DRUGS 2008, Vol 68, No. 4

DRUGS 2008, Vol 68, No. 4

Drugs

Issue Table of Contents

2008, Volume 68, Issue 4 Page # Article/Title

Current Opinion

399

Gastro-Oesophageal Reflux Disease in Asia: Birth of a 'New' Disease? Ting K Cheung; Benjamin C Y Wong; Shiu K Lam

Leading Article

407

Overview of the Management of Acute Gout and the Role of Adrenocorticotropic Hormone. Naomi Schlesinger

Review Article

417

Oral Colorectal Cleansing Preparations in Adults. Sherief Shawki; Steven D Wexner

Adis Drug Profile

439

Nelarabine. Mark Sanford; Katherine A Lyseng-Williamson

449

Nilotinib. Greg L Plosker; Dean M Robinson

Guest Commentaries

460

Nilotinib: A Viewpoint by Gianantonio Rosti. Gianantonio Rosti

460

Nilotinib: A Viewpoint by Philipp le Coutre. Philipp le Coutre

Adis Drug Evaluation

463

Dutasteride: A Review of its Use in the Management of Prostate Disorders. Susan J Keam; Lesley J Scott

487

Bevacizumab: A Review of its Use in Metastatic Colorectal Cancer. Paul L McCormack; Susan J Keam

507

Zoledronic Acid: A Review of its Use in the Management of Bone Metastases · of Malignancy. Sohita Dhillon; Katherine A Lyseng-Williamson

535

Levofloxacin: A Review of its Use as a High-Dose, Short-Course Treatment for· Bacterial Infection. Vanessa R Anderson; Caroline M Perry

Drugs 2008; 68 (4): 399-406 0012-6667/08/0004-0399/$53.45/0

CURRENT OPINION

© 2008 Adis Data Information BV. All rights reserved.

Gastro-Oesophageal Reflux Disease in Asia Birth of a ‘New’ Disease? Ting K. Cheung, Benjamin C.Y. Wong and Shiu K. Lam Department of Medicine, University of Hong Kong, Hong Kong

Abstract

Gastro-oesophageal reflux disease (GORD) is one of the most common gastrointestinal diseases in the Western world and imposes a heavy burden on society. Although its prevalence in Asia is much lower, there is evidence that this is rapidly rising in Asia. The reported population prevalence of GORD in Eastern Asia ranges from 2.5% to 6.7% for at least weekly symptoms of heartburn and/or acid regurgitation. In general, Asians tend to have a milder spectrum of the disease. Most Asian patients have non-erosive GORD; erosive oesophagitis is less commonly seen than in the Western population. Complicated GORD, such as oesophageal stricture and Barrett’s oesophagus, is seldom encountered. The mechanisms of GORD may be different in the Chinese population compared with the Western population. Chest pain is the most predominant extra-oesophageal manifestation of GORD in China, whereas an association with asthma has been shown in Japanese patients. The prevalence of GORD appears to be increasing and possible factors for GORD in Asian populations include Helicobacter pylori infection, obesity and increasing dietary fat intake. The adoption of a Western lifestyle in many developing Asian countries may account for the increasing prevalence of GORD. Proton pump inhibitors remain the most effective medical treatment for GORD. GORD will undoubtedly be a great challenge to clinicians both in primary care and in gastroenterology practice in the Asia-Pacific region in the coming years.

Gastro-oesophageal reflux disease (GORD) is a common disease in the Western world. It has been estimated that between 10% and 30% of the population is affected by GORD.[1] In 2002, GORD was reported to incur the highest annual direct costs in the US and cost more than $US9.3 billion per year.[2] GORD is believed to be less prevalent in Asian countries and the perception is that Asians tend to have a milder spectrum of the disease. This may be partly as a result of under-recognition or it may truly reflect a lower frequency of the disease in this region. However, the prevalence and impact of GORD seem to be increasing.

1. Definition of Gastro-Oesophageal Reflux Disease (GORD) The study of GORD and its epidemiology has been restricted by the lack of consensus over the definition of the disease. The Genval Workshop defined GORD as an illness due to the reflux of gastric contents into the oesophagus, leading to physical complication or significant impairment in quality of life.[3] The working group of the AsiaPacific consensus on the management of GORD defined GORD as “a disorder in which gastric contents recurrently reflux into the oesophagus causing heartburn and other symptoms”.[4] A recent initia-

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Table I. Prevalence of gastro-oesophageal reflux disease (reflux symptoms at least once weekly) in different Asian countries Study

Country/area

Study year

Sample size

Prevalence (reflux symptoms at least once weekly) [%]

Hu et al.[24]

China/Hong Kong

1996

1649

4.8

Wong et al.[13]

China/Hong Kong

2002

2209

2.5

Wong et al.[16] (follow-up study)

China/Hong Kong

2003

772

2.7

Pan et al.[25]

China/Beijing, Shanghai

1996

4992

HB 3.1

Wang et al.[17]

China/Xian

(Not provided)

2789

HB 1.7 AR 3.5

Chen et al.[26]

China/South China

2003

3514

6.2

Cho et al.[27]

Korea

2000–1

1902

3.5

Watanabe et al.[19]

Japan/Kansai

2001

4095

6.7

Fujiwara et al.[18] Japan/Kansai AR = acid regurgitation; HB = heartburn.

2001

6035

6.6

tive to develop a global consensus for GORD (Montreal definition) defined GORD as a “condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications”.[5] In this consensus, it also recognized that gastro-oesophageal reflux not only causes oesophageal syndromes but can also result in extraoesophageal manifestations, e.g. reflux cough, reflux laryngitis syndrome and asthma. 2. Symptoms of GORD Heartburn and acid regurgitation are the most commonly encountered symptoms and thus considered typical for GORD. The problem of defining GORD in Asian populations is complicated by the fact that there is no direct translation of the word ‘heartburn’ in most Asian languages.[6] It has been shown that the word ‘heartburn’ was interpreted unreliably by patients.[7-10] Spechler et al.[10] examined patients attending general medical clinics and found that 35% of Whites, 46% of Blacks and 3% of East Asian patients reported that they had heartburn (p < 0.01), but the term ‘heartburn’ was understood only by 35%, 54% and 13% of Whites, Blacks and East Asians, respectively, (p < 0.01). It has also been recognized that non-cardiac chest pain,[11-13] globus sensation[13,14] and asthma[15] are not uncommon manifestations of GORD in Asian patients. 3. Prevalence of GORD Symptoms The reported population prevalence of GORD in Eastern Asia ranges from 2.5% to 6.7% for at least © 2008 Adis Data Information BV. All rights reserved.

weekly symptoms of heartburn and/or acid regurgitation.[13,16-19] Typical GORD symptoms are consistently less common among the general populations of Asia than those in the West, which have a prevalence of around 20% for weekly reflux symptoms (table I).[1,2,20-23] 3.1 Erosive Oesophagitis in Asia

No reliable data are available on the prevalence of oesophagitis in the general population.[28] In case studies, the prevalence of reflux oesophagitis ranged from 3.4% to 16.3%.[29-31] However, these are likely to overestimate the true prevalence. A large study in Hong Kong in patients undergoing routine or emergency upper endoscopy (n = 16 606) showed that 3.8% of the patients had oesophagitis demonstrated by endoscopy; the majority of these patients (94%) had Los Angeles Classification Grade A or B oesophagitis and only 14 patients (0.08%) had oesophageal stricture.[29] A large Japanese study reported oesophagitis in 16.3% of patients visiting a hospital for routine physical examinations (n = 6010) and 87% had mild oesophagitis.[30] Lee et al.[31] examined 7015 patients going for self-paid check-ups and 3.4% of patients were found to have oesophagitis, of which 98.3% were classified as mild oesophagitis. In summary, the prevalence of reflux oesophagitis appears to be lower in the Asian population than in the West. Drugs 2008; 68 (4)

GORD in Asia

Barrett’s oesophagus is characterized by a columnar epithelium replacing the squamous mucosa that normally lines the distal oesophagus and it is believed to be related to the development of oesophageal adenocarcinoma. The prevalence of Barrett’s oesophagus varies between different countries. In a study of a multi-ethnic Malaysian population, long-segment Barrett’s oesophagus was reported in 1.6% and short-segment Barrett’s oesophagus in 4.6% of those undergoing elective endoscopy for upper abdominal or reflux complaints.[32] Indians (8.2%) had the highest prevalence of Barrett’s oesophagus (long and short combined) compared with Chinese (5.7%) or Malays (4.4%).[32] A much lower prevalence was found in Southern Chinese patients undergoing upper endoscopy, of whom 0.06% had Barrett’s oesophagus (n = 22 628).[29] More data are required to determine the true prevalence of Barrett’s oesophagus in Asians. 3.3 Non-Erosive Reflux Disease in Asia

Non-erosive reflux disease (NERD) is defined by the presence of troublesome reflux-associated symptoms and the absence of mucosal breaks at endoscopy.[5] NERD has been reported in >50% of the population in the primary care setting in the Western world.[33-38] In a prospective study, Rosaida and Goh[39] reported that 65.5% of their patients had NERD. In another study from Hong Kong, it was found that 46.7% (215 of 460) of patients with typical reflux symptoms had no endoscopic evidence of oesophagitis.[40] In a study from Singapore,[41] patients with NERD were significantly younger, more likely to have minor psychiatric morbidity and were less likely to respond to proton pump inhibitors (PPIs) compared with patients with erosive oesophagitis. 4. Mechanisms of Reflux in Asia Transient relaxation of the lower oesophageal sphincter has been implicated as the main pathophysiological mechanism causing GORD in the Western population.[3,42-44] Prolonged oesophageal acid clearance has been attributed to peristaltic dysfunction in patients with GORD.[45,46] However, in a study in Chinese patients, it was found that the © 2008 Adis Data Information BV. All rights reserved.

frequency of transient relaxation of the lower oesophageal sphincter was similar between patients with GORD and controls.[47] The frequency of such transient relaxation in patients with GORD in the Chinese population (approximately one per hour)[47] was lower when compared with the Western population, which ranged from three to eight per hour in patients with reflux disease and from two to six per hour in healthy subjects.[44] In this study, primary peristalsis was significantly impaired in patients with GORD in the Chinese population, suggesting that oesophageal motor dysfunction may contribute to the development of GORD in the Chinese population. The mechanisms of GORD may be different in the Chinese population compared with the Western population; however, further study will be required to clarify this interesting finding. 5. Is the Prevalence of GORD Increasing in Asia? The prevalence of oesophagitis in Asia may be increasing.[28,48] An increase in the prevalence of reflux oesophagitis from 3% in the 1970s to 10–15% in the late 1990s has been suggested by a Japanese comparative endoscopic study.[49] In a 1999 re-survey of a cohort of community residents in Singapore who were interviewed in an earlier study in 1994, Lim et al.[50] reported a >6-fold increase in the reporting of reflux symptoms, from a prevalence of 1.6% to a prevalence of 9.9% (figure 1). In a 1-year follow-up study in Hong Kong, Wong et al.[13,16] reported an increase in the annual, monthly and weekly prevalence of GORD symptoms from 29.8%, 8.9% and 2.5%, to 34.1%, 10.1% and 2.7%, 12 9.9

10 Prevalence (%)

3.2 Barrett’s Oesophagus in Asia

401

8 6 4 2

1.6

0 1994 (n = 696)

1999 (n = 237)

Fig. 1. Increasing population prevalence of gastro-oesophageal reflux disease in Singapore.[50] Increased prevalence was not related to age, smoking, alcohol, bodyweight or ethnicity.

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Cheung et al.

6. Extra-Oesophageal Manifestations of GORD A long list of other symptoms in addition to heartburn and acid regurgitation has been demonstrated in subsets of patients with GORD.[59,60] Some of these symptoms originate from the oesophagus and others from the oro-pharynx, larynx and the pulmonary system. In a population study from Hong Kong,[13] a significant association of GORD was found with chest pain, chronic cough and hoarseness of voice, asthma and pneumonia. However, only chest pain remained to be significantly associated with GORD on multiple logistic regression analyses (odds ratio: 2.7; 95% CI 2.1, 3.5). In this study, the prevalence of non-cardiac chest pain was found to be 14%. Being female, reports of symptoms of heartburn and/or acid regurgitation, and feeling that the chest pain compromised social life were independent factors for health seeking behaviour in this Chinese population. The association of GORD and non-cardiac chest pain was supported by a second © 2008 Adis Data Information BV. All rights reserved.

study from Hong Kong in which abnormal gastrooesophageal reflux was observed in 29% of chest pain patients with a normal coronary angiogram (n = 78) who underwent 24-hour pH monitoring.[12] An association of GORD with symptoms other than chest pain has been observed with other chronic disorders such as asthma. The treatment of severe reflux oesophagitis has been reported to be associated with the improvement in asthma symptoms in Japan (n = 72).[15] Another study from Japan showed that an improvement in asthma (>20% increase in peak expiratory flow) was observed in 38% of subjects with GORD compared with no improvement in those without GORD.[61] 7. Management of GORD The main goals in the treatment of GORD are to alleviate symptoms, heal oesophagitis, maintain remission, prevent any complications and improve quality of life.[4] 7.1 Lifestyle Modification

The American College of Gastroenterology updated guidelines for the treatment of GORD[62] state that elevation of the head of the bed, decreased fat, chocolate, alcohol, peppermint and coffee intake, cessation of smoking and avoiding recumbency for 3 hours postprandially may benefit many patients with GORD. However, these recommendations have not been well substantiated. A recent review of the effect of lifestyle measures on GORD[63] showed that there is a lack of high-quality, randomized, controlled studies evaluating lifestyle interventions 2002 2003

40 35

35 Prevalence (%)

respectively (figure 2). There have been some suggestions that the decrease in Helicobacter pylori infections may play a role in the increasing prevalence. The effects of H. pylori infection in patients with GORD has been vigorously debated in recent years. Most Asian epidemiological studies reported a lower prevalence of H. pylori infection among GORD patients.[51,52] Interventional studies investigating the effect of H. pylori eradication on GORD also yielded conflicting results. In a randomized study, H. pylori eradication did not produce any effect on symptom relapse after therapy with PPIs.[53] In contrast, another randomized controlled study performed in Hong Kong showed that H. pylori eradication led to more resilient GORD that was harder to control.[54] Obesity has been reported to be associated with oesophagitis.[55] An increase in body mass index and moderate weight gain among females of healthy weight has been shown in a recent study that it may cause or exacerbate symptoms of reflux.[56] It has been well documented that a highfat diet provokes reflux.[57,58] Obesity and increasing dietary fat intake has become more prevalent in the last decade in the Asia-Pacific region with the adoption of a Western lifestyle. These may contribute to the increasing prevalence of GORD in this region.

