Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2015.1010037
Vol. 31, No. 3, 2015, 421–422
Article FT-0003/1010037 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Editorial The ibuprofen–famotidine combined pill – a promise fulfilled
Ali S. Taha University Hospital Crosshouse/University of Glasgow, Kilmarnock, Scotland, UK Address for correspondence: Ali S. Taha MD PhD FRCP, Department of Medicine and Gastroenterology, University Hospital Crosshouse/ University of Glasgow, Kilmarnock KA2 0BE, Scotland, UK. Tel: +44 1563 827 280; [email protected] Key words: Degenerative arthritic diseases – Gastro-protection – Ibuprofen–famotidine combination – NSAIDs Accepted: 15 January 2015; published online: 25 February 2015 Citation: Curr Med Res Opin 2015; 31:421–2
! 2015 Informa UK Ltd www.cmrojournal.com
The medical and orthopedic management of inflammatory and degenerative arthritic diseases continue to improve, with new diagnostic and therapeutic approaches being explored and implemented to good effect. Despite such welcome improvements, the use of non-steroidal anti-inflammatory drugs (NSAIDs) remains both integral to arthritis management and as popular as ever with both patients and clinicians alike. This is the case at a time when the potential complications of these agents continue to be highlighted by researchers and regulatory authorities. The simple truth to explain their popularity is the fact that NSAIDs do work in providing the desirable anti-inflammatory and analgesic activities. One of the most popular NSAIDs is ibuprofen1. Using novel technology, ibuprofen has been combined in a single pill with famotidine, the latter being the most potent histamine-2 receptor antagonist2,3. Combining the two drugs was meant to serve two vital functions: firstly, to improve patients’ compliance with the use of the gastro-protective component, famotidine; and secondly, it provided hope, or perhaps a promise, to minimize the frequency of the gastro-intestinal side effects that can follow the use of therapeutic doses of ibuprofen. The natural question here is whether such promise has been fulfilled; and if so, what evidence there is to support the answer. To understand the available evidence for the favorable effects of the combined ibuprofen–famotidine pill, it would be helpful to define what is meant by the un-favorable effects of ibuprofen particularly when prescribed in therapeutic doses of 800 mg to be taken three times per day. Like other NSAIDs, ibuprofen may cause dyspeptic symptoms and gastro-duodenal ulcers and erosions. Some of these lesions might be totally silent, i.e., asymptomatic, or they can result in serious complications including bleeding, perforation, obstruction or, sometimes, death4,5. In addition, the cardio-vascular side effects of NSAIDs have recently been of particular interest to the regulatory authorities such as the Food and Drug Administration, USA. The effects of the combined pill (ibuprofen 800 mg þ famotidine 26.6 mg) vs. ibuprofen 800 mg, each comparator taken three times daily, on gastric and duodenal ulcers were investigated in two 24 week randomized double-blind studies, the REDUCE-1 and -2 trials6. In REDUCE-1, the primary end point analysis of gastric ulcers at 24 weeks with the combined pill vs. ibuprofen was 12.7% vs. 22.9% (P ¼ 0.0044) in the post-adjudication analysis. In REDUCE-2, the primary end point analysis of upper gastrointestinal (GI) ulcers was 13.0% vs. 20.5% (P ¼ 0.0587) in the post-adjudication analysis. Pre-specified pooled analyses showed significantly fewer gastric (12.5% vs. 20.7%) and duodenal ulcers (1.1% vs. 5.1%) with the combined pill vs. ibuprofen. Proportional hazards analysis of multiple potential risk factors showed the risk ratio of upper GI ulcers with the combined pill vs. ibuprofen was 0.46, 95% confidence Ibuprofen–famotidine combined Taha
421
Curr Med Res Opin Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 3
March 2015
interval was 0.34–0.61. The results of the two REDUCE trials indicate that famotidine plus ibuprofen, at the doses mentioned above and given as a combination tablet, decrease endoscopic upper GI ulcers compared with ibuprofen alone6. It is worth noting that a patient needs to take all three of the combined pills daily in order to ensure the availability of 80 mg of famotidine, known to protect against both gastric and duodenal ulcers2. In this issue of Current Medical Research and Opinion, Dr Bello and colleagues aimed to evaluate the safety of the combined ibuprofen–famotidine pill compared with ibuprofen alone from the two 24 week REDUCE-1 and -2 trials and a 28 week double-blind extension study7. Safety was analyzed by pooling data