Association Between Citalopram and GI Bleed

Demonstration site

Association between citalopram and GI bleed.

Patient admitted to hospital with a GI bleed.

Been taking citalopram 40mg OD for past 2 months.

Nil other medication.

Consultant thinks citalopram might be cause of bleed.

Junior Dr not familiar with the association between citalopram and GI bleeds.

Is citalopram likely to be the cause of the bleed?

• SSRIs are thought to increase the risk of GI bleeding.
• Precise mechanism not clearly established.
• SSRIs have an antiplatelet effect and can also increase gastric acid secretion.
• Increased risk has been shown to be highest
• Those on concomitant medicines that increase the risk of GI bleeding
• Patients >80yr
• Those who have recently started taking the drug.
• Licensed dose of citalopram for depression in >65yr is 20mg OD.

• As this patient is 83yr, has recently started taking citalopram and is on a high dose that would lead me to suspect citalopram could be the cause of the GI bleed.

• This serious ADR should be reported to the CHM via a yellow card. This can be easily done online via

• Offer copy of UKMi Q&A if wanted.

Source: <Past Enquiry>

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Date Added: 25/08/2015 11:50:10

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Gen search KW = citalopram = 27 hits – nil relevant

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Source: BNF (British National Formulary) Online *

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Publisher: RPS Publishing

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Date Added: 25/08/2015 11:51:44

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BNF August 20154 Central nervous system4.3 Antidepressant drugs4.3.3 Selective serotonin re-uptake inhibitors

CITALOPRAM

Side-effects

seenotes above; ... haemorrhage ...

Dose

• By mouth as tablets, depressive illness, 20mg once daily increased if necessary in steps of 20mg daily at intervals of 3–4 weeks; max. 40mg daily (elderlyover 65 years, max. 20mg daily)

4.3.3Selective serotonin re-uptake inhibitors

Cautions

SSRIs should be used with caution in patients with ... a history of mania or bleeding disorders (especially gastro-intestinal bleeding), and if used with other drugs that increase the risk of bleeding.

Side-effects

Side-effects of the SSRIs include gastro-intestinal effects (dose-related and fairly common—include nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, constipation), ... and bleeding disorders including ecchymoses and purpura.

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Source: EMC (Electronic Medicines Compendium)*

Edition: online

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Publisher: DataPharm

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Date Added: 25/08/2015 11:57:34

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Cipramil Tablets (citalopram hydrobromide)

Lundbeck Limited

Last Updated on eMC 04-Aug-2015

Date of revision of the text29 July 2015

4.2 Posology and method of administration

Elderly patients (> 65 years of age)

For elderly patients the dose should be decreased to half of the recommended dose, e,g, 10-20 mg daily. The recommended maximum dose for the elderly is 20 mg daily.

4.4 Special warnings and precautions for use

Elderly patients

Caution should be used in the treatment of elderly patients (see section 4.2).

Haemorrhage

There have been reports of prolonged bleeding time and /or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, gastrointestinal bleeding and other cutaneous or mucous bleedings with SSSRIs (see section 4.8). Caution is advised in patients taking SSRIs, particularly with concomitant use of active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage, as well as in patients with a history of bleeding disorders (see section 4.5).

4.8 Undesirable effects

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Source: Drugdex

Edition: online

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Publisher: Micromedex

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Date Added: 25/08/2015 12:00:19

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Citalopram Hydrobromide

In-Depth Answers

Dosing/Administration

Adult Dosing

Dosage in Geriatric Patients

A)Citalopram Hydrobromide

1)The maximum recommended dose for elderly patients over 60 years of age is 20 mg once daily[35].