29.8

30 25 20 15 8.9

10 5

10.4

5.6 2.5

0 Weekly

Monthly

Yearly

GORD symptoms Fig. 2. Increasing population prevalence of gastro-oesophageal reflux (GORD) in Hong Kong over 12 months.[13,16]

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GORD in Asia

in GORD management and there is no convincing evidence for their efficacy. However, lifestyle modifications in the management of GORD should not be discarded entirely because they may play an adjunctive role with acid suppressing therapy or anti-reflux surgery.[64] Future research with well designed, randomized, controlled studies may help to answer this question.

403

demand fashion. Studies have shown that on-demand or intermittent treatments are effective and well tolerated in the management of NERD or mild erosive oesophagitis.[82] The disease spectrum of GORD is milder in Asians and therefore on-demand or intermittent therapy may also be useful for patients in the Asia-Pacific region. However, studies or data focused on patients in this region are lacking and further research in the area will be useful.

7.2 Medical Treatment

The medications that have been used to alleviate GORD symptoms include antacids, histamine H2 receptor antagonists, PPIs and prokinetic agents. Antacids have been shown to be more effective than placebo in relieving GORD symptoms;[65] however, the effect of antacids is generally mild. Both H2 receptor antagonists[66-68] and PPIs[69-72] have been shown to be effective in a large number of studies compared with placebo.[73] However, PPIs are more effective for control of symptoms and healing of oesophagitis than H2 receptor antagonists.[74-76] Despite this, H2 receptor antagonists are still used widely in many countries because of their availability and lower cost. Daily PPI therapy results in the healing of about 80% of moderate to severe reflux oesophagitis.[72,77,78] PPIs have been used for more than a decade and have been shown to be well tolerated with minor adverse effects.[79] A lower dose of PPI may be sufficient for control of symptoms in the Chinese compared with the Western population. A study performed in Hong Kong showed that lansoprazole 15 mg once daily provides a satisfactory decrease for oesophageal acid exposure and is equally effective for the treatment of GORD in the Chinese population.[80] Continuous therapy with PPIs has been shown to be effective in the control of symptoms and maintaining remission in patients with oesophagitis.[79] However, it has also been shown that a step-down therapy may be suitable for some patients. A study from the US demonstrated that >50% of the patients can be taken off PPIs and stepped down to H2 receptor antagonists or even no medication.[81] However, the only advantage of using less-effective therapy is purely economic.[62] As the cost of PPIs decreases, this strategy will become less favourable. Another strategy is intermittent or on-demand therapy. Many patients take their medication intermittently or in an on© 2008 Adis Data Information BV. All rights reserved.

7.3 Surgery

Laparoscopic fundoplication is well established as the main surgical treatment of GORD.[83] It corrects the cause of the disease and can prevent the need for long-term medication. One study had shown that during a follow-up period of 10–13 years, patients with complicated GORD who were treated with anti-reflux surgery were significantly less likely to take anti-reflux medications regularly, and when those medicines were discontinued, their GORD symptoms were significantly less severe than those of medically treated patients.[84] However, 62% of surgical patients took medications for GORD on a regular basis, and there were no significant differences between the medical and surgical treatment groups in the rates of neoplastic and peptic complications of GORD, overall physical and mental well-being scores, and satisfaction with antireflux therapy.[84] In addition, the benefit of surgery must be balanced against a 0.5–1% risk of operative mortality.[73,85] There are few publications on surgical treatment of GORD in Asia. Studies in Japan have shown that laparoscopic fundoplication can be safe and effective in selected patients.[86,87] Further research from other parts of Asia would be useful. 7.4 Endoscopic Therapy

The Asia-Pacific consensus on the management of GORD concluded in 2004 that endoscopic therapy is still evolving and should be performed in the context of clinical trials.[4] The same statement still holds true today. A lot of enthusiasm was generated when endoscopic treatment of GORD first appeared on the scene. These techniques and devices appeared to produce some improvement in symptoms, although many issues remain unanswered including long-term durability, safety and efficacy in routine Drugs 2008; 68 (4)

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Cheung et al.

clinical use outside of clinical trials, and its efficacy in atypical presentation of GORD.[62] It is outside the scope of this article to review these techniques in detail; at present, these should only be performed in a clinical trial setting.

10.

11.

8. Conclusions 12.

GORD will undoubtedly be a great challenge to clinicians both in primary care and in gastroenterology practice in the Asia-Pacific region in the coming years. Although typical reflux symptoms are less common than in the Western population, and the prevalence of erosive oesophagitis is lower and of a milder spectrum in the Asian population, the impact of the illness on the general population is huge and there is evidence of an increasing prevalence of GORD in Asia. PPIs remain the most effective medical treatment for GORD. Further research is needed to improve our knowledge of GORD in this region. Acknowledgements No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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27. Cho YS, Choi MG, Jeong JJ, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Asan-si, Korea. Am J Gastroenterol 2005 Apr; 100 (4): 74753 28. Wong BC, Kinoshita Y. Systematic review on epidemiology of gastroesophageal reflux disease in Asia. Clin Gastroenterol Hepatol 2006 Apr; 4 (4): 398-407 29. Wong WM, Lam SK, Hui WM, et al. Long-term prospective follow-up of endoscopic oesophagitis in southern Chinese: prevalence and spectrum of the disease. Aliment Pharmacol Ther 2002 Dec; 16 (12): 2037-42 30. Furukawa N, Iwakiri R, Koyama T, et al. Proportion of reflux esophagitis in 6010 Japanese adults: prospective evaluation by endoscopy. J Gastroenterol 1999 Aug; 34 (4): 441-4 31. Lee SJ, Song CW, Jeen YT, et al. Prevalence of endoscopic reflux esophagitis among Koreans. J Gastroenterol Hepatol 2001 Apr; 16 (4): 373-6 32. Rajendra S, Kutty K, Karim N. Ethnic differences in the prevalence of endoscopic esophagitis and Barrett’s esophagus: the long and short of it all. Dig Dis Sci 2004 Feb; 49 (2): 237-42 33. Johansson KE, Ask P, Boeryd B, et al. Oesophagitis, signs of reflux, and gastric acid secretion in patients with symptoms of gastro-oesophageal reflux disease. Scand J Gastroenterol 1986 Sep; 21 (7): 837-47 34. Johnsson F, Joelsson B, Gudmundsson K, et al. Symptoms and endoscopic findings in the diagnosis of gastroesophageal reflux disease. Scand J Gastroenterol 1987 Aug; 22 (6): 714-8 35. Lind T, Havelund T, Carlsson R, et al. Heartburn without oesophagitis: efficacy of omeprazole therapy and features determining therapeutic response. Scand J Gastroenterol 1997 Oct; 32 (10): 974-9 36. Galmiche JP, Barthelemy P, Hamelin B. Treating the symptoms of gastro-oesophageal reflux disease: a double-blind comparison of omeprazole and cisapride. Aliment Pharmacol Ther 1997 Aug; 11 (4): 765-73 37. Carlsson R, Dent J, Watts R, et al. Gastro-oesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole. International GORD Study Group. Eur J Gastroenterol Hepatol 1998 Feb; 10 (2): 119-24 38. Robinson M, Earnest D, Rodriguez-Stanley S, et al. Heartburn requiring frequent antacid use may indicate significant illness. Arch Intern Med 1998 Nov 23; 158 (21): 2373-6 39. Rosaida MS, Goh KL. Gastro-oesophageal reflux disease, reflux oesophagitis and non-erosive reflux disease in a multiracial Asian population: a prospective, endoscopy based study. Eur J Gastroenterol Hepatol 2004 May; 16 (5): 495-501 40. Wu JC, Chan FK, Ching JY, et al. Empirical treatment based on “typical” reflux symptoms is inappropriate in a population with a high prevalence of Helicobacter pylori infection. Gastrointest Endosc 2002 Apr; 55 (4): 461-5 41. Ang TL, Fock KM, Ng TM, et al. A comparison of the clinical, demographic and psychiatric profiles among patients with erosive and non-erosive reflux disease in a multi-ethnic Asian country. World J Gastroenterol 2005 Jun 21; 11 (23): 3558-61 42. Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980 Feb; 65 (2): 256-67 43. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982 Dec 16; 307 (25): 1547-52 44. Mittal RK, Holloway RH, Penagini R, et al. Transient lower esophageal sphincter relaxation. Gastroenterology 1995 Aug; 109 (2): 601-10 45. Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988 Jan; 94 (1): 73-80


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46. Holloway RH. Esophageal body motor response to reflux events: secondary peristalsis. Am J Med 2000 Mar 6; 108 Suppl 4a: 20-6S 47. Wong WM, Lai KC, Hui WM, et al. Pathophysiology of gastroesophageal reflux diseases in Chinese: role of transient lower esophageal sphincter relaxation and esophageal motor dysfunction. Am J Gastroenterol 2004 Nov; 99 (11): 2088-93 48. Ho KY, Cheung TK, Wong BC. Gastroesophageal reflux disease in Asian countries: disorder of nature or nurture? J Gastroenterol Hepatol 2006 Sep; 21 (9): 1362-5 49. Hongo M, Shoji T. Epidemiology of reflux disease and CLE in East Asia. J Gastroenterol 2003 Mar; 38 Suppl. 15: 25-30 50. Lim SL, Goh WT, Lee JM, et al. Changing prevalence of gastroesophageal reflux with changing time: longitudinal study in an Asian population. J Gastroenterol Hepatol 2005 Jul; 20 (7): 995-1001 51. Wu JC, Sung JJ, Ng EK, et al. Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux disease: a study from the East. Am J Gastroenterol 1999 Jul; 94 (7): 1790-4 52. O’Connor HJ. Review article: Helicobacter pylori and gastrooesophageal reflux disease-clinical implications and management. Aliment Pharmacol Ther 1999 Feb; 13 (2): 117-27 53. Moayyedi P, Bardhan C, Young L, et al. Helicobacter pylori eradication does not exacerbate reflux symptoms in gastroesophageal reflux disease. Gastroenterology 2001 Nov; 121 (5): 1120-6 54. Wu JCY, Chan FKL, Ching JYL, et al. Effect of Helicobacter pylori eradication on treatment of gastro-oesophageal reflux disease: a double blind, placebo controlled, randomised trial. Gut 2004; 53 (2): 174-9 55. Wilson LJ, Ma W, Hirschowitz BI. Association of obesity with hiatal hernia and esophagitis. Am J Gastroenterol 1999 Oct; 94 (10): 2840-4 56. Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006 Jun 1; 354 (22): 2340-8 57. Holloway RH, Lyrenas E, Ireland A, et al. Effect of intraduodenal fat on lower oesophageal sphincter function and gastro-oesophageal reflux. Gut 1997 Apr; 40 (4): 449-53 58. Galmiche JP. Gastro-oesophageal reflux: does it matter what you eat? Gut 1998 Mar; 42 (3): 318-9 59. Richter JE. Extraesophageal presentations of gastroesophageal reflux disease: an overview. Am J Gastroenterol 2000 Aug; 95 (8 Suppl.): S1-3 60. Fennerty MB. Extraesophageal gastroesophageal reflux disease. Presentations and approach to treatment. Gastroenterol Clin North Am 1999 Dec; 28 (4): 861-73, vi 61. Tsugeno H, Mizuno M, Fujiki S, et al. A proton-pump inhibitor, rabeprazole, improves ventilatory function in patients with asthma associated with gastroesophageal reflux. Scand J Gastroenterol 2003 May; 38 (5): 456-61 62. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005 Jan; 100 (1): 190-200 63. Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med 2006 May 8; 166 (9): 965-71 64. Wani S, Sharma P. Review: sparse evidence supports lifestyle modifications for reducing symptoms of gastroesophageal reflux disease. ACP J Club 2006 Sep-Oct; 145 (2): 44 65. Weberg R, Berstad A. Symptomatic effect of a low-dose antacid regimen in reflux oesophagitis. Scand J Gastroenterol 1989 May; 24 (4): 401-6 66. Breen KJ, Desmond PV, Whelan G. Treatment of reflux oesophagitis: a randomized, controlled evaluation of cimetidine. Med J Aust 1983 Nov 26; 2 (11): 555-8