from these three trials, and was assessed by monitoring the incidence, causality, and severity of adverse events (AEs). They found that discontinuation rates due to any cause and dyspepsia were significantly lower for the combined pill versus ibuprofen alone. Other than dyspepsia, gastrointestinal and cardiovascular AEs of special interest were similar. Events judged to be treatment related were significantly lower with the combined pill (20.6% vs. 25%). They also reported that the incidence of cardiovascular-related AEs of special interest were 11% for the combined pill (including three cases of hypertension considered as treatment related) and 2% for ibuprofen, P ¼ 0.06; they attributed this to the possibility that a higher number of rheumatoid arthritis patients were in the combined-pill group. The probability of a cardiovascular event decreased during days 112–167 of treatment and remained low with continued treatment7. Assessment of the long-term, i.e., over a period of 12 months or longer, safety of the combined ibuprofen–famotidine pill was the objective of another study published in this issue of Current Medical Research and Opinion by the same authors, Dr Bello and colleagues8. In a phase 3b open-label study, they included 86 adults who required daily NSAIDs for 12 months. The combined pill was self-administered orally three times daily for up to 54 consecutive weeks. AEs were recorded after the first dose and throughout the 54 weeks of the study, including formal assessment of dyspepsia. They found that the use of the combined pill was associated with lower withdrawal and gastrointestinal AE rates than previously reported with ibuprofen alone. Dyspepsia scores demonstrated improvement by week 6 and improved significantly at week 24 and week 54. Of the cardiovascular AEs, hypertension was reported most frequently (9/86, 9.3%), with 3.5% determined to be drug related. There were no reports of serious gastrointestinal or CV complications. Most AEs were mild or moderate in severity and not considered drug related8. It could, therefore, be argued with justification that the efficacy and superior tolerability of the combined ibuprofen–famotidine pill is proven by the lower withdrawal rates
422
Ibuprofen–famotidine combined Taha
and the fewer AEs reported in trials lasting 24–54 weeks6–8. In particular, the use of the combined pill was associated with less dyspepsia and fewer gastric and duodenal ulcers. While these trials were not powered to evaluate the rates of serious ulcer complications such as bleeding or perforation, the incidence of the latter did not increase even when 1533 subjects were studied, 1022 of whom took the combined pill6–8. Likewise, the rates of serious cardiovascular events were not increased; and the development of hypertension in a few patients with multiple comorbidities is of uncertain significance7,8. In conclusion, and taking all the above evidence into account, it would seem that improving the safety profile of ibuprofen by having it combined with famotidine in a single pill is a promise that has been fulfilled.
Transparency Declaration of funding This editorial was not funded. Declaration of financial/other relationships A.S.T. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.
References 1. Paulose-Ram R, Hirsch R, Dillon C, et al. Prescription and non-prescription analgesic use among the US adult population: results from the third National Health and Nutrition Examination Survey (NHANES III). Pharmacoepidemiol Drug Saf 2003;12:315-26 2. Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal anti-inflammatory drugs. N Engl J Med 1996;334:1435-9 3. Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase-III, randomised, double-blind, placebo-controlled trial. Lancet 2009;374:119-25 4. Taha AS, Kelly C, McCloskey C, et al. Gastroprotective policy and the incidence of upper gastrointestinal bleeding. Frontline Gastroenterology 2013;4:108-11 5. Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual patient data from randomised trials. Lancet 2013;382:769-79 6. Laine L, Kivitz AJ, Bello AE, et al, on behalf of the REDUCE-1 and -2 Study Investigators. Double-blind randomized trials of single-tablet ibuprofen/highdose famotidine vs ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol 2012;107:379-86 7. Bello AE, Grahn AY, Ball J, et al. 1-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled analyses of two 24-week randomized, double-blind trials and a follow-on extension. Curr Med Res Opin 2015 8. Bello A, Kent J, Grahn A, et al. One-year open-label safety evaluation of the fixed combination of ibuprofen and famotidine with a prospective analysis of dyspepsia. Curr Med Res Opin 2015
