Duloxetine should not be used in children and adolescents aged < 18 years. There is no evidence for its use in this population and antidepressants increase the risk of suicidal thinking and behaviour in children, adolescents and young adults.
  • Nausea is common when starting duloxetine and can cause patients to stop treatment. Venlafaxine or escitalopram may be better tolerated at the recommended starting doses.
  • Duloxetine is contraindicated in combination with strong inhibitors of CYP1A2 (e.g. ciprofloxacin).
  • Monitor the blood pressure of people with cardiovascular disease, as it can be increased by duloxetine.
  • To avoid discontinuation symptoms such as dizziness, nausea, headache and paraesthesia, halve the dose for 2 or more weeks before stopping.

PBS listing

Restricted benefit

Duloxetine (Cymbalta) 30 mg and 60 mg capsules can be prescribed on the Pharmaceutical Benefit Scheme (PBS) for people with a major depressive disorder.1

The 30 mg capsule is listed as a month's supply with no repeats. People with renal impairment who require this strength on an ongoing basis will need an authority for any repeats.

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee (PBAC) considered duloxetine to be as effective as venlafaxine (Efexor-XR), but with more adverse effects in the first 6 weeks of therapy. In the following 6 weeks the incidence of adverse effects was similar for the two drugs.2

The PBAC had previously accepted as plausible the argument that the discontinuation rate with duloxetine could be reduced by slower dose titration. However, it remained concerned that in trials twice as many people stopped taking duloxetine because of adverse events as stopped taking venlafaxine. 3

Place in therapy

Antidepressants are effective in moderate or severe major depressive disorder. There are many different antidepressants available in a number of classes, with similar efficacy but differences in adverse effects. Duloxetine provides another treatment option, but does not offer any particular advantages over existing therapies.

Duloxetine is a serotonin and noradrenaline reuptake inhibitor

Like venlafaxine, duloxetine has a primary effect of potentiating serotonergic and noradrenergic activity in the CNS. The adverse-effect profile of duloxetine, as with venlafaxine, includes serotonergic effects similar to those of SSRIs, and noradrenergic effects. The latter include mydriasis — a hazard for people with raised intraocular pressure or at risk of acute narrow-angle glaucoma — and a slight increase in heart rate and blood pressure. People with cardiovascular disease may need additional blood pressure monitoring.4 There have been 2 published case reports of tachycardia and worsening symptoms in people with advanced heart failure.5

Psychological therapies are recommended before antidepressants in mild depression

Drug therapy is not indicated initially in adjustment disorder or milder forms of depression.6–9 Major depression can be diagnosed according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), with severity depending on the number of depressive symptoms, the degree that functioning is impaired, the history of depression and the risk of suicide.6,7,9 Specific psychological therapies such as cognitive behavioural therapy (CBT) and interpersonal therapy (IPT) are recommended:

  • as first-line treatment for mild or moderate major depression
  • as adjunctive therapy in moderate to severe major depression (if an adequate response is not achieved with a drug alone)
  • to prevent relapse in people who are in remission.7

Duloxetine has similar efficacy to that of other antidepressants

Newer antidepressants, including duloxetine, selective serotonin reuptake inhibitors (SSRIs), moclobemide, mirtazapine, reboxetine and venlafaxine, do not differ greatly in efficacy or tolerability.10,11 While there is evidence that the newer non-SSRIs may have a modest efficacy advantage over SSRIs, the difference is unlikely to be clinically significant (24 patients would need to be treated with the alternative drug to achieve 1 additional response).12

A combined analysis of 2 double-blind randomised controlled trials comparing duloxetine 60 mg daily with venlafaxine 150 mg daily found that the 2 drugs had similar efficacy after 6 weeks of treatment.2,13 Furthermore, 2 trials comparing duloxetine 60 mg daily and escitalopram (Esipram, Lexapro) 10–20 mg daily, found that these drugs had similar efficacy after 8 weeks of treatment.14,15 In all 4 trials more people dropped out in the duloxetine groups than in the comparator groups (see Safety issues).