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67. Johansson KE, Boeryd B, Johansson K, et al. Double-blind crossover study of ranitidine and placebo in gastro-oesophageal reflux disease. Scand J Gastroenterol 1986 Sep; 21 (7): 769-78 68. Palmer RH, Frank WO, Rockhold FW, et al. Cimetidine 800mg twice daily for healing erosions and ulcers in gastroesophageal reflux disease. J Clin Gastroenterol 1990; 12 Suppl. 2: S29-34 69. Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988 Oct; 95 (4): 903-12 70. Cloud ML, Enas N, Humphries TJ, et al. Rabeprazole in treatment of acid peptic diseases: results of three placebo-controlled dose-response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). The Rabeprazole Study Group. Dig Dis Sci 1998 May; 43 (5): 9931000 71. Earnest DL, Dorsch E, Jones J, et al. A placebo-controlled doseranging study of lansoprazole in the management of reflux esophagitis. Am J Gastroenterol 1998 Feb; 93 (2): 238-43 72. Richter JE, Bochenek W. Oral pantoprazole for erosive esophagitis: a placebo-controlled, randomized clinical trial. Pantoprazole US GERD Study Group. Am J Gastroenterol 2000 Nov; 95 (11): 3071-80 73. Moayyedi P, Talley NJ. Gastro-oesophageal reflux disease. Lancet 2006 Jun 24; 367 (9528): 2086-100 74. Armstrong D, Pare P, Pericak D, et al. Symptom relief in gastroesophageal reflux disease: a randomized, controlled comparison of pantoprazole and nizatidine in a mixed patient population with erosive esophagitis or endoscopy-negative reflux disease. Am J Gastroenterol 2001 Oct; 96 (10): 2849-57 75. Bardhan KD, Hawkey CJ, Long RG, et al. Lansoprazole versus ranitidine for the treatment of reflux oesophagitis. UK Lansoprazole Clinical Research Group. Aliment Pharmacol Ther 1995 Apr; 9 (2): 145-51 76. Dehn TC, Shepherd HA, Colin-Jones D, et al. Double blind comparison of omeprazole (40mg od) versus cimetidine (400mg qd) in the treatment of symptomatic erosive reflux oesophagitis, assessed endoscopically, histologically and by 24h pH monitoring. Gut 1990 May; 31 (5): 509-13 77. Gillessen A, Beil W, Modlin IM, et al. 40mg pantoprazole and 40mg esomeprazole are equivalent in the healing of esophageal lesions and relief from gastroesophageal reflux disease-related symptoms. J Clin Gastroenterol 2004 Apr; 38 (4): 332-40


Cheung et al.

78. Vakil N. Review article: esomeprazole, 40mg once daily, compared with lansoprazole, 30mg once daily, in healing and symptom resolution of erosive oesophagitis. Aliment Pharmacol Ther 2003 Feb; 17 Suppl. 1: 21-3 79. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2000 Apr; 118 (4): 661-9 80. Wong WM, Lai KC, Hui WM, et al. Double-blind, randomized controlled study to assess the effects of lansoprazole 30mg and lansoprazole 15mg on 24-h oesophageal and intragastric pH in Chinese subjects with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2004 Feb 15; 19 (4): 455-62 81. Inadomi JM, Jamal R, Murata GH, et al. Step-down management of gastroesophageal reflux disease. Gastroenterology 2001 Nov; 121 (5): 1095-100 82. Bardhan KD. Intermittent and on-demand use of proton pump inhibitors in the management of symptomatic gastroesophageal reflux disease. Am J Gastroenterol 2003 Mar; 98 (3 Suppl.): S40-8 83. Booth MI, Stratford J, Thompson E, et al. Laparoscopic antireflux surgery in the treatment of the acid-sensitive oesophagus. Br J Surg 2001 Apr; 88 (4): 577-82 84. Spechler SJ, Lee E, Ahnen D, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001 May 9; 285 (18): 2331-8 85. Finlayson SR, Laycock WS, Birkmeyer JD. National trends in utilization and outcomes of antireflux surgery. Surg Endosc 2003 Jun; 17 (6): 864-7 86. Katada N. Review article: surgical and endoscopic therapy of gastro-oesophageal reflux disease in Japan. Aliment Pharmacol Ther 2004 Dec; 20 Suppl. 8: 28-31 87. Takeyama S, Numata A, Nenohi M, et al. Laparoscopic Nissen fundoplication for gastroesophageal reflux disease in Japan. Surg Today 2004; 34 (6): 506-9

Correspondence: Dr Ting K. Cheung, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. E-mail: [email protected]

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Drugs 2008; 68 (4): 407-415 0012-6667/08/0004-0407/$53.45/0

LEADING ARTICLE


Overview of the Management of Acute Gout and the Role of Adrenocorticotropic Hormone Naomi Schlesinger Division of Rheumatology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Abstract

It is important to distinguish between therapy used to reduce acute inflammation in gout and therapy used to manage hyperuricaemia in patients with chronic gouty arthritis. This article discusses treatments for acute gout, emphasizing the use of corticotrophin (adrenocorticotropic hormone; ACTH) and the evidence on which we base our treatment of acute gout. There are no formal guidelines for the treatment of acute gout and only a few randomized controlled trials have been conducted to evaluate the efficacy of the various treatments for acute gout. The options available for the treatment of acute attacks of gout are NSAIDs, colchicine, corticosteroids, corticotropin and intra-articular corticosteroids. Most rheumatologists practicing in the US use combination therapy to treat acute gout, a practice that merits study. In a patient without complications, NSAIDs are the preferred therapy. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon NSAID therapy is initiated. Exciting new research shows that corticotropin acts peripherally by activation of the melanocortin type 3 receptor, and this could be responsible, at least in part, for its efficacy in acute gout. Hopefully, this will lead to renewed interest in corticotropin as a treatment for acute gout.

Gouty arthritis is the most common inflammatory arthritis in men aged >40 years.[1] The US National Health Interview Survey from 1983 to 1985 determined the prevalence rate of self-reported gout to be 13.6 cases per 1000 men and 6.4 cases per 1000 women. These numbers reflect an approximate 3-fold increase in the prevalence of gout since 1969.[2] Ongoing reviews of the Cochrane collaboration show that there is little reliable information on which to base treatment decisions in acute gout.[3-5] Wortmann[6] uses the analogy “Gout is like matches”. Everyone has uric acid in their blood and high levels may cause gout. When too much uric

acid accumulates around the joints, the uric acid acts like matches. An acute gout attack may be likened to “setting the joint on fire” and is characterized by rapid onset and build-up of pain. During an acute gout attack, the patient endures exquisite pain associated with warmth, redness, swelling and decreased range of motion of the affected joint. The initial episode is usually monoarticular. The first metatarsophalangeal joint is the initial joint involved in approximately one-half of the patients. Other joints involved (in decreasing order of frequency) include insteps, heels, knees, wrists, fingers and elbows.[7] Systemic symptoms and signs of fatigue, fever and

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chills may accompany the acute arthritis. The natural course of the untreated arthritis varies from episodes that last several hours to those lasting several weeks. There are three stages in the management of gout: (i) treating the acute attack; (ii) lowering excess stores of uric acid to prevent tissue deposition of urate and flares of gouty arthritis; and (iii) providing prophylaxis to prevent acute flares. It is important to distinguish between therapy used to reduce acute inflammation in acute gout and therapy used to manage hyperuricaemia in patients with chronic gouty arthritis. A single trial, conducted by Bellamy and colleagues,[8] examined the natural course of acute gout. In the absence of adequate placebo-controlled trials, this study serves as a benchmark for comparing the efficacy of treatments for gout. In this 7-day study, 2 of 11 patients withdrew because of severe persistent pain after 4 days. All of the remaining patients showed some improvement in pain by day 5 and in swelling by day 7. Tenderness improved in seven of the nine remaining patients; however, full resolution of pain was observed in only three patients. This review addresses accepted pharmacological treatment of acute gout and focuses on corticotrophin (adrenocorticotropic hormone; ACTH) as an option for the management of acute gout. 1. Treatment of Acute Gout The goal of therapy in an acute gout attack is prompt and safe termination of pain and inflammation. Acute gout is usually treated with NSAIDs and/ or colchicine.[9,10] Other treatments for acute gout need further evaluation. These include (i) intra-articular administration of corticosteroids once infection is excluded; (ii) oral or intravenous corticosteroids in patients in whom NSAIDs are contraindicated; and (iii) intramuscular or subcutaneous injections of corticotropin. Few randomized controlled trials have been conducted to evaluate the efficacy of the various treatments for acute gout. Current treatment for acute gout is based more on practitioners’ experience and small uncontrolled trials than on evi© 2008 Adis Data Information BV. All rights reserved.

dence-based medicine.[3,4,11] The perceived potency of drugs, adverse effect profiles, tolerability and clinicians’ preference for available drugs for acute gout dictate treatment choices made by physicians. 1.1 Non-Pharmacological Treatment

Joint motion may increase inflammation in experimental gout, whereas rest of affected joints may aid in its resolution.[12] Less medication is needed if the patient can rest the afflicted joint for 1–2 days.[13] Cold applications to the affected joints may be a useful adjunct to treatment of acute gout. In a prospective randomized trial, patients with acute gout treated with topical ice had a greater reduction in pain (p = 0.021), joint circumference and synovial fluid volume compared with the control group.[14] In an animal study, heat application to an inflamed joint exacerbated the inflammation.[15] 1.2 Pharmacological Treatment

Colchicine and NSAIDs are the most commonly used drugs in the treatment of acute gout.[9] In the largest survey of rheumatologists evaluating the treatment of gout to be conducted in the US to date,[16] most rheumatologists (64%) were found to use combination therapy to treat acute gout, whereas internists tended to use monotherapy (p = 0.0005). The most frequently used combination therapies for acute gout attacks in an otherwise healthy patient were (i) NSAIDs with intra-articular corticosteroid (43%); (ii) NSAIDs with oral corticosteroids (33%); (iii) NSAIDs with oral colchicine (32%); and (iv) NSAIDs alone (27%). In the French study by Rozenberg et al.,[17] the most widely prescribed treatments in acute gout attack were colchicine alone (63%), colchicine with an NSAID (31.7%) and NSAID alone (5.2%). Another study evaluating the treatment of hospitalized patients with acute gout found combination antiinflammatory agents to be used in >50% of patients.[18] The use of combination anti-inflammatory drugs to treat acute gout is not what is described in most textbooks and reviews.[9,19] There is little or no Drugs 2008; 68 (4)

Management of Acute Gout

literature to support such a practice; therefore, this common practice merits study. In the large, American survey study,[16] NSAIDs were reported to be the most commonly used monotherapy (77%) in an otherwise healthy patient, followed by intra-articular corticosteroid injections (47%), oral prednisone (42%), oral colchicine (37%), intramuscular triamcinolone (11%) and intramuscular corticotropin (5%). Intravenous colchicine was used by 4% of rheumatologists. Oral corticosteroids were reported to be the most commonly used monotherapy in a patient with renal failure. NSAIDs were the most commonly used drugs in acute gout in other survey studies too.[20-22] Among Canadian doctors, only 11% of family physicians and 6% of rheumatologists would use colchicine in acute gout.[20] A similar preference for NSAIDs has been noted in Australia[21] and New Zealand.[22] In contrast, a French study found colchicine to be the most commonly used drug as monotherapy.[17] 1.2.1 Oral Colchicine

Colchicine is an alkaloid derived from the autumn crocus, Colchicum Autumnale, also known as meadow saffron. Colchicum in the form of extracts from the bulb of the meadow saffron was known from antiquity, although it came into widespread use only around 1800.[23,24] Padanius Dioscorides, a Greek surgeon in the Roman Army during the rule of Nero (AD 54–68), first described the meadow saffron in his influential De Materia Medica, a pharmacopeia that systematically described about 600 plants.[25] Throughout the years, many historians, physicians and pharmacopeias have noted the beneficial effects of colchicum extracts for the treatment of gout. It was not until 1820 when colchicine, the pharmacologically active constituent of the plant, was isolated by the French chemists Pelletier and Caventon.[26] The absolute configuration was determined by Corrodi and Hardegger[27] in 1955. The precise mechanism by which colchicine relieves the intense pain of gout is not known. However, it is believed that the major relief of pain involves the significant pharmacological action of 1

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colchicine is binding to tubulin dimers.[28] Colchicine is also suspected to interfere with many leukocyte functions, including diapedesis (ameboid movement), mobilization, lysosomal degranulation and, most importantly, leukocyte chemotaxis. Colchicine alters the expression of a number of cell surface proteins, including: (i) downregulation of tumour necrosis factor-α receptors, insulin and βadrenergic receptors;[29,30] (ii) inhibition of the release of chemotactic factors, which inhibit signalling for activation in neutrophils exposed to monosodium urate (MSU) crystals, and reduce adhesion and recruitment of polymorphonuclear leukocytes to the inflamed joint via suppression of neutrophil L-selectin expression and alteration of Eselectin distribution on stimulated endothelial cells; and (iii) suppression of MSU crystal-induced NALP31 inflammasome-driven caspase-1 activation and interleukin (IL)-1β processing.[31] The absorption of oral colchicine is rapid but incomplete (time to maximum concentration is 2 hours; bioavailability is 25–50%). However, absorption can be highly variable. The onset of action (relief of gout pain) is 8 hours when given intravenously and approximately 24 hours when given orally. The half-life of colchicine after an oral dose in patients with normal renal and hepatic functions is 9 hours; whereas, in patients with renal failure, it is 2–3 times longer than normal (about 24 hours), and in cirrhotic patients with renal failure, it is ten times longer than normal (approximately 4 days).[32] Ongoing reviews of the Cochrane collaboration[33] found only one placebo-controlled trial of colchicine treatment in acute gout.[34] All other data reported were accumulated by review rather than prospective studies. In this placebo-controlled study, Ahern et al.[34] studied 43 patients (40 men and 3 women); 22 patients received colchicine 1 mg then 0.5 mg every 2 hours until complete response or toxicity. The remaining 21 patients received placebo. No NSAIDs were used during the study. All patients had MSU crystals in their synovial fluid. In this study, two-thirds of the colchicine-treated patients improved after 48 hours, but only one-third of

Nacht domain-, leucin-rich repeat-, and pyrin domain containing protein 3.