Medication Safety

Adverse Effects

Gastrointestinal Effects

Citalopram Hydrobromide

Gastrointestinal hemorrhage

See Drug Consult reference:CONCOMITANT USE OF SSRIs AND NSAIDs - INCREASED RISK OF GASTROINTESTINAL BLEEDING

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Source: Drug Consults

Edition: online

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Publisher: Micromedex

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Date Added: 25/08/2015 12:04:11

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CONCOMITANT USE OF SSRIs AND NSAIDs - INCREASED RISK OF GASTROINTESTINAL BLEEDING

Drug Consults

RESPONSE

Selective serotonin reuptake inhibitors (SSRIs) are currently the most widely prescribed antidepressants. Through the 1990s, an increasing number of individual cases of bleeding disorders were reported with the use of SSRIs, initiating several epidemiological and pharmacological studies[1]. Nearly all circulating serotonin is transported by platelets in dense granules[1][2]. Platelets do not synthesize serotonin; rather, they take it up from plasma using the same transporter used by neurons[2]. In the presence of proaggregatory factors such as adenosine diphosphate, epinephrine, and collagen, serotonin significantly potentiates aggregation[3]. In fact, serotonin plays a major role in thrombosis when it is released from platelets during heparin-induced thrombocytopenia[4]. Therefore, some investigators have suggested that any drug which interacts with serotonin uptake could have an impact on hemostasis and thrombosis. A recent review of the literature estimated that the risk of upper gastrointestinal bleeding with the use of an SSRI relative to non-use is 2.6 (95% confidence interval, 1.7 to 3.8)[1]. The following table is from a 1999 case-control study that compared the relative risk of an upper gastrointestinal bleed with the use of an SSRI, the use of an NSAID, or both in combination[5]:

Another recent review of the literature evaluated the evidence of an interaction between SSRIs and NSAIDs which may produce an increased risk of gastrointestinal bleeding. Data were synthesized from four retrospective studies that examined the gastrointestinal adverse outcomes from the combination of SSRIs and NSAIDs. The calculated risk ratio for an upper gastrointestinal bleed from the combination of an SSRI and an NSAID ranged from 3.3-15.6 relative to not receiving either agent. Two of the four studies found that the risk ratio for an upper gastrointestinal bleed from the drug combination was greater than the additive risk of either agent alone[6].

CONCLUSION

Although further studies are needed, current research indicates that the concurrent use of an SSRI and an NSAID increases the risk of a gastrointestinal adverse outcome more than the use of either agent alone. Therefore, any patient taking an SSRI, an NSAID, or particularly if they are taking these agents together, should be educated about an increased risk of gastrointestinal bleeding. They should also be educated about the signs and symptoms of gastrointestinal bleeding, such as blood in stool, blood in vomit, dark specks in vomit, black-tarry stool, weakness, shortness of breath, and pale skin.

Reference

1. deAbajo FJ, Montero D, Rodriguez LA, et al: Antidepressants and risk of upper gastrointestinal bleeding. Basic Clin Pharmacol Toxicol 2006; 98(3):304-310.
2. Lesch KP, Wolozin BL, Murphy DL, et al: Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 1993; 60(6):2319-2322.
3. Skop BP & Brown TM: Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics 1996; 37(1):12-16.
4. Spinler SA: New concepts in heparin-induced thrombocytopenia: diagnosis and management. J Thromb Thrombolysis 2006; 21(1):17-21.
5. deAbajo FJ, Rodriguez LA, & et al: Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999; 319(7217):1106-1109.
6. Mort JR, Aparasu RR, & Baer RK: Interaction between selective serotonin reuptake inhibitors and nonsteroidal antiinflammatory drugs: review of the literature. Pharmacotherapy 2006; 26(9):1307-1313.

Last Modified: July 10, 2007

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Source: Martindale: The Complete Drug Reference

Edition: online

Author: Sweetman, SC et al (Eds)

Publisher: Pharmaceutical Press

URL:

Date Added: 24/02/2015 12:06:24

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Citalopram

MARTINDALE - The Complete Drug Reference

Adverse Effects, Treatment, and Precautions

As for SSRIs in general (see Fluoxetine,Fluoxetine Hydrochloride)

Nil on haemorrhage or GI bleed

Uses and Administration

Elderly patients should be given half the recommended adult doses, up to a maximum of 20 mg (or their equivalents as the concentrate) daily.

Fluoxetine Hydrochloride

MARTINDALE - The Complete Drug Reference

Adverse Effects

Effects on the gastrointestinal tract.