Safety issues

Duloxetine causes a similar range of adverse effects to those seen with venlafaxine or the SSRIs. Nausea is the most common adverse effect, and may cause some people to stop treatment. Antidepressants are associated with increased suicidality in children, adolescents and young adults, and duloxetine is unlikely to be an exception. Duloxetine may exacerbate existing liver disease, including alcohol-related liver damage. As with SSRIs, prescribers should guard against serotonin toxicity (also known as serotonin syndrome) caused by co-prescribing with other serotonergic drugs.

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Ask about suicidal thoughts and assess risk

Assessing depressive symptoms should include asking if the patient has had suicidal thoughts.6 The initial period of antidepressant treatment is recognised as a risk period for suicide attempts.6 For further information about risk assessment refer to NPS Prescribing Practice Review 27: Managing Depression.

Duloxetine should not be used in children and adolescents aged < 18 years

Duloxetine is not registered for use by people aged < 18 years, and there are no clinical trials in this age group.4 Antidepressants have an uncertain balance of benefits and harms for children and adolescents with major depressive disorder: see the Adverse Drug Reactions Advisory Committee (ADRAC) advice about use of SSRI antidepressants in children and adolescents and the NPS RADAR review Selective serotonin re-uptake inhibitors in child and adolescent depression.

A comprehensive analysis of clinical trials by the US Food and Drug Administration found that antidepressants increased the risk of suicidal thinking and behaviour in children, adolescents and young adults (up to age 24). There were no completed suicides among those < 18 years, and too few among adults to draw a conclusion.16

Nausea is common when starting duloxetine

In placebo-controlled trials, 20% of participants receiving duloxetine experienced nausea4 and about 1% discontinued because of it.17 The nausea began within a few days of starting the drug and persisted for a week on average, and was mostly mild or moderate in intensity.17 Other common or very common adverse effects of duloxetine include headache, dry mouth, constipation, diarrhoea, decreased appetite, increased sweating, dizziness, fatigue, somnolence and insomnia.4

Venlafaxine or escitalopram may be better tolerated than duloxetine at the recommended starting doses

In clinical trials, duloxetine 60 mg daily caused more discontinuations due to adverse effects than either venlafaxine 150 mg daily or escitalopram 10–20 mg daily.13–15 In a pooled analysis, 12% of participants assigned to duloxetine 60 mg daily had discontinued because of adverse effects, compared with 6% of participants assigned to venlafaxine 150 mg daily, after 6 weeks of treatment.13

Duloxetine 60 mg daily caused more insomnia and constipation than escitalopram 10–20 mg daily after 8 weeks of treatment.14,15 It also caused more nausea and dizziness than venlafaxine 150 mg daily after 6 weeks of treatment.13 Starting with a lower dose of duloxetine (30 mg daily) or taking duloxetine with food may reduce nausea (see Dosing issues).

Duloxetine is contraindicated for people with hepatic impairment and should not be taken by heavy drinkers

Plasma clearance of duloxetine is slowed considerably in people with hepatic impairment. In addition, duloxetine may aggravate pre-existing liver disease.4 Postmarketing reports have described isolated cases of liver failure, including fatalities, which were possibly related to duloxetine.4,18 Most cases were in people with past or current risk factors for liver injury, including alcohol abuse.4 In trials for any indication, alanine aminotransferase (ALT) elevations to > 3 times the upper limit of normal occurred in 1% of people who took duloxetine, compared with 0.2% of placebo-treated individuals.

Evaluate the patient's level of alcohol consumption when considering duloxetine and avoid prescribing it for heavy drinkers.