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the patients receiving placebo demonstrated similar improvement. Colchicine was more effective when used within 24 hours of an acute attack. However, >80% of patients experienced nausea, vomiting, diarrhoea and abdominal pain after oral administration of colchicine before full clinical improvement.[34] Colchicine has the smallest benefit-to-toxicity ratio of the drugs that are used in the management of gout.[35] There have been published cases of death occurring after colchicine doses as low as 6 or 7 mg.[36] In response, maximum recommended doses have been reduced to 6 mg (in New Zealand)[37,38] and 10 mg (in the UK).[39] Guidelines for the prescription of colchicine prepared by Medsafe, New Zealand’s drug safety agency,[37] recommend reducing the maximum dose in the first 24 hours to 2.5 mg and reducing maximum cumulative dose to 6 mg over 4 days (3 mg in the elderly). Doses of colchicine as advised by the British National Formulary are as follows: 1 mg initially followed by 500 µg every 2–3 hours until relief of pain is obtained, vomiting or diarrhoea occurs, or until a total dose of 6 mg has been reached; the course should not be repeated within 3 days.[39] To prevent adverse effects, Morris et al.[40] suggest that in acute gout, colchicine should be used at lower doses (500 µg three times a day or less frequently, especially in those with renal impairment). Colchicine should not be used if the glomerular filtration rate (GFR) is 100 000 hospitalizations and 16 500 deaths each year in the US alone. Endoscopic studies indicate that gastric or duodenal ulcers develop in between 15% and 30% of patients who regularly take NSAIDs.[45] The gastrointestinal adverse effects of NSAIDs may be lessened by co-administration of a proton pump inhibitor. Other adverse effects of NSAIDs include reduced creatinine clearance, hyperkalaemia, fluid overload in patients with CHF and elevations in liver enzymes. Elderly patients, those with established gastrointestinal disease and those with impaired renal function are at greatest risk for NSAID-associated adverse effects.[46] A number of head-to-head randomized controlled studies conducted between 1973 and 2007 in patients with acute gout show equivalence between many NSAIDs, including Smythe and Percy,[47] Ruotsi and Vainio,[48] Altman et al.,[49] Weiner et al.,[50] Shrestha et al.,[51] Macagno et al.,[52] Schumacher et al.,[53] Rubin et al.[54] and Willburger et al.[55] There are no randomized controlled trials directly comparing colchicine with NSAIDs. 1.2.4 Intra-Articular Corticosteroids

Intra-articular corticosteroids are currently accepted as beneficial when one or two joints are actively inflamed.[56] Patients with polyarticular gout who demonstrate suboptimal or delayed response to oral NSAIDs or who have contraindications to usual NSAIDs may also benefit from adjunctive corticosteroid injections into joints with persistent synovitis.[57] Ensuring that the joint is not infected prior to injecting intra-articular corticosteroids is particularly important. [58]

In an open trial, small intra-articular doses of triamcinolone (10 mg in knees and 8 mg in small joints) helped resolve 20 attacks of gout in 19 men. The joints involved were 11 knees, four metatarsophalangeal joints, three ankles and two wrists. All had MSU crystals identified in the joints. After intra-articular injection of triamcinolone, the attack had resolved in 11 joints (55%) at 24 hours and in nine joints (45%) at 48 hours. All the attacks were fully resolved at 48 hours. © 2008 Adis Data Information BV. All rights reserved.

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1.2.5 Systemic Corticosteroids

Systemic corticosteroids have been used for the treatment of acute gout since 1952. Corticosteroids can be given to those patients who cannot use NSAIDs or colchicine, and administered orally, intravenously or intramuscularly. Prednisone can be given at a dose of approximately 30 mg for 1–3 days and then tapered over 1–2 weeks. Tapering more rapidly can result in a rebound flare. Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications. In a prospective trial using systemic corticosteroid treatment for acute gout in patients who had contraindications to the use of NSAIDs, Groff et al.[59] noted improvement within 12–48 hours. Thirteen consecutive patients with 15 episodes of acute gout were treated with systemic corticosteroids. Sufficient records were available for 12 patients and 13 attacks (mean age was 65 years; seven men and five women). Eight of 12 patients had MSU crystalproven gout. In 11 of 13 attacks, complete resolution of the signs and symptoms occurred within 7 days and within 10 days in the remaining two attacks. Patients with more than five involved joints required longer courses of therapy (mean of 17 days). Nine patients received an initial dose of 20–50 mg/day with a tapering dose over a mean time of 10.5 days (4–20 days). Three patients with greater than five joints involved, longer duration of symptoms and one patient with multiple myeloma received either intravenous prednisolone or a prolonged prednisone taper over a mean of 17 days. Comparison of different administration regimens has not been done. Alloway et al.[60] reported 23 patients presenting within 5 days of onset of an acute gout attack. They noted that resolution of all symptoms occurred at an average of 8 days for patients treated with oral indometacin (50 mg twice daily) and 7 days for patients treated with intramuscular triamcinolone (60 mg). Despite the fact that the patients receiving triamcinolone tended to have a longer duration of symptoms before the onset of therapy and a greater number of joints involved, resolution of all symptoms tended to occur more quickly in this group; Drugs 2008; 68 (4)

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however, the difference was not statistically significant. 1.3 Corticotropin

For >50 years, researchers have questioned the benefits of corticotropin in the treatment of acute gout. In 1949, Hench et al.[61] showed corticotropin possessed anti-arthritic properties. Early anecdotal reports[62-64] reported alleviation of pain and inflammation when using corticotropin in acute gout. ACTH is a hormone secreted by the pituitary gland, which stimulates the production of cortisol, corticosterone and androgens by the pituitary. The exact mechanism of action of corticotropin upon the inflammatory process in gout is not well understood. Studies involving corticotropin biochemistry, analogously using α and γ melanocyte stimulating hormones (MSH) [fragmented portions of ACTH] sheds some light upon the pharmacophysiology of this treatment. The use of corticotropin was believed to exert its main beneficial effect by adrenal corticosteroid release. New evidence shows that corticotropin acts peripherally by activation of a melanocortin receptor, the melanocortin type 3 receptor (MC3R), and this could be responsible, at least in part, for the efficacy of corticotropin in acute gout.[65,66] Getting et al.[67] demonstrated that smaller fragments of α-MSH and β-MSH could inhibit MSU crystal-induced neutrophil migration, and release of pro-inflammatory cytokines and chemokines; a phenomenon previously described in other acute inflammation models.[68,69] These antiinflammatory effects occurred in a corticosteroneindependent manner, hence, no reflex stimulation of the hypothalamic-pituitary-adrenal (HPA) axis was observed. A rat knee joint model of inflammation was developed where, following MSU crystal injection, there was migration of neutrophils preceded by the release of IL-1β and IL-6. Local corticotropin administration inhibited inflammation in a corticosterone-independent manner and displayed efficacy in adrenelectomized rats. This demonstrated that significant anti-inflammatory effects of corticotropin are HPA axis independent because this was not mediated by the MC2R expressed on the adrenal © 2008 Adis Data Information BV. All rights reserved.

gland.[70] Electron microscopy was able to demonstrate the specific distribution of the MC3R on the cell protrusions of knee joint macrophages.[65] MC3R is present on cells of the CNS, peripheral tissues and immune cells, namely, the brain and gut, yet not expressed in the adrenal gland. Ritter et al.[71] conducted a retrospective chart review of 33 patients with acute gout (38 episodes) and five patients with acute pseudogout (five episodes) who received corticotropin. These patients had multiple medical problems. Eleven patients had a MSU crystal-confirmed diagnosis. The most commonly documented indications for corticotropin were as follows: CHF (n = 18), chronic renal failure (n = 20), history of gastrointestinal bleeding (n = 10) and lack of response to NSAIDs or colchicine (n = 6). The mean age of patients was 66 years (range 43–93 years). Patients were treated with intravenous (n = 27), intramuscular (n = 6) or subcutaneous (n = 5) corticotropin. Thirty-four episodes of gout were treated with corticotropin 40 IU every 8 hours and four episodes were treated with 80 IU every 8 hours. Doses were tapered each day according to clinical improvement (e.g. decrease in synovitis and improved range of movement). The most common regimen (90%) was 40 IU every 8 hours, followed by 40 IU every 12 hours and then 40 IU once a day. Duration of therapy was 1–14 days. Prophylactic colchicine was given in 79% of patients (n = 30) as the corticotrophin dose was tapered. A 97% resolution rate was reported. In some patients, resolution was within the first day. Mean time to complete resolution was 5.5 days. A relapse rate of 11% (n = 4) was noted. The authors concluded that corticotropin is effective in patients with multiple medical problems such as CHF, renal failure and gastrointestinal bleeding. In a prospective, quasi-randomized, non-blinded, controlled study involving 76 patients who presented within 24 hours of onset of an acute gouty attack, Axelrod and Preston[72] compared parental corticotropin (a single dose of 40 IU administered intramuscularly) with oral indometacin 50 mg four times daily with food until pain subsided. For subsequent attacks, patients continued treatment with the asDrugs 2008; 68 (4)


signed study medication and were followed for 1 year. During each treatment course, the patients were treated and observed for 5 hours until released. Patients reported for follow-up 5–7 days after each attack and were assessed for time to pain relief, ability to walk and occurrence of adverse effects. Diagnosis was confirmed by MSU crystals in all patients. The mean pain interval from administration of the study drug to complete pain relief was 3 ± 1 hour with corticotropin and 24 ± 10 hours with indometacin (p < 0.0001). Pain resolved within 4 hours and no adverse effects were noted in 36 patients who received intramuscular corticotropin for their gouty attack. They concluded that the patients who received corticotropin experienced a quicker onset of pain relief than those who received oral indometacin. However, the patients in this study had to present within 24 hours of the onset of an acute gout attack, could not have tophaceous gout or renal insufficiency, and could not be taking colchicine, allopurinol or probenecid. Therefore, these results may not be reproducible in a more complicated patient population. In addition, the study was not blinded and adverse effects with corticotropin were not mentioned. Siegel et al.,[73] in a non-randomized, non-blinded, controlled study, prospectively compared patients receiving a single dose of intramuscular corticotropin 40 IU (n = 16) with patients receiving intramuscular triamcinolone 60 mg (n = 15) in acute gout. Both groups had similar mean times to complete resolution (7.9 and 7.6 days, respectively). The triamcinolone group required fewer repeat injections compared with the corticotropin group. Repeat injection was needed in 9 of 15 patients receiving corticotropin but only 5 of 16 receiving triamcinolone. In addition, many corticotropin recipients required a third injection to treat rebound attacks. This could have been related to a lack of equivalent doses between the two medications. Thus, there are no convincing data that such therapy is superior to corticosteroids. In a recent review, Taylor et al.[74] concluded that corticotropin alone or in combination with colchicine is effective in the treatment of acute gout. © 2008 Adis Data Information BV. All rights reserved.

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Potential adverse effects include hypokalaemia, worsened glycaemic control in patients with diabetes mellitus, fluid retention, and possible gout relapse and flares. Corticotropin may be useful in treating acute gout in patients in whom traditional agents, such as NSAIDS, have failed, and in patients with renal and or gastrointestinal contraindications to other therapies. 2. Summary and Conclusions There are no formal guidelines for the treatment of acute gout, and only a few randomized controlled trials have been conducted to evaluate the efficacy of the various treatments for acute gout. Therefore, adverse effects and clinical preferences have dictated drug choices. The optimal therapy for any given patient should be tailored to suit the individual’s needs. The options available for the treatment of acute gout attacks are NSAIDs, colchicine, corticosteroids, corticotropin and intra-articular corticosteroids. Most American rheumatologists use combination therapy to treat acute gouty arthritis, a practice which merits study. In a patient without complications, NSAIDs are the preferred therapy. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon NSAID therapy is initiated. In >90% of patients, complete resolution of the attack occurs within 5–8 days of initiation of therapy. Exciting new research shows that ACTH acts peripherally by activation of the melanocortin type 3 receptor, and this could be responsible, at least in part, for the efficacy of corticotropin in acute gout. This will hopefully lead to renewed interest in corticotropin as a treatment for acute gout. Randomized, long-term, prospective, placebo-controlled trials are needed to evaluate the therapeutic role of corticotropin versus NSAIDs and other treatment modalities, such as corticosteroids, in the treatment of acute gout. Acknowledgements No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review.