• A case-control study1suggested that treatment with SSRIs produced a moderately increased risk of upper gastrointestinal bleeding (adjusted relative risk 3.0). The risk was greatly increased if SSRIs were given with NSAIDs (relative risk 15.6). Treatment with SSRIs did not appear to increase the risk of ulcer perforation. The absolute risk of bleeding was estimated at one case per 8000 prescriptions, a risk similar to that of low-dose ibuprofen. A more recent cohort study2found a similar increase in risk. However, others have questioned whether such an association exists.3
• A retrospective cohort study4in elderly patients found that there was an increasing risk of upper gastrointestinal bleeding as the extent of inhibition of serotonin reuptake by the antidepressant used increased. The effect was considered to be clinically important for patients with a high risk of such bleeding, namely the very elderly and those with a history of previous upper gastrointestinal bleeding.
• Some5consider that gastroprotection is unlikely to be justified in those given SSRIs alone and furthermore there are no studies to suggest that gastroprotective drugs reduce the risk of SSRI-associated haemorrhage. However, it has been recommended5that such protection should be considered when SSRIs and NSAIDs are used together because of the increased risk. (Last reviewed: 2013-06-14; last modified: 2006-03-04)

1. de Abajo FJ, et al. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999; 319: 1106-9. (PubMed id:10531103)

2. Dalton SO, et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003; 163: 59-64. (PubMed id:12523917)

3. Dunn NR, et al. Association between SSRIs and upper gastrointestinal bleeding. BMJ 2000; 320: 1405-6. (PubMed id:10858059)

4. van Walraven C, et al. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001; 323: 655-8. (PubMed id:11566827)

5. Paton C, Ferrier IN. SSRIs and gastrointestinal bleeding. BMJ 2005; 331: 529-30. (PubMed id:16150746)

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Source: AHFS Drug Information

Edition: online

Author: McEvoy GK (ed)

Publisher: American Society of Health-System Pharmacists

URL:

Date Added: 25/08/2015 12:11:18

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AHFS Drug InformationCentral Nervous System Agents 28:00Psychotherapeutic Agents 28:16Antidepressants 28:16.04Selective Serotonin-reuptake Inhibitors 28:16.04.20

Dosage and Administration

Dosage in Geriatric Patients

Major Depressive Disorder

For the management of depression in geriatric patients over 60 years of age, the maximum recommendedcitalopramdosage is 20 mg once daily due to the risk of QT-interval prolongation.399424(See Cautions: Cardiovascular Effects.)

For the management of depressive symptoms associated with dementia of the Alzheimer’s type in geriatric patients, some experts recommend a lower initialcitalopramdosage of 5–10 mg once daily.407The dosage may then be gradually increased at intervals of at least several weeks up to the maximum recommended dosage of 20 mg once daily.399407424

Cautions

GI Effects

Epidemiologic case-control and cohort design studies have suggested that selective serotonin-reuptake inhibitors may increase the risk of upper GI bleeding.15455377378Although the precise mechanism for this increased risk remains to be clearly established, serotonin release by platelets is known to play an important role in hemostasis, and selective serotonin-reuptake inhibitors decrease serotonin uptake from the blood by platelets thereby decreasing the amount of serotonin in platelets.154378In addition, concurrent use of aspirin or other nonsteroidal anti-inflammatory agents was found to substantially increase the risk of GI bleeding in patients receiving selective serotonin-reuptake inhibitors in 2 of these studies.15455377Although these studies focused on upper GI bleeding, there is some evidence suggesting that bleeding at other sites may be similarly potentiated.1Further clinical studies are needed to determine the clinical importance of these findings.54378(See Cautions: Hematologic Effectsand see alsoDrug Interactions: Drugs Affecting Hemostasis.)

Colitis,1gastric ulcer,1duodenal ulcer,1cholecystitis,1cholelithiasis,1gastroesophageal reflux,1glossitis,1diverticulitis,1and rectal hemorrhage1have been reported in less than 0.1% of patients receivingcitalopram.1However, these adverse effects have not been definitely attributed to the drug.1

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Source: <Other E-Source>

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Date Added: 25/08/2015 12:14:08

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Search: citalopram

Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects

Authors
Michael Hirsch, MD
Robert J Birnbaum, MD, PhD

Section Editor
Peter P Roy-Byrne, MD

Deputy Editor
David Solomon, MD

Literature review current through:Jul 2015.|This topic last updated:Jun 18, 2015.