Duloxetine should not be used together with strong inhibitors of CYP1A2

Strong inhibitors of CYP1A2 (such as ciprofloxacin) may increase the plasma concentration of duloxetine by preventing its metabolism.4

Duloxetine is itself a moderate inhibitor of CYP2D6 and therefore may interact with drugs that are extensively metabolised by CYP2D6.4 This may lead to clinically significant increases in plasma levels of CYP2D6 substrates that have a narrow therapeutic index (such as metoprolol, perhexiline, phenothiazines, or flecainide).4,19,20 Similarly, duloxetine has the potential to reduce the analgesic effect of codeine by preventing its activation by CYP2D6.21

Avoid co-prescribing duloxetine with other drugs that can increase serotonin levels

Duloxetine may interact with other serotonergic drugs to cause serotonin toxicity (also known as serotonin syndrome). These drugs include SSRIs, venlafaxine, tricyclic antidepressants, monoamine oxidase inhibitor (MAOI) antidepressants (including moclobemide), triptans, tramadol, pethidine, fentanyl, St John's wort and the illicit drugs MDMA ('ecstasy'), cocaine and LSD.4,22,23 Serotonin toxicity can range from mild to life threatening.23 The risk of toxicity and drug interactions from antidepressant combinations outweighs the marginal evidence of added efficacy in almost all cases.24

Dosing issues

The usual dose is a single 60 mg capsule once daily. A reduced dose of 30 mg once daily is indicated for people with end-stage renal disease and may also be used for titration for the first week of therapy. Stopping duloxetine abruptly can cause symptoms such as dizziness and nausea, so tapering is advised.

The standard dose is 60 mg once daily, with or without food

Doses below 60 mg daily were not consistently superior to placebo in clinical trials. On the other hand, there was no adequate evidence that doses above 60 mg provided any benefit to people who did not respond to 60 mg daily.4

Duloxetine is formulated with an enteric coating designed to protect the drug from the acid environment of the stomach. Under strongly acidic conditions, duloxetine breaks down into pharmacologically inactive compounds, including naphthol, an irritant to the gastric and intestinal mucosa.

A lower starting dose or taking duloxetine with food may reduce nausea

Some patients may benefit from a lower starting dose of 30 mg once daily for 1 week before increasing to 60 mg once daily, if adverse effects are a concern.4 There is some evidence that this alternative initiation regimen results in less nausea.25,26 Alternatively, taking duloxetine with food (at either dose) improves tolerability, according to limited evidence from one study.26

While the lower starting dose may reduce adverse effects, it is unlikely to eliminate them. It may also delay the onset of therapeutic effect.25,26 One trial (for generalised anxiety disorder rather than depression) that used the lower initial starting dose still found significantly more nausea with duloxetine than with placebo (32% vs 14%) and a significant rate of discontinuation due to adverse events (14% vs 2%).27

Reduce the dose for people with end-stage renal disease

People with a creatinine clearance ≥ 30 mL/min do not require any dose adjustment. For people with more severe renal impairment than this (e.g. in end-stage renal disease), use a lower dose of 30 mg once daily.4

Duloxetine is toxic in overdose

There have been fatal, acute overdoses with duloxetine alone at doses of 1000 mg and above. However, most fatal overdoses have involved combinations with other drugs.4 Signs and symptoms of overdose (either with duloxetine alone or with mixed drugs) included somnolence, coma, serotonin toxicity, seizures, syncope, tachycardia, hypotension, hypertension and vomiting.28

Prescribe and dispense duloxetine in the smallest quantity practicable, to reduce the risk of overdose.4

Switch to or from another antidepressant as for venlafaxine

Like venlafaxine, duloxetine has a short washout period, but should be withdrawn slowly to prevent discontinuation symptoms (see Halve the dose for 2 or more weeks before stopping). There is potential for a dangerous interaction with MAOIs: do not administer duloxetine within 14 days of stopping an MAOI, and wait at least 5 days after stopping duloxetine before starting an MAOI.4 The risk of serotonin toxicity is lower for moclobemide, but concomitant use is not recommended.29