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ticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949 Apr 13; 24: 181-97

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63. Wolfson WQ, Cohn C, Levine R. Rapid treatment of acute gouty arthritis by concurrent administration of pituitary a adrenocorticotropic hormone (ACTH) and colchicine. J Lab Clin Med 1949; 34: 1766-8

47. Smythe CJ, Percy JS. Comparison of indomethacin and phenylbutazone in acute gout. Ann Rheum Dis 1973; 32 (4): 351-3 48. Ruotsi A, Vainio U. Treatment of acute gouty arthritis with proquazone and indomethacin: a comparative double-blind trial. Scan J Rheumatol 1978; Suppl. 21: 15-7

64. Hollander JL, Brown EM, Elkinton JR. ACTH and testosterone in gouty arthritis: preliminary report. In: Mote J, editor. Proceedings of the Second Clinical ACTH Conference. Vol. 2. Philadelphia (PA): Blakston, 1951: 122-5

49. Altman RD, Honig S, Levin JM, et al. Ketoprofen versus indomethacin in patients with acute gouty arthritis: a multicenter, double blind comparative study. J Rheumatol 1988; 15: 1422-6

65. Getting SJ, Christian HC, Flower RJ, et al. Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum 2002 Oct; 46 (10): 2765-75

50. Weiner GI, White SR, Weitzner RI, et al. Double blind study of phenoprofen versus phenylbutazone in acute gouty arthritis. Arthritis Rheum 1979; 22: 425-6

66. Getting SJ, Lam CW, Chen AS, et al. Melanocortin 3 receptors control crystal-induced inflammation. FASEB J 2006; 20: 2234-24

51. Shrestha M, Morgan DL, Moreden JM, et al. Randomized double-blind comparison of the analgesic efficacy of intramuscular ketorolac and oral indomethacin in the treatment of acute gouty arthritis. Ann Emerg Med 1995; 26: 682-6 52. Macagno A, Di Giorgio E, Romanowicz A. Effectiveness of etodolac (lodine) compared with naproxen in patients with acute gout. Curr Med Res Opin 1991; 12: 423-9 53. Schumacher HR, Boice J, Dahikh DI, et al. Randomized double blind trial of etoricoxib and indomethacin in treatment of acute gouty arthritis. BMJ 2002; 324: 1488-92 54. Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120mg once daily compared with indomethacin 50mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004; 50: 598606 55. Willburger RE, Mysler E, Derbot J, et al. Lumiracoxib 400mg once daily is comparable to indomethacin 50mg three times daily for the treatment of acute flares of gout. Rheumatology 2007; 46: 1126-32 56. Gordon GV, Schumacher HR. Management of gout. Am Fam Physician 1969; 10: 62-6 57. Gray RG, Tenenbaum J, Gottlieb NL. Local corticosteroid injection treatment in rheumatic disorders. Semin Arthritis Rheum 1979; 10: 231-54 58. Fernandez C, Noguera R, Gonzalez JA, et al. Treatment of acute attacks of gout with small doses of intraarticular triamcinolone acetonide. J Rheumatol 1999; 26: 2285-6 59. Groff GD, Franck WA, Raddatz DA. Systemic steroid therapy for acute gout: a clinical trial and review of the literature. Semin Arthritis Rheum 1990; 19: 329-36 60. Alloway JA, Moriarty MJ, Hoogland YT, et al. Comparison of triamcinolone acetonide with indomethacin in the treatment of acute gouty arthritis. J Rheumatol 1993; 20: 111-3 61. Hench PS, Kendall EC, Slocumb CH, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocor-


67. Getting SJ, Gibbs L, Clark AJL, et al. POMC gene derived peptides activate MC3R on murine macrophages, suppress cytokine release and inhibit neutrophil migration in acute experimental inflammation. J Immunol 1999; 162: 7446-53 68. Cannon JG, Tatro JB, Reichlin S, et al. Alpha melanocyte stimulating hormone inhibits immunostimulatory and inflammatory actions of interleukin 1. J Immunol 1986; 137: 2232-6 69. Hiltz ME, Catania A, Lipton JM. α-MSH peptides inhibit acute inflammation induced in mice by rIL-1β, rIL-6, rTNF and endogenous pyrogen but not that caused by LTB4, PAF and IL-8. Cytokine 1992; 4: 320-32 70. Getting SJ. Targeting melanocortin receptors as potential novel therapeutics. Pharmacol Ther 2006; 111: 1-15 71. Ritter J, Kerr LD, Valeriano-Marcet J, et al. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol 1994; 21 (4): 696-9 72. Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum 1988; 31: 803-5 73. Seigel LB, Alloway JA, Nashel DJ. Comparison of adrenocorticotropic hormone and triamcinolone acetonide in the treatment of gouty arthritis. J Rheumatol 1994; 21: 1325-7 74. Taylor CT, Brooks NC, Kelley KW. Corticotropin for acute management of gout. Ann Pharmacother 2001; 35: 365-8

Correspondence: Dr Naomi Schlesinger, Chief, Division of Rheumatology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Pl., P.O. Box 19, New Brunswick, NJ 08903-0019, USA. E-mail: [email protected]

Drugs 2008; 68 (4)

Drugs 2008; 68 (4): 417-437 0012-6667/08/0004-0417/$53.45/0

REVIEW ARTICLE


Oral Colorectal Cleansing Preparations in Adults Sherief Shawki and Steven D. Wexner Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, Florida, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 1. Aim of Bowel Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418 2. Historical Background and Review of Modes of Action of Various Bowel Preparation Methods and Adjuncts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418 3. Current Preparations: an Evidence-Based Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420 3.1 Polyethylene Glycol (PEG) Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420 3.1.1 PEG-Electrolyte Lavage Solution (PEG-ELS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420 3.1.2 Sulfate-Free (SF)-PEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 3.1.3 Low-Volume PEG-ELS and PEG-3350 with Bisacodyl Delayed Release . . . . . . . . . . . . . . . . 424 3.1.4 Dose Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 3.2 Sodium Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 3.2.1 Aqueous Sodium Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 3.2.2 Electrolyte, Haemodynamic and Mucosal Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 3.2.3 Sodium Phosphate Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 3.2.4 Adjuncts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 3.2.5 Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 3.2.6 Dose Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 4. Current Status of Mechanical Bowel Preparation before Elective Colorectal Surgery . . . . . . . . . . . . 429 4.1 Oral Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 5. Cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 6. Conclusions and General Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 6.1 Contraindication to Any Bowel Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 6.2 Inadequate Bowel Preparation for Colonoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 6.3 Bowel Preparation in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 6.4 Bowel Preparation in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 6.5 Bowel Preparation in Inflammatory Bowel Disease (IBD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 6.5.1 During the Initial Onset of IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 6.5.2 During Quiescent IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 6.5.3 During Active IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

Abstract

Bowel preparation has been a much-debated issue for both colonoscopy and for colorectal surgery. While bowel preparation for colonoscopy is clearly mandatory for optimal intraluminal visualization, bowel preparation for surgery has recently been challenged. This review evaluates oral bowel preparation, based on evidence in the literature, in order to provide a practical guide for physicians and practitioners about oral bowel cleansing preparations in current use for both colonoscopy and for colorectal surgery. A MEDLINE search, limited to publications in English language, was done through Ovid including articles published from 1966 to 2007 about bowel preparation using terms ‘pre-operative care’ and ‘colonoscopy’ or ‘surgical proce-

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dure’ associated with ‘polyethylene glycol’ and ‘sodium phosphate’. The references lists from the identified articles were also included in the review. No bowel preparation method meets the ideal criteria for bowel cleansing prior to colonoscopy. However, polyethylene glycol-electrolyte lavage solution (PEGELS) and sodium phosphate are the most commonly used bowel preparations before colonoscopy and colon surgery. Both preparations are safely used and effective; however, some precautions should be considered, particularly with sodium phosphate. In addition, the efficacy of low-volume PEG-ELS can be improved by the addition of preparation adjuncts. Timing and dose are important considerations regardless of the method used. Mechanical bowel preparation for surgery has been questioned, and shown to have no extra benefits and possibly the association with increased morbidity. Regardless of the evidence, there are many randomized controlled trials showing the lack of benefit of mechanical bowel preparation.

1. Aim of Bowel Preparation For a colonoscopy, ideal bowel cleansing includes multiple aspects such as the individual patient’s physiological condition. The aim of the ideal bowel preparation is to reliably empty the colon of all solid and liquid faecal material without any adverse effect on the gross or microscopic appearance of the colonic mucosa. In addition, the preparation should not cause discomfort and should be easy to tolerate, resulting in good compliance and thus a good preparation. Furthermore, the preparation should induce minimal shifts in electrolytes and water, require a short period for transit (again facilitating its use) and lastly should be cost effective.[1,2] Sadly, none of the available preparations fulfil all of these criteria, as concerns exist about compliance, safety and efficacy of cleansing of every available preparation.[1,3] Suboptimal bowel preparation may increase the risk of complications, including the time required to perform a colonoscopy, the discomfort associated with the procedure and the ability to identify all lesions[1] (bowel preparation for colorectal surgery is discussed in section 4.) 2. Historical Background and Review of Modes of Action of Various Bowel Preparation Methods and Adjuncts Bowel-cleansing regimens were first used in radiology as preparation for barium enema tests in order to obtain a suitably clean colonic mucosa to © 2008 Adis Data Information BV. All rights reserved.

help ensure optimal quality films and thereby accurate interpretation (table I). Early preparations largely included diet control, laxatives and enemas. Diet control aimed at decreasing faeces in the colon by allowing patients to have a clear liquid or low-residue diet for 2–3 days before the procedure. This restriction was accompanied by a laxative to facilitate emptying of the colon. A tap water enema was then used to ensure cleaning of the colonic mucosa by washing out any faecal residue. Surprisingly, in a prospective study comparing the two regimens, a clear liquid diet was found to be less effective than low-residue diets.[1] Although these regimens provided a relatively clean colon for radiographic examination, they were time consuming and uncomfortable for the patient. In addition, the inadequate calorie intake and resultant malnutrition could potentially have an adverse impact on the patient. Accordingly, a special diet regimen, an oral elemental diet, was designed in order to overcome the malnutrition and hypoproteinaemia adverse effects. It proved to be efficacious but continued to be time consuming and required preoperative admission for at least 5 days.[6] Although enemas were effective in colonic cleansing, they were inconvenient, caused significant patient discomfort and were associated with anal trauma. In some studies, they were thought to induce inflammation of the rectal mucosa.[7] The problems inherent in dietary restriction and enemas prompted the use of oral gut lavage, which involved washing out the entire gastrointestinal tract using a saline solution or a balanced electrolyte Drugs 2008; 68 (4)

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Table I. Mode of action of different bowel preparations Type

Mode of action

Traditional method

↓ Food intake + clear liquid/low-residue diet ± enemas

Clear fluid diet

Iso-osmotic preparation[4]

Non-absorbable, osmotically balanced solution → mechanical ‘washout’ of colonic mucosa

Polyethylene glycol

Hyperosmotic preparation[4]

Draw plasma water into the lumen to facilitate cleansing and evacuation.

Mannitol and sodium phosphate

in sodium phosphate

Example

After first and second doses, respectively: mean onset of bowel activity is 1.7 and 0.7 hours; mean duration of action is 4.6 and 2.9 hours; bowel activity ends within 4–5 hours in 83–87% of patients[5]

Stimulant laxatives[4] diphenylmethane

Poorly absorbed in small intestine

Bisacodyl

Hydrolyzed by endogenous esterases anthracene derivatives

Prokinetic agents[4]

Processed by colonic bacteria (active metabolites stimulates colonic motility) The active metabolites of both substances stimulate colonic motility

Senna

↑ Amplitude of gastric contraction → ↑ peristalsis of the small intestine → ↓ transit time, believed to be via tissue sensitization to acetylcholine

Metoclopramide

Potent serotonin 5-HT4 receptor agonist Osmotically active agents[4] (saline laxatives)

Besides being a hyperosmotic agent, release of cholecystokinin → secretion of intestinal fluids in addition to stimulating intestinal motility ↑ indicates increases; ↓ indicates decreases; → indicates yields.

solution. Orthograde gut lavage provided relatively rapid and effective preparation of the colon; however, it requires a large volume intake that may need nasogastric administration with its associated adverse effects. A total of 11% of patients could not tolerate this method in one study.[8,9] Besides intolerability, these solutions have led to weight gain, fluid shifts and electrolyte imbalance, all of which are associated with high risks for those patients who cannot tolerate major volume and/or electrolyte changes.[8] These limitations again prompted the study of alternative preparations without the aforementioned adverse effects and with at least the same efficacy. Osmotically balanced solutions were developed and preliminary compounds contained mannitol, a nonabsorbable oligosaccharide, which resulted in osmotic catharsis. Mannitol (10%) resulted in effective and rapid cleansing with little physiological disturbance when compared with saline lavage.[10] Despite the rather sweet taste of 10% mannitol, it is fermented by the colonic bacteria to combustible gases, methane and hydrogen, and thus safety considerations precluded widespread acceptance. Despite the concerns of over combustion, there were only a few sporadic explosions in the 1930s and © 2008 Adis Data Information BV. All rights reserved.