Side effects

Bleeding—High quality studies (randomized trials) indicate that SSRIs do not cause bleeding [58,59]. Although many observational studies have found an association between SSRIs and an increased risk of abnormal bleeding [60-62], the low quality of this evidence leads us to suggest that clinicians should generally not change their practice with regard to using SSRIs [63]. Associations between SSRIs and bleeding that are found in observational studies may be confounded by many factors, such as intracranial small vessel disease, diabetes mellitus, smoking, and alcohol abuse.

Bleeding complications of SSRIs identified in observational studies include upper gastrointestinal bleeding, stroke, and intraoperative bleeding, as well as more minor problems such as easy bruising, petechiae and purpura, epistaxis, and hematomas [64-67]. The association between SSRI exposure and abnormal bleeding across multiple studies appears to be more consistent with upper gastrointestinal bleeding than stroke. In addition, the risk of bleeding in observational studies was amplified in patients who were taking other medications that can cause bleeding, such as nonsteroidal antiinflammatory drugs (NSAIDS; eg,aspirin,ibuprofen, ornaproxen) or anticoagulants (eg,clopidogrelorwarfarin) [62,68-70]. Among the different SSRIs, there is little indication that any specific SSRI is more strongly associated with bleeding.

The biological plausibility of the association between SSRIs and increased bleeding is supported by the finding that SSRIs can inhibit serotonin uptake into platelets and decrease intraplatelet serotonin concentrations, which may affect platelet aggregation [71-73]. In addition, SSRIs may increase gastric acid secretion [73].

Upper gastrointestinal bleeding—Multiple meta-analyses of observational studies suggest that SSRIs are associated with an elevated risk of upper gastrointestinal bleeding [74-76]; however, the absolute risk is low [73]. As an example, one meta-analysis compared the risk of upper gastrointestinal bleeding in SSRI users with the risk in non-SSRI users, pooling data from 22 observational studies (n >1,000,000 individuals, including more than 56,000 cases of bleeding) [77]. Exposure to SSRIs was associated with an increased risk of bleeding (odds ratio 1.6, 95% CI 1.4-1.8). The risk was even greater in the subgroup of patients who took SSRIs plus NSAIDS (odds ratio 3.7, 95% CI 3.0-4.7). By contrast, a separate subgroup analysis found that the risk of bleeding was comparable for patients who took SSRIs plus NSAIDS plus acid suppressing drugs and for patients who were not exposed to SSRIs. Based upon these findings, some clinicians use non-SSRI antidepressants in patients at high risk for bleeding (eg, prior history of upper gastrointestinal bleeding), or prescribe a proton pump inhibitor when SSRIs are used in conjunction with NSAIDS; however, this is not standard practice.

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Source: Medicines Q&A

Edition: online

Author:

Publisher: UKMi

URL:

Date Added: 25/08/2015 12:20:03

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Search citalopram > filter: source=UKMI

Q&A 163.3

What is the risk of gastrointestinal bleeding associated with selective serotonin reuptake inhibitors (SSRIs)?

Date prepared: 2nd March 2015

Background
An association between selective serotonin reuptake inhibitor (SSRI) use and upper gastrointestinal (GI) bleeding was reported in 1999 following analysis of data from a UK general practice research database (1). Further evidence supporting this association has emerged since (2-5), but recent publications have found SSRI use to result in a more modest increase in the risk of upper GI bleeding than originally reported (6-8) and some have found no association at all (9,10). In several studies in which an increased risk has been noted with SSRIs alone, the risk has been found to be elevated further by the concomitant use of SSRIs and non-steroidal anti-inflammatory drugs (NSAIDs) (6-8).

Two main mechanisms have been proposed for SSRI-associated upper GI bleeding. Firstly, serotonin plays an important role in the haemostatic response to injury by promoting platelet aggregation (1,11,12). Serotonin is not synthesised in platelets but is taken up into platelets from the bloodstream. At therapeutic doses SSRIs block this reuptake of serotonin leading to a depletion of serotonin and, ultimately, an increased risk of bleeding. Secondly, SSRIs have been shown to directly increase gastric acidity which could increase the risk of ulcer development, and therefore, bleeding (5). Due to reports of bleeding, including GI bleeding, manufacturers advise caution in patients with a history of bleeding disorders and in those taking SSRIs concomitantly with antiplatelets and other drugs that might increase the risk of bleeding (13-18).