Halve the dose for 2 or more weeks before stopping

As with other SSRI and SNRI antidepressants, stopping duloxetine abruptly can cause adverse effects. About 40% of trial participants experienced adverse events in the 1–2 weeks after abrupt discontinuation.30 About 40% of these events were mild, and 10% were severe. Symptoms associated with discontinuation included dizziness, nausea, headache, paraesthesia, vomiting, irritability and nightmares. The duloxetine product information recommends tapering the dose when discontinuing, by switching to the 30 mg strength or by taking duloxetine on alternate days, for a period of not less than two weeks.4

Discontinuation symptoms were less common with duloxetine than escitalopram or venlafaxine in two trials. In one trial, about 20% of venlafaxine users reported the most common symptom of dizziness, compared with 15% of duloxetine users.13 In the other trial, which used a longer taper period of 2 weeks, 11% of escitalopram users reported dizziness, compared with 6% of duloxetine users.15

Information for patients

People with depression require careful counselling to encourage persistence with medication. Explain that mood may not improve immediately, and that initial side effects usually decrease with time.

Encourage patients and carers to seek urgent medical assistance in the event of suicidal thoughts or behaviours (particularly when these are new or worsening).

Advise patients:

  • not to chew, crush or open the capsules because this will stop the medication from working and may irritate the digestive system
  • that side effects such as nausea, dizziness and headache are quite common but tend to decrease after a week or so; taking the capsule with a meal may reduce nausea
  • not to stop taking duloxetine abruptly, because of possible withdrawal effects such as dizziness or nausea
  • to consult a doctor or pharmacist before using any herbal medicines or nutritional supplements as these may interact with duloxetine to cause side effects
  • to consult a doctor or pharmacist before using any migraine medicines or strong painkillers such as codeine or tramadol as these may interact with duloxetine
  • to drink alcohol only lightly or not at all, to avoid harmful effects on the liver.

Discuss the Cymbalta consumer medicine information (CMI) leaflet with the patient.

Medicine Update The Medicine Update logo

An NPS Medicine Update leaflet on duloxetine is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with other medicines.

References

  1. Australian Government Department of Health and Ageing. March 2008 PBAC outcomes: positive recommendations. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-mar08-positive (accessed 1 May 2008).
  2. Australian Government Department of Health and Ageing. Public summary document for duloxetine hydrochloride, capsules, 30 mg and 60 mg, Cymbalta March 2008. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-duloxetine-mar08 (accessed 19 June 2008).
  3. Australian Government Department of Health and Ageing. Public summary document for duloxetine hydrochloride, capsules, 30 mg and 60 mg, Cymbalta July 2007. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-duloxetine-july07 (accessed 23 April 2008).
  4. Eli Lilly Australia. Cymbalta product information. 21 January 2008.
  5. Colucci VJ, Berry BD. Heart failure worsening and exacerbation after venlafaxine and duloxetine therapy. Ann Pharmacother 2008;42:882-7. [PubMed]
  6. Therapeutic Guidelines: Psychotropic. Version 5, 2003.
  7. Ellis PM, Smith DAR. Treating depression: the beyondblue guidelines for treating depression in primary care. MJA 2002;176 Suppl:S77-83.
  8. National Institute for Health and Clinical Excellence. Depression (amended): management of depression in primary and secondary care. NICE clinical guideline 23 (amended). 2004, 2007. http://www.nice.org.uk/nicemedia/pdf/CG23NICEguidelineamended.pdf (accessed 23 April 2008).
  9. Royal Australian and New Zealand College of Psychiatrists. Australian and New Zealand clinical practice guidelines for the treatment of depression. Aust N Z J Psychiatry 2004;38:389-407.
  10. Hansen RA, Gartlehner G, Lohr KN, et al. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med 2005;143:415-26. [PubMed]
  11. National Institute for Health and Clinical Excellence. Depression: Management of depression in primary and secondary care. National Clinical Practice Guideline Number 23 [Full Guideline]. 2004. http://www.nice.org.uk/nicemedia/pdf/CG23fullguideline.pdf (accessed 29 April 2008).
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