Tegaserod Magnesium citrate

1940s, and this problem did not cause alarm until the 1970s. The explosive range of hydrogen and methane in the air is 4–72% and 5–15%, respectively. Neither of these gases are combustible if the oxygen concentration is less than 5% in the gas mixture. However, if enough hydrogen and methane exist in the colon, this may result in an explosion when insufflation starts to add oxygen to the mixture and an energy source is used.[11] Although some endoscopists advocate the use of antimicrobials with mannitol to decrease the amount of bacteria and thereby decrease the gas production, the need for electrocautery and the fear of explosion resulted in the mannitol preparation being abandoned.[11] In 1980, Davis et al.[12] formulated a new solution, polyethylene glycol-electrolyte lavage solution (PEG-ELS), which is not fermentable and is associated with minimal water and electrolyte absorption or secretion. Physiologically, sodium ion inside the lumen of the intestine is actively absorbed against an electrochemical gradient. This absorption occurs when sodium is linked with chloride as an accompanying anion. When sulfate is substituted for chloride, the active absorption mechanism is hugely reduced, resulting in minimal water and electrolyte shifts.[13] Although PEG-ELS was proven to be efDrugs 2008; 68 (4)

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Table II. Levels of evidence and grade recommendation[19] Level (source of evidence) I. Meta-analysis of multiple, well designed, controlled studies; randomized trials with low false-positive and low false-negative errors (high power) II. At least one well designed experimental study; randomized trials with high false-positive or high false-negative errors or both (low power) III. Well designed quasi-experimental studies, non-randomized, controlled, single-group, preoperative-postoperative comparison, cohort, time or matched case-control series IV. Well designed, non-experimental studies, such as comparative and correlation descriptive and case studies V. Case reports and clinical examples Grade (recommendation) A. Evidence of type I or consistent findings from multiple studies of level II, III or IV B. Evidence of type II, III or IV and generally consistent findings C. Evidence of type II, III or IV but inconsistent findings D. Little or no systematic empirical evidence

fective as a bowel preparation, the salty taste and the bad smell resulting from sodium sulfate affected patient compliance. Fordtran et al.[14] described another solution, sulfate-free PEG (SF-PEG), without sodium sulfate in an attempt to improve taste and thereby patient compliance. This was followed by another study conducted as a part of a US FDA phase II trial confirming its effectiveness and safety.[15] It should be noted that the mechanism of action of PEG-ELS was mediated by the osmotic properties of PEG and the electrochemical gradient created by the sodium sulfate. However, after removal of the sodium sulfate, SF-PEG relies on its osmotic characteristic as a mechanism of action.[16] In 1990, Vanner et al.[17] introduced sodium phosphate, a reduced volume, better tolerated, safer and effective bowel preparation. Subsequently, several randomized controlled studies were conducted to assess its efficacy, safety, tolerability and cost effectiveness. In the late 1990s, Aronchick et al.[18] introduced the tablet form of sodium sulfate as a novel purgative for a colonoscopy preparation with equal effectiveness, safety and better tolerability. In 2001, the American Society for Gastrointestinal Endoscopy (ASGE) introduced a report regarding colonic preparations by providing the status of various bowel-cleansing methods.[2] In 2006, a consensus statement was published by a task force from representatives of the American Society of Colon and Rectal Surgeons (ASCRS), the ASGE and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). This consensus provided an evidence-based document on the different meth© 2008 Adis Data Information BV. All rights reserved.

ods of bowel-cleansing preparation for a colonoscopy.[3] Both documents confirmed that the most commonly used bowel preparations were PEG-ELS and sodium sulfate. In this review, the level and grade of evidence proposed by Cook et al.[19] is applied to the various studies from the literature included. Depending on this grading (table II), evidence is provided regarding both methods of bowel preparation. The studies used grading or scoring systems to evaluate the adequacy of preparation, including adequacy of faecal matter removal and quality of visualizing the mucosa or residual liquid inside the colon; all were endoscopist-blinded studies. Others included questionnaires of patients’ acceptance and willingness of repeating the evaluated method. Although these systems were not ideal, they were used as a method of obtaining and presenting the outcomes.[3] 3. Current Preparations: an Evidence-Based Review 3.1 Polyethylene Glycol (PEG) Preparations 3.1.1 PEG-Electrolyte Lavage Solution (PEG-ELS)

Numerous clinical trials have been conducted to assess the efficacy, safety and tolerability of PEGELS compared with previously used methods. These trials found PEG-ELS to be a safely used method, without an associated significant change in bodyweight or vital signs, or clinically significant haematological, biochemical, electrolyte or metabolic abnormalities. The results of some of these Drugs 2008; 68 (4)


studies are summarized in table III. PEG-ELS was found to be more effective and better tolerated than the prior regimen of diet and cathartics.[20,21] PEGELS had been compared with the osmotically balanced electrolyte solutions used previously. These solutions were ingested orally or introduced via a nasogastric tube in large volumes. PEG-ELS provided a better cleansing outcome with a relatively much lower volume required for preparation.[22] In some of the trials, patients who tried standard traditional methods of bowel cleansing were randomized to receive PEG-ELS. A total of 90% or more favoured PEG-ELS than the previously used regimen.[24,25] The effectiveness of the PEG-ELS preparation was also proven after colorectal surgery with better efficacy shown compared with the traditional methods.[31] The addition of enemas to PEG-

421

ELS did not provide any incremental discernable benefit but instead added significant patient discomfort.[7] Timing and dose administration have been shown to be helpful regarding cleansing quality and patient compliance. Allowing the patient to ingest 3 L the evening before and 1 L the morning of the procedure was found to have the same effectiveness and better acceptance than the standard 4 L regimen given the day before the procedure.[32] Apart from the fact that time spacing between doses could help tolerability and compliance, it was also shown that proper spacing between the last dose and the examination is important. Ingestion of PEG-ELS solution about 5 hours before the procedure revealed better quality than when taken 19 hours before the procedure, which is another reason to prefer the morning dose a

Table III. Polyethylene glycol-electrolyte lavage solution (PEG-ELS) compared with traditional bowel preparations Author (year)

No. of Indication pts

Comparison (no.of pts per treatment)

Quality

Tolerability acceptance

Complication

Comment

Goldman and Reichelderfer[23] (1982)

43

Scope

Non comparative

Equal

42 of 43 good No major to excellent complication

At risk and no complication. Metoclopramide reduced associated nausea and vomiting

Thomas et al.[24] (1982)

20

Scope

PEG-ELS (12) Standard (8)

Equal

More

NSDa

8/12 favoured PEGELSb

Ernstoff et al.[25] (1983)

46

Scope


Better

More

NSDa

At risk and no complication. 13 of 26 favoured PEGELSb

DiPalma et al.[26] (1984)

197

Scope

PEG-ELS (49) Standard 148

Better

More

NSDa

↓ In hydrogen after PEG-ELS consumption

Adler et al.[22] (1984)

240

Scope

PEG-ELS (149) BEL (91)

Better

More

NSDa

52 at risk with no complication

Ambrose et al.[27] (1983)

77

Surgery

PEG-ELS (51) Equal Senna + rectal wash (26)

Equal

NSDa

No associated explosive gases

Beck et al.[28] (1986)

80

Surgery

PEG-ELS (40) Mannitol (40)

Better

More

NSDa

No associated explosive gases

Fleites et al.[29] (1985)

53

Surgery


Better

More

NSDa

↓ Infectious complication with PEG-ELS

Makino et al.[30] (1998)

26

Surgery

2 L PEG-ELS (12) Senna + TPN + magnesium citrate (14)

Equal

Equal

NSDa

a

No physiologically detected changes were associated with clinical manifestations.

b

Number of pts in the study who had tried standard methods before and when randomized to PEG-ELS preferred it.

At risk = pts at risk with congestive heart failure, renal failure, liver failure and chronic obstructive pulmonary disease; BEL = basic electrolyte lavage; NSD = no significant difference; pts = patients; scope = colonoscopy; standard = traditional bowel preparations; TPN = total parenteral nutrition;↓ indicates decrease.


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Table IV. Effect of timing and administration on effectiveness of polyethylene glycol-electrolyte lavage solution (PEG-ELS) Author (year)

No. of pts

Indication

Comparison (no. of pts per treatment)

Quality


Comment

Church[33] (1998)

317

Scope

Same day (157) Day before (160)

Better

Equal

Timing is important for afternoon procedures

Paoluzi et al.[35] 160 (1993)

Scope

Split dose (80) Standard (80)

Better

Better

Split dose improves compliance and outcome

Sharma et al.[36] 150 (1998)

Scope

2 L PEG-ELS (91) 4 L PEG-ELS (59)

Better

Better

2 L PEG-ELS with laxative improved quality and tolerance

El Sayed et al.[37] (2003)

187

Scope

Split dose (91) Whole dose (96)

Better

More

Split dose provides compliance and quality

Aoun et al.[34] (2005)

141

Scope

Split dose (68) Whole dose (73)

Better

More

Same observation

Ker[38] (2006)

300

Scope

2 L PEG-ELS (150) + bisacodyl 4 L PEG-ELS (150)

Equal

Equal

Low volume has favorable acceptance among patients with similar outcome

pts = patients; scope = colonoscopy.

few hours before colonoscopy.[33] Another clinical study showed that the method and timing (two doses, with the second one on the morning of the procedure) are more effective in terms of quality improvement regardless of dietary restriction associated with the preparation.[34] Table IV shows the effect of timing and administration on the effectiveness of PEG-ELS. In some instances, an urgent colonoscopy is mandatory in acute lower gastrointestinal haemorrhage. Concerns about quality of visualization as a result of intraluminal blood and faeces, and safety of using a bowel preparation in such patients were a barrier to performing a colonoscopy. However, PEG-ELS was shown to be a safely used and tolerated bowelcleansing method in patients with lower gastrointestinal bleeding after stabilization.[39,40] PEG-ELS is a suitable solution for patients whose body mechanisms cannot cope with states of overload or electrolyte shifts, including those with congestive heart failure, renal failure and advanced liver disease with ascites.[41] However, caution is mandatory as two studies revealed an increased plasma volume following PEG-ELS ingestion.[42,43] Mucosal Changes

Bucher et al.[44] studied morphological alterations associated with PEG-ELS and found moderate to severe loss of superficial mucous and epithelial cells in 96% and 88% versus 52% and 40% in the 1

no preparation group, respectively. Another study found flattening of the surface epithelium and depletion of goblet cells as well as an increase in lamina propria oedema.[45] Adjuncts

The addition of prokinetics, such as metoclopramide to a PEG-ELS solution, was thought to improve patient tolerance and cleansing quality; however, studies did not reveal any effect on bowel cleansing using prokinetics combined with PEGELS lavage, but prokinetics significantly reduced nausea and bloating.[46-48] Another recent trial confirmed this finding by evaluating tegaserod combined with PEG-ELS. There was no improvement regarding tolerance, effectiveness and adverse effects.[49] In addition, the use of bisacodyl as an adjunct with a full-volume PEG-ELS solution did not improve either the quality of cleansing or the tolerability of the solution.[50] However, combining bisacodyl with magnesium citrate in addition to PEG-ELS resulted in a smaller volume being required for colon cleansing.[51] This effect of magnesium citrate was also confirmed by Sharma et al.,[36] where Picolax® 1 (sodium picosulfate plus magnesium citrate) was found to be similarly effective as PEG-ELS and more tolerable.[52] One should remember that magnesium citrate should be used with caution in pa-

The use of trade names is for identification purposes only and does not imply endorsement.


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tients with renal failure as it is excreted via the kidneys.[3] The use of senna as an adjunct with PEG-ELS has shown improved quality of preparation and has decreased the amount of volume required for effective preparation. In a clinical randomized trial, 90% of patients in the senna group had a clean colon versus 67% of the placebo group.[53] Another study demonstrated the efficacy of combined senna and PEG-ELS 2 L, and excellent or good preparations were found in 90% and 97% of patients, respectively.[54] The addition of simethicone to PEG-ELS was found to eliminate foam formation, thereby improving visualization of the mucosa with better efficacy. Surprisingly, only 5% of the randomly assigned patients to the simethicone group had residual stool versus 39% of patients who did not use simethicone in combination with PEG-ELS.[55] Simethicone was also found to enhance tolerability.[56] In an attempt to improve tolerability, carbohydrate-electrolyte solutions have been used with PEG-ELS to make it more palatable.[57,58] Despite the theoretical attractiveness of this methodology, at the time of writing these solutions have not yet been widely employed. Recommendations

Compared with the previous methods of bowel cleansing, including dietary restriction and cathartics, large-volume gut lavage and mannitol, PEGELS is a rapid, safer, more effective and more tolerable method (grade IA).

