Gastrointestinal bleed induced by a fixed dose combination of rabeprazole and diclofenac sodium.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to cause gastrointestinal (GI) bleed. Co-administration of proton pump inhibitors (PPIs) has been widely suggested as one of the strategies to prevent these GI complications among NSAIDs users. Herein, we present a case of severe GI bleeding in a patient taking fixed dose combination (FDC) of rabeprazole (20 mg) and diclofenac sodium (100 SR).

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed and used medications worldwide in pain management. Non-selective NSAIDs frequently cause gastrointestinal (GI) toxicity. The spectrum of upper GI tract damage caused by NSAIDs has been well established. It can range from simple dyspepsia to serious and potentially life-threatening complications of ulcers, hemorrhages and perforations.[1]

Various strategies to prevent these GI complications have been advocated like the use of cyclooxygenase-2 inhibitor, prostaglandin analogs, co-administration of H2 blockers and proton pump inhibitors (PPIs) as well as use of nitric oxide-releasing and hydrogen sulfide (H2S)-releasing NSAIDs compounds to reduce lower GI injury.[2]

Various studies have suggested that in acute NSAID or aspirin users, co-treatment with proton pump inhibitors (PPIs), may reduce the risk of GI bleeding[3] and uncomplicated peptic ulcer[4] compared with non NSAID-users. Reports also suggest that long-term treatment with PPIs is efficacious for preventing ulcer recurrence among NSAID users with a previous history of peptic ulcer.[5]

Furthermore, American College of Rheumatology in their 2012 recommendations also favored the concomitant use of PPIs along with NSAIDs for the treatment of osteoarthritis (OA) patient requiring long-term treatment.[6]

Fixed dose combination (FDC) of rabeprazole and diclofenac sodium is available in the Indian market and is in extensive use by the practitioners. The combination of PPIs along with NSAID prevent GI toxicity and the drugs in this FDC has been shown bioequivalent with respect to rate and extent of drug absorption.[7]

We report a case of severe GI bleeding in a patient taking FDC of rabeprazole (20 mg) and diclofenac sodium 100 sustained release (SR). A similar case has not yet been reported in literature, to the best of our knowledge.

Case Report

A male patient, 58 years old, weighing 86 kg, a known patient of osteoarthritis (OA) of both knees was on treatment with topical NSAID, hot fomentation and controlled exercise for past two months. When problem continued, he was prescribed a FDC containing rabeprazole (20 mg) and diclofenac sodium (100 SR) orally once daily by a local practitioner along with a FDC containing (Glucosamine + Diacerine) and calcium plus Vitamin D preparation on daily basis. He had no history of any regular or long-term NSAIDs use in recent past. There was no history of gastric or duodenal ulcer or GI bleeding, chronic abuse of alcohol tobacco; concomitant treatment with a corticosteroid, antiplatelet drug, anticoagulant, or selective serotonin reuptake inhibitor (SSRI) antidepressant. He presented in medical out patient department with a complaint of black stools after 15 days of the FDC intake. There was mild epigastric tenderness on examination. Ultrasonography of abdomen suggested fatty liver grade-1. His Hemoglobin was 9.5 gm%, liver function test, lipid profile, renal function test, bleeding time, clotting time, international normalized ratio (INR) were normal. Electrocardiograph was also found normal whereas endoscopy done after 2 days revealed gastropathy [Figure 1]. Based on endoscopy findings a diagnosis of FDC induced GI bleeding was established. All drugs prescribed for the treatment of OA were stopped. Injection pantoprazole (intravenous) twice daily for 3 days along with drug refixamine 400 mg three times a day orally and sucralfate 4 tea spoon full, three times a day, were prescribed. After 3 days he was prescribed cap pantoprazole 40 mg twice daily for 15 days. He was discharged on recovery, after 5 days of hospitalization and is now on regular follow-up. The adverse drug reaction (ADR) suffered was serious and most likely suspected to be associated with FDC containing diclofenac sodium.

Figure 1

Gastroscopy reveals GI bleed and collected blood in lumen of stomach

Dechallenge of suspected drug and medical intervention caused ADR to ameliorate. Further re-challenge was not done to prevent the relapse of ADR and due to ethical constraints as well. Thus, the appearance of GI bleeding was not explained by any concurrent disease, any other drug or chemicals and the dechallenge improved the condition of the patient.

Discussion

Hence, this ADR can be labeled ‘Probable/likely’ as assessed by Naranjo's causality assessment scale with the score 6.[8] Since this ADR was not studied for dose-dependent response and was predictable as per mechanism of action of diclofenac sodium is known, hence it could be clearly labeled as Type-A class of ADR.[9]

Severity of the reaction as assessed using Hartwig ADR Severity Assessment Scale[10] classified the said ADR into level 4 which states any ADR requiring treatment with suspected drug be held, discontinued, or otherwise changed, and or an antidote or other treatment which increases length of stay by at least one day.

Preventability assessment was done by using Schumock and Thornton scale[11] classified the ADR as not preventable.

Upper GIT symptoms like, dyspepsia, occur in 15% to 60%, gastric or duodenal ulcers in approximately 15% to 30% and serious complications (severe bleeding, perforation, and obstruction) in 1% to 1.5% of the long-term NSAIDs users.[1]

It is well established that inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective prostaglandins, especially prostaglandin I2 (PGI2) and prostaglandin E2 (PGE2) as central mechanism and local irritation allowing back diffusion of acid into the gastric mucosa inducing tissue damage is usually responsible for NSAIDs induced GI toxicity.

The current case is in contradiction to various studies recommending co-administration of PPIs along with NSAIDs.[3456] FDC of rabeprazole (20 mg) and diclofenac sodium (100 SR) has been studied for its efficacy in preventing GI events among NSAIDs users. One study suggested components of such FDC to be bioequivalent in terms of rate and extent of drug absorption.[7] It is well known that diclofenac has rapid absorption, extensive protein binding and a short half-life thus usually daily divided dose is recommended. Rabeprazole is recommended to be taken once daily in the morning. It is acid liable with 58% of oral bioavailability. Food usually does not alter the absorption or peak plasma concentration but can delay time to achieve peak plasma concentration of the drug, thus has to be preferably administered on empty stomach. Furthermore, such FDC may create sense of false security for both prescriber and the patient. One isolated case report is not sufficient to draw any definitive conclusion about the safety of this FDC. Cohort or case control studies are required to evaluate the incidence of GI bleed of NSAIDs with or without PPIs. However, the current case report warrant the need to carry GI screening before prescribing such combination in high risk patients or those in whom this drug may be used for longer periods.