www.cmrojournal.com ! 2015 Informa UK Ltd
Vol. 31, No. 3, 2015, 421–422
Article FT-0003/1010037 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Editorial The ibuprofen–famotidine combined pill – a promise fulfilled
Ali S. Taha University Hospital Crosshouse/University of Glasgow, Kilmarnock, Scotland, UK Address for correspondence: Ali S. Taha MD PhD FRCP, Department of Medicine and Gastroenterology, University Hospital Crosshouse/ University of Glasgow, Kilmarnock KA2 0BE, Scotland, UK. Tel: +44 1563 827 280; [email protected] Key words: Degenerative arthritic diseases – Gastro-protection – Ibuprofen–famotidine combination – NSAIDs Accepted: 15 January 2015; published online: 25 February 2015 Citation: Curr Med Res Opin 2015; 31:421–2
! 2015 Informa UK Ltd www.cmrojournal.com
The medical and orthopedic management of inflammatory and degenerative arthritic diseases continue to improve, with new diagnostic and therapeutic approaches being explored and implemented to good effect. Despite such welcome improvements, the use of non-steroidal anti-inflammatory drugs (NSAIDs) remains both integral to arthritis management and as popular as ever with both patients and clinicians alike. This is the case at a time when the potential complications of these agents continue to be highlighted by researchers and regulatory authorities. The simple truth to explain their popularity is the fact that NSAIDs do work in providing the desirable anti-inflammatory and analgesic activities. One of the most popular NSAIDs is ibuprofen1. Using novel technology, ibuprofen has been combined in a single pill with famotidine, the latter being the most potent histamine-2 receptor antagonist2,3. Combining the two drugs was meant to serve two vital functions: firstly, to improve patients’ compliance with the use of the gastro-protective component, famotidine; and secondly, it provided hope, or perhaps a promise, to minimize the frequency of the gastro-intestinal side effects that can follow the use of therapeutic doses of ibuprofen. The natural question here is whether such promise has been fulfilled; and if so, what evidence there is to support the answer. To understand the available evidence for the favorable effects of the combined ibuprofen–famotidine pill, it would be helpful to define what is meant by the un-favorable effects of ibuprofen particularly when prescribed in therapeutic doses of 800 mg to be taken three times per day. Like other NSAIDs, ibuprofen may cause dyspeptic symptoms and gastro-duodenal ulcers and erosions. Some of these lesions might be totally silent, i.e., asymptomatic, or they can result in serious complications including bleeding, perforation, obstruction or, sometimes, death4,5. In addition, the cardio-vascular side effects of NSAIDs have recently been of particular interest to the regulatory authorities such as the Food and Drug Administration, USA. The effects of the combined pill (ibuprofen 800 mg þ famotidine 26.6 mg) vs. ibuprofen 800 mg, each comparator taken three times daily, on gastric and duodenal ulcers were investigated in two 24 week randomized double-blind studies, the REDUCE-1 and -2 trials6. In REDUCE-1, the primary end point analysis of gastric ulcers at 24 weeks with the combined pill vs. ibuprofen was 12.7% vs. 22.9% (P ¼ 0.0044) in the post-adjudication analysis. In REDUCE-2, the primary end point analysis of upper gastrointestinal (GI) ulcers was 13.0% vs. 20.5% (P ¼ 0.0587) in the post-adjudication analysis. Pre-specified pooled analyses showed significantly fewer gastric (12.5% vs. 20.7%) and duodenal ulcers (1.1% vs. 5.1%) with the combined pill vs. ibuprofen. Proportional hazards analysis of multiple potential risk factors showed the risk ratio of upper GI ulcers with the combined pill vs. ibuprofen was 0.46, 95% confidence Ibuprofen–famotidine combined Taha
421
Curr Med Res Opin Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 3
March 2015
interval was 0.34–0.61. The results of the two REDUCE trials indicate that famotidine plus ibuprofen, at the doses mentioned above and given as a combination tablet, decrease endoscopic upper GI ulcers compared with ibuprofen alone6. It is worth noting that a patient needs to take all three of the combined pills daily in order to ensure the availability of 80 mg of famotidine, known to protect against both gastric and duodenal ulcers2. In this issue of Current Medical Research and Opinion, Dr Bello and colleagues aimed to evaluate the safety of the combined ibuprofen–famotidine pill compared with ibuprofen alone from the two 24 week REDUCE-1 and -2 trials and a 28 week double-blind extension study7. Safety was analyzed by pooling data from these three trials, and was assessed by monitoring the incidence, causality, and severity of adverse events (AEs). They found that discontinuation rates due to any cause and dyspepsia were significantly lower for the combined pill versus ibuprofen alone. Other than dyspepsia, gastrointestinal and cardiovascular AEs of special interest were similar. Events judged to be treatment related were significantly lower with the combined pill (20.6% vs. 25%). They also reported that the incidence of cardiovascular-related AEs of special interest were 11% for the combined pill (including three cases of hypertension considered as treatment related) and 2% for ibuprofen, P ¼ 0.06; they attributed this to the possibility that a higher number of rheumatoid arthritis patients were in the combined-pill group. The probability of a cardiovascular event decreased during days 112–167 of treatment and remained low with continued treatment7. Assessment of the long-term, i.e., over a period of 12 months or longer, safety of the combined ibuprofen–famotidine pill was the objective of another study published in this issue of Current Medical Research and Opinion by the same authors, Dr Bello and colleagues8. In a phase 3b open-label study, they included 86 adults who required daily NSAIDs for 12 months. The combined pill was self-administered orally three times daily for up to 54 consecutive weeks. AEs were recorded after the first dose and throughout the 54 weeks of the study, including formal assessment of dyspepsia. They found that the use of the combined pill was associated with lower withdrawal and gastrointestinal AE rates than previously reported with ibuprofen alone. Dyspepsia scores demonstrated improvement by week 6 and improved significantly at week 24 and week 54. Of the cardiovascular AEs, hypertension was reported most frequently (9/86, 9.3%), with 3.5% determined to be drug related. There were no reports of serious gastrointestinal or CV complications. Most AEs were mild or moderate in severity and not considered drug related8. It could, therefore, be argued with justification that the efficacy and superior tolerability of the combined ibuprofen–famotidine pill is proven by the lower withdrawal rates
422
Ibuprofen–famotidine combined Taha
and the fewer AEs reported in trials lasting 24–54 weeks6–8. In particular, the use of the combined pill was associated with less dyspepsia and fewer gastric and duodenal ulcers. While these trials were not powered to evaluate the rates of serious ulcer complications such as bleeding or perforation, the incidence of the latter did not increase even when 1533 subjects were studied, 1022 of whom took the combined pill6–8. Likewise, the rates of serious cardiovascular events were not increased; and the development of hypertension in a few patients with multiple comorbidities is of uncertain significance7,8. In conclusion, and taking all the above evidence into account, it would seem that improving the safety profile of ibuprofen by having it combined with famotidine in a single pill is a promise that has been fulfilled.
Transparency Declaration of funding This editorial was not funded. Declaration of financial/other relationships A.S.T. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.
References 1. Paulose-Ram R, Hirsch R, Dillon C, et al. Prescription and non-prescription analgesic use among the US adult population: results from the third National Health and Nutrition Examination Survey (NHANES III). Pharmacoepidemiol Drug Saf 2003;12:315-26 2. Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal anti-inflammatory drugs. N Engl J Med 1996;334:1435-9 3. Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase-III, randomised, double-blind, placebo-controlled trial. Lancet 2009;374:119-25 4. Taha AS, Kelly C, McCloskey C, et al. Gastroprotective policy and the incidence of upper gastrointestinal bleeding. Frontline Gastroenterology 2013;4:108-11 5. Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual patient data from randomised trials. Lancet 2013;382:769-79 6. Laine L, Kivitz AJ, Bello AE, et al, on behalf of the REDUCE-1 and -2 Study Investigators. Double-blind randomized trials of single-tablet ibuprofen/highdose famotidine vs ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol 2012;107:379-86 7. Bello AE, Grahn AY, Ball J, et al. 1-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled analyses of two 24-week randomized, double-blind trials and a follow-on extension. Curr Med Res Opin 2015 8. Bello A, Kent J, Grahn A, et al. One-year open-label safety evaluation of the fixed combination of ibuprofen and famotidine with a prospective analysis of dyspepsia. Curr Med Res Opin 2015
www.cmrojournal.com ! 2015 Informa UK Ltd