PEG-ELS is relatively safe and thus preferred for patients with renal failure, congestive heart failure and advanced liver disease (grade IA). Dividing a 4-L dose into one dose the night before and the second the morning of the procedure is a good alternative to improve patient tolerability and efficacy (grade IIB). The time period between consumption and colonic examination is of importance. If the procedure is scheduled in the afternoon, instructions should be given to ingest part of the solution on the morning of the procedure (grade IIB). Adjuncts to full-volume PEG-ELS (bisacodyl, metoclopramide, enemas) have not proven to enhance the effect of PEG-ELS regarding colon cleansing and tolerability, and therefore these adjuncts are unnecessary. However, they do improve the efficacy of low-volume PEG-ELS (grade IIB).[3] 3.1.2 Sulfate-Free (SF)-PEG

Although PEG-ELS has generally proven to be safely used, effective and accepted, 5–15% of patients cannot complete the preparation either because of poor palatability or large volume.[59] SFPEG-ELS achieved its goal as a product that is less salty and more palatable than regular PEG-ELS for those patients who were not able to overcome the taste and smell of PEG-ELS. It was also comparable regarding effectiveness and safety.[13] Table V shows SF-PEG-ELS compared with other bowel preparations.

Table V. Sulfate-free polyethylene glycol-electrolyte lavage solution (SF-PEG-ELS) compared with other bowel preparations Author (year)

No. of pts

Indication


Quality


Comment

DiPalma and Marshall[15] (1990)

152

Scope

SF-PEG-ELS (74) PEG-ELS (78)

Better

Equal

No clinically or laboratory significant changes

Beck and DiPalma[16] (1991)

60

Surgery

SF-PEG-ELS (30) Standard (30)

Better

Equal

SF-PEG-ELS is a safe and effective method

Raymond et al.[60] (1996)

50

Scope

4 L SF-PEG-ELS (25) 4 L PEG-ELS (25)

Equal

Equal

SF-PEG-ELS improved acceptability and compliance

Wang and Lin[61] (2003)

94

Scope

2 L SF-PEG-ELS (45) Bisacodyl tab (49)

Equal

Equal

SF-PEG-ELS provides better taste and less discomfort

186

Scope

2 L SF-PEG-ELS + bisacodyl (93) 4 L PEG-ELS (93)

Equal

Better

2 L SF-PEG-ELS + bisacodyl has better compliance and same quality

DiPalma[62] (2003)

pts = patients; scope = colonoscopy.


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Recommendations

SF-PEG-ELS is less salty and more palatable than PEG-ELS and is comparable regarding safety and efficacy of cleansing. However, it still requires the ingestion of 4 L as does the original form. SFPEG-ELS is an accepted method and good alternative in patients who require PEG-ELS-dependent bowel cleansing (grade IIB). 3.1.3 Low-Volume PEG-ELS and PEG-3350 with Bisacodyl Delayed Release

The aim of low-volume PEG-ELS was to overcome the volume-related problems. Several studies have compared low-volume PEG-ELS, combined with bisacodyl or magnesium citrate, with full-volume PEG-ELS in terms of tolerance and effectiveness. Studies in which low-volume PEG-ELS was used in combination with other agents have shown better tolerability and similar bowel-cleansing capability.[51,63] Another study compared a full-dose regimen PEG-ELS with low-volume PEG-ELS without any diet restriction and found no significant difference in cleansing quality or tolerability.[34] Improved palatability and tolerability was also shown with a combination of PEG-3350 laxative powder (Miralax®) and a carbohydrate-electrolyte solution.[64] Recommendations

PEG-ELS 2 L combined with bisacodyl or magnesium citrate have proven to be of equal efficacy to a full-dose regimen PEG-ELS. In addition, they have better tolerance and are more acceptable to the patients, thereby making low-volume PEG-ELS an accepted alternative to the 4-L regimen (grade IA). 3.1.4 Dose Administration For Whole-Volume PEG-ELS and SF-PEG-ELS

No solid food is allowed at least 2 hours before ingestion of the solution. A total of 240 mL (8 oz) is ingested every 10 minutes until rectal effluent is clear or 4 L is consumed. The nasogastric dosage is 20–30 mL/min, about 1.2–1.8 L/hour. For Low-Volume PEG-ELS

Only clear liquids are allowed on the day of preparation. A total of 240 mL (8 oz) is ingested every 10 minutes until the entire 2 L has been consumed. Four bisacodyl delayed-release tablets © 2008 Adis Data Information BV. All rights reserved.

should be ingested about 4 hours before the start of taking the preparation. 3.2 Sodium Phosphate

Sodium phosphate is a hyperosmotic agent, which is associated with significant water and electrolyte shifts. Dilution is important to decrease the emetic sensation and accompanying hydration is vital to avoid dehydration. 3.2.1 Aqueous Sodium Phosphate

Several clinical trials have provided evidence for the efficacy, tolerability and safety of sodium phosphate (table VI). These trials have shown sodium phosphate to be equal or more effective and better tolerated than full-volume PEG-ELS. Furthermore, as shown in this section and in table VI, it has been rated by colonoscopists to be more acceptable than PEG solutions. These studies were all undertaken in very controlled settings enrolling only ‘healthy’ patients. Vanner et al.[17] introduced sodium phosphate as a more effective and more tolerable preparation than PEG. In their randomization to sodium phosphate, 37 patients had previously taken PEG-ELS as a preparation prior to colonoscopies; all patients found sodium phosphate easier to tolerate and >90% felt it caused less discomfort. Kolts et al.[65] and Marshall et al.[66] found sodium phosphate comparable to PEG-ELS and both authors confirmed it as an effective method. Cohen et al.[67] were the first to compare sodium phosphate with the available forms of PEG-ELS (PEG-ELS 4 L and SF-PEG-ELS 4 L). They showed that, compared with PEG, sodium phosphate was not associated with clinically significant problems, caused no increase in adverse effects and was better tolerated and more effective. Subsequently, several randomized controlled trials were conducted comparing sodium phosphate with PEG-ELS, alone or combined with other laxatives, and other preparations; most trials showed at least an equal effect with better tolerability and/or cost effectiveness (table VI). In a meta-analysis of eight clinical trials among 1286 subjects comparing sodium phosphate with PEG-ELS as a bowel-cleansing method pre-colonoscopy, the relative risk of inability to complete the Drugs 2008; 68 (4)


425

Table VI. Sodium phosphate (NaP) compared with other preparations Author (year)

No. of pts

Indication


Quality


Comment

Vanner et al.[17] (1990)

102

Scope, adults

NaP (54) PEG-ELS (48)

Better

Better

A, B, C, D, E, F

Kolts et al.[65] (1993)

114

Scope, adults

NaP (34) PEG-ELS (38) Castor oil (41)

Best

Equal

A, B, E

Marshall et al.[66] (1993)

143

Scope, adults


Equal

Equal

C

Cohen et al.[67] (1994)

422

Scope, adults

NaP (143) PEG-ELS (138) SF-PEG-ELS (141)

Best

Better

A, B, C

Afridi et al.[68] (1995)

147

Scope, adults

NaP (72) PEG-ELS + bisacodyl (75)

Equal

Better

A, B, C, E

Golub et al.[59] (1995)

329

Scope, adults

NaP (106) PEG-ELS (124) PEG-ELS + metoclop (99)

Equal

Better

E

Henderson et al.[69] (1995)

218

Scope, adults

NaP (122) PEG-ELS (106)

Equal

Better

F

Frommer[70]

486

Scope, adults

1 day NaP (161)

Equal

Better

F, split-dose regimen with second

2 days NaP (166)

Best

Better

PEG-ELS (160)

Equal

(1997)

one on morning of exam. Improves cleansing capacity

Thomson et al.[71] (1996)

118

Scope, elderly


Better

Better

A, B, F

Lee et al.[72] (1999)

159

Scope, adults


Equal

Equal

E

Young et al.[73] (2000)

323

Scope, adults

MaP (169) 2 L PEG-ELS + bisacodyl (154)

Better

Better

B, dose timing is important

Poon et al.[74]

191

Scope, adults

NaP (97)

Equal

Equal

2 L PEG-ELS is an effective

(2002) Ell et al.[75]

2 L PEG-ELS (94) 173

Scope, adults

(2003)

alternative for NaP

NaP (60) 4 L PEG-ELS (59)

A, B, dose timing was not Best

Equal

3 L PEG-ELS (54) Huppertaz-Hauss

231

Scope, adults

et al.[76] (2005)

NaP (84)

standardized; PEG-ELS: second dose on morning of exam; NaP: on day before

Best

Best

A, B, D, F

4 L PEG-ELS (76)

2 L PEG-ELS + Poor bisacodyl (71) A = laboratory changes were transient and returned to normal within 24 hours; B = no associated serious complications (cardiac, renal, pulmonary or cerebral); C = no clinically evident haemodynamic changes; D = no histological difference between regimens and the morphological association is not major; E = NaP is less expensive than PEG-ELS; F = trial included patients that experienced PEG-ELS before and preferred NaP; metoclop = metoclopramide; PEG-ELS = polyethylene glycol-electrolyte lavage solution; pts = patients; scope = colonoscopy; SF-PEG-ELS = sulfate-free polyethylene glycol-electrolyte lavage solution.

preparation was 0.23 (95% CI 0.18, 0.28), in favour of sodium phosphate. Re-examination rates were 3% and 8% for sodium phosphate and PEG-ELS, respectively. Neither regimen was associated with clinically important adverse effects.[77] © 2008 Adis Data Information BV. All rights reserved.

The efficacy of oral sodium phosphate was confirmed in two large surveys that included 627 patients in one[78] and 638 patients in the other,[79] with 88% and 71% of patients who received sodium phosphate with ‘good’ or ‘excellent’ bowel cleansDrugs 2008; 68 (4)

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ing, respectively. Recently, De Salvo et al.[80] showed that sodium solution provided better bowel preparation, with the same compliance, than either senna or PEG-ELS and, in addition, in constipated patients was associated with good cleansing rates similar to those of non-constipated patients. Dividing the dosage of sodium phosphate into the first dose on the evening before and a second dose on the morning of the colonoscopy was found to be more effective than administering the two doses the day before the procedure[70] or using full-dose PEGELS.[17,65,67,73] This finding is consistent with the pharmacological action of sodium phosphate and is especially helpful in afternoon procedures. Henderson et al.[69] found that administering sodium phosphate in a single-day, two-dose regimen, one at 16:00 h and the other at 20:00 h, showed similar effectiveness and better tolerance compared with PEG-ELS when taken the day before colonoscopy. However, a two-centre study reported 173 patients for analysis of efficacy and concluded that PEG-ELS 4 L was much more effective than PEGELS 2 L and sodium phosphate.[75] It should be noted that in this study there was no standardization in the method of administering the preparations. The PEG-ELS-based solution was given in divided doses with a second dose on the morning of the procedure, while the sodium phosphate dose was given in one day with a second dose at 19:00 h (more than 12 hours before the procedure). This regimen is diametrically opposed to the regimens of Marshall et al.,[66] Cohen et al.,[67] Afridi et al.[68] and Frommer.[70] Barclay[81] suggested that even a threedose regimen of orally administered sodium phosphate in healthy patients was more effective than the two-dose regimen. However, it was associated with reduced patient tolerance. A more recent study[82] evaluated the timing of bowel preparation as a significant factor in determining the quality of preparation in 177 patients. The authors randomized patients to either sodium phosphate or PEG-ELS with two subgroups in each arm; the groups were divided according to the timing of the second dose, either on the day before the procedure or on the morning of the procedure. The investigators found that the second dose on the morning of examination improved cleansing capacity and was associated with better compliance. Another recent study[83] in © 2008 Adis Data Information BV. All rights reserved.

Shawki & Wexner

200 patients showed that sodium phosphate in a divided dose regimen was more effective than PEGELS, the latter of which was associated with more residual colonic fluids. In a randomized controlled trial in colonic surgery patients, sodium phosphate was shown to have superior efficacy to PEG-ELS,[84] while another clinical study showed that the mean faecal residue in the resected colon was less with sodium phosphate than with sodium picosulfate.[85] Sodium phosphate has been shown to have similar or superior efficacy to a variety of other bowelcleansing regimens including magnesium citrate with added sodium picosulfate.[86,87] However, sodium picosulfate has been shown in one study of 400 subjects to be as effective as sodium, but with superior taste and better tolerability with fewer adverse effects.[88] Chilton et al.[89] compared a ‘triple regimen’ with sodium phosphate and found it produced a cleaner colon; however, this triple regimen included 50 mL sennosides, one packet of Picolax® and one packet of PEG-3350 in 1 L of water versus the regular two 45 mL doses of sodium phosphate; tolerability was not assessed in this study. A recent study (n = 134) concluded that sodium phosphate was more effective than senna in bowel preparation for colonoscopy; however, senna could be considered as an effective alternative laxative.[90] 3.2.2 Electrolyte, Haemodynamic and Mucosal Changes Changes in Electrolytes

Oral sodium phosphate solution has been shown to be associated with changes in serum electrolyte levels. These changes are within normal ranges and are asymptomatic, and return to normal levels (baseline) within 24 hours. However, caution should be used when administering sodium phosphate in the paediatric and geriatric populations.[91] Transient hyperphosphotaemia with a compensatory fall in ionized and total serum calcium levels has been noted in several clinical trials.[17,65,67,71,75,76] Other studies have revealed an increase in serum sodium levels and a decrease in potassium levels.[57,92,93] Despite all of these objective biochemical changes, there have been no relevant adverse effects associated with these changes and electrolyte levels in the blood returned to within normal limits within Drugs 2008; 68 (4)


24 hours. However, more recently, phosphate nephropathy was reported in patients with compromised renal function, dehydration or hypertension, and in patients who were being treated with ACE inhibitors or angiotensin receptor antagonists.[94] After careful scrutiny, this effect was found to be age and dose related.[3,95] As a hyperosmotic agent associated with significant water and electrolyte shifts, potentially fatal complications can occur in elderly patients, patients with renal failure, congestive heart failure, recent myocardial infarction, small intestinal disorders, poor gut motility and advanced liver disease.[96] The literature also contains some case reports of serious electrolyte disturbances accompanying oral sodium phosphate ingestion including hypernatraemia, hyperphosphotaemia, hypokalaemia and hypocalcaemia.[97-102] It should be mentioned that these disturbances occurred in those patients who were at risk of developing complications, and either sodium phosphate ingestion was contraindicated or mandated caution and close monitoring. Other adverse effects occurred with an increased intake more than the recommended dosage. Relatively few studies have evaluated the effect of sodium phosphate in the paediatric and geriatric populations. However, these few studies have demonstrated that sodium phosphate is as effective in the elderly as in young adults and it has comparable safety to PEG.[71,93,103] Haemodynamic Changes

Haemodynamic measurement has revealed some changes that suggest intravascular volume changes are associated with oral sodium phosphate ingestion. Systolic blood pressure was found to decrease approximately 10 mmHg in 12–28% of patients among the different study populations. A change in postural pulse exceeding 10 beats per minute was also found in up to 30% of patients in these studies.[17,59,104] However, these changes were transient and not associated with any relevant clinical manifestations.[96] Other measurements, such as haematocrit, serum osmolality and bodyweight, were used as indirect parameters of intravascular volume depletion associated with oral sodium phosphate administration.[17,67,71,87,104] © 2008 Adis Data Information BV. All rights reserved.

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Carbohydrate-electrolyte rehydration was used as a co-agent to limit the degree of intravascular depletion associated with oral sodium phosphate. In one study, this resulted in a decreased volume of contraction,[57] while in another study, E-Lyte® solution resulted in improved patient tolerance and overall efficacy.[58] Mucosal Changes

Sodium phosphate has been associated with alterations in colonic mucosa by some investigators,[105,106] but not by others[107,108] who have questioned the significance of these findings. One explanation for the mucosal changes is that perhaps the improved and better bowel cleansing achieved by sodium phosphate allows better visualization of the mucosa; however, these changes resolve on followup and are therefore of no clinical significance. These finding are not consistent with those ulcerations associated with inflammatory bowel disease (IBD). The sodium phosphate-associated lesions are small (1–3 mm) with a surrounding halo and are generally not friable, preserving glandular architecture and normal background mucosa, without ulcers or linear fissures.[96] Adverse Effects

Like all bowel preparations, sodium phosphate solution has some associated adverse effects, most of which are gastrointestinal. These adverse effects include abdominal pain, cramping, bloating and/or fullness, nausea or vomiting. However, weakness, fatigue, dizziness, headache, thirst and sleep loss have also been reported.[96] Compared with PEGELS, clinical trials have shown a similar incidence of gastrointestinal disturbances with both preparations; however, other studies have revealed a significantly lower incidence in patients who received oral sodium phosphate.[46,67,68,84] 3.2.3 Sodium Phosphate Tablets

Several phase III trials compared sodium phosphate tablets with PEG-ELS 4 L regimens and found the tablet to have equal efficacy of colon cleansing and with fewer adverse effects.[109,110] Multiple studies have been conducted to compare the tablet with the liquid aqueous forms of sodium phosphate. Balaban et al.[111] demonstrated that aqueous sodium phosphate was more effective and accepted by patients than the tablet form. Aronchick Drugs 2008; 68 (4)

428

et al.[18] compared aqueous sodium phosphate, tablet sodium phosphate and a PEG-ELS 4 L regimen, showing that tablet sodium phosphate is as safely used and effective as both aqueous sodium phosphate and PEG-ELS; in addition, in contrast to the study by Balaban et al.,[111] the tablets were preferred by the patients. Despite the potential benefits, sodium phosphate tablets have been associated with two problems. First, the ingredients of the tablet contain microcrystalline cellulose, which produces a residue on the colonic mucosa resulting in obscured vision. Second, the requirement of ingesting a large number of tablets (n = 40) within a short period of time made preparations difficult. These obstacles have been resolved by reducing the amount of microcrystalline cellulose per tablet[112] and by reducing the number of tablets required for preparation from 40 to 28–32.[110] A laboratory study showed that administration of ginger ale with sodium phosphate tablets results in a decrease in the amount of microcrystalline cellulose.[3] Recently, a multicentre trial compared the administration of 40 or 32 residue-free sodium phosphate tablets with 40 regular sodium phosphate tablets.[113] Among the three arms, the 32 residue-free sodium phosphate tablet regimen was superior in the efficacy of colonic cleansing. Still pending is a study comparing low-dose, residue-free sodium phosphate tablets with aqueous sodium phosphate and PEG 2 L. In a recent, prospective, randomized, investigator-blinded, multicentre trial,[114] 205 patients were randomized to receive 32 sodium phosphate tablets and 206 were randomized to receive 2 L PEG-ELS plus bisacodyl tablets for bowel preparation. More patients receiving sodium phosphate tablets found it without taste (47% vs 6%), easy to take, as is (77% vs 42%) and in respect to the associated volume of liquid required to be ingested (72% vs 27%), and would try the same preparation in the future (96% vs 74%), than patients who received 2 L PEG-ELS plus bisacodyl group (p < 0.0001 for all). Nausea, vomiting, bloating and abdominal pain were reported less by patients in the sodium phosphate tablet group than in the PEG-ELS group. This study indicated that the 32-tablet sodium phosphate regimen is more © 2008 Adis Data Information BV. All rights reserved.

Shawki & Wexner

acceptable and tolerable than the 2 L PEG-ELS with bisacodyl tablets. A similar randomized, investigator-blinded but multicentre trial[115] was undertaken to assess preparation quality in addition to safety and tolerability among 411 patients. The mean overall and ascending colon cleansing quality among patients who received sodium phosphate tablets were significantly better than in the 2 L PEG-ELS (plus four bisacodyl tablets) group (p < 0.0001). Patients receiving sodium phosphate tablets were less likely to experience adverse events (66% vs 82%; p = 0.0003), gastrointestinal symptoms (64% vs 79%; p = 0.0001), and experienced less abdominal distention, abdominal pain, and vomiting than patients receiving PEG-ELS plus bisacodyl (p < 0.0012). There were changes in the laboratory parameters in both groups; however, these were more common in the group receiving sodium phosphate tablets including mainly phosphorous, sodium and potassium. These changes were not associated with clinically significant adverse events. 3.2.4 Adjuncts

Bisacodyl has been studied as an adjunct with aqueous sodium phosphate. This combination was found to be as effective and as well tolerated as standard PEG 4 L.[68] Carbohydrate-electrolyte solution has been used with aqueous sodium phosphate to help make it more palatable, and help prevent volume depletion and electrolyte imbalance.[58] 3.2.5 Recommendations Aqueous Sodium Phosphate

Aqueous sodium phosphate bowel preparation is an effective alternative to a PEG-based solution. However, sodium phosphate should not be used in elderly patients, children aged 80 y

Otherwise healthy

2 L PEG-ELS ± adjuncts

Adult

Acute or chronic renal failure, advanced liver disease, ascites, congestive heart failure, recent myocardial infarction, dehydration, electrolyte imbalance, ACEI, ARB



Age >65 y

Renal, cardiac, liver, dehydration, ACEI, ARB

Any patient

Suspected of having IBD


Pregnant

If benefit outweighs risks

2 L PEG-ELS, NaP selectively

Any patient Lower gastrointestinal haemorrhage 2 L PEG-ELS ACEI = ACE inhibitor; ARB = angiotensin receptor blocker (antagonist); IBD = inflammatory bowel disease; NaP = sodium phosphate; PEGELS = polyethylene glycol-electrolyte lavage solution.

time and eventually the need to repeat the procedure, and therefore obviously the preparation. Both physicians and patients should understand the financial implications of a repeat colonoscopy.[3] The few minutes spent with the patient for education and explanation of how to take the preparation may save time, costs and the effort of repeating the procedure. Written forms of instructions are also helpful. The best resource to use and decide upon which bowel preparation to utilize is the recently published joint intersociety task force document.[3] 6.3 Bowel Preparation in the Elderly

According to the ASGE/ASCRS/SAGES guidelines, advanced age is not a contraindication for a colonoscopy as long as the results will affect the clinical management of the patient. Both PEG-ELS and oral sodium phosphate have been shown to be safely used and effective with better tolerability than the lower volume sodium phosphate. However, caution is required in patients with renal and cardiac dysfunction in whom fluid and electrolyte shifts are of extra risk.[139] 6.4 Bowel Preparation in Pregnancy

Endoscopy during pregnancy should be performed when its benefits outweigh the potential risks, and whenever it can be postponed to the second trimester it should be; however, it is contraindicated in obstetric complications. Neither PEGELS nor sodium phosphate have been studied in pregnancy, and are FDA category C for drugs used during pregnancy. The fluid and electrolyte shifts © 2008 Adis Data Information BV. All rights reserved.

associated with sodium phosphate mean its use should be used with caution in pregnant women.[140] 6.5 Bowel Preparation in Inflammatory Bowel Disease (IBD) 6.5.1 During the Initial Onset of IBD

Since sodium phosphate can be associated with histological changes that mimic those of IBD, it may be advisable to use PEG-ELS as the bowel preparation prior to the initial colonoscopy in patients in whom IBD is suspected.[3] 6.5.2 During Quiescent IBD

A patient with quiescent IBD can be prepared for a colonoscopy based on safety, tolerability, efficacy and the presence of any co-morbidities.[1] 6.5.3 During Active IBD

In patients with active IBD, colonic tissues are very friable thereby increasing the risk of colonoscopic complications. Therefore, during these episodes, bowel preparation should generally be avoided.[1] Acknowledgements Our thanks to Ms Vislava Tylman and Ms Elektra McDermott for their assistance in completing this article. Dr Wexner is a member of the Scientific Advisory Board of C.B. Fleet and SaLix companies, and receives honoraria from both. No sources of funding were used in the preparation of this review.

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94. Markowitz GS, Stokes MB, Radhakrishnan J, et al. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an under recognized cause of chronic renal failure. Am Soc Nephrol 2005; 16: 3389-96 95. Gumurdulu Y, Serin E, Ozer B, et al. Age as a predictor of hyperphosphatemia after oral Phospho-Soda administration for colon preparation. J Gastroenterol Hepatol 2004; 19: 68-72 96. Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colonic cleanser. Drugs 2004; 64: 1697714 97. Frizelle FA, Colls BM. Hyponatremia and seizures after bowel preparation: report of three cases. Dis Colon Rectum 2005; 48: 393-6 98. Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004; 35: 675-84 99. Schroppel B, Segerer S, Keuneke C, et al. Hyponatremic encephalopathy after preparation for colonoscopy. Gastrointest Endosc 2001; 53: 527-9 100. Ullah N, Yeh R, Ehrinpreis M. Fatal hyperphosphatemia from a Phospho-Soda bowel preparation. J Clin Gastroenterol 2002; 34: 457-8 101. Ehrenpreis ED, Wieland JM, Cabral J, et al. Symptomatic hypocalcemia, hypomagnesemia, hyperphosphatemia, secondary to Fleet’s Phospho-Soda colonoscopy preparation in a patient with jejunoileal bypass. Dig Dis Sci 1997; 42: 858-60 102. Fass R, Do S, Hixson LJ. Fatal hyperphosphatemia following Fleet Phospho-Soda in a patient with colonic ileus. Am J Gastroenterol 1993; 88: 929-32 103. Seinela L, Pehkonen E, Laasanen T, et al. Bowel preparation for colonoscopy in very old patients: a randomized prospective trial comparing oral sodium phosphate and polyethylene glycol electrolyte lavage solution. Scand J Gastroenterol 2003; 68: 216-20 104. Huynh T, Vanner S, Paterson W. Safety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia. Am J Gastroenterol 1995; 90: 104-7 105. Zws FR, Cirllo NW, el-Serag HB, et al. Colonic mucosal abnormalities associated with oral sodium phosphate solution. Gastrointest Endosc 1996; 43: 463-6 106. Driman DK, Preiksaitis HG. Colorectal inflammation and increased cell proliferation associated with oral sodium phosphate bowel preparation solution. Hum Pathol 1998; 29: 972-8 107. Watts DA, Lessells AM, Penman ID, et al. Endoscopic and histologic features of sodium phosphate bowel preparationinduced colonic ulceration: case report and review. Gastrointest Endosc 2002; 55: 584-7 108. Wexner SD. Preoperative preparation prior to colorectal surgery [letter]. Gastrointest Endosc 1996; 43: 530-1 109. Kastenberg D, Chasen R, Chaudhary C, et al. Efficacy and safety of sodium phosphate tablets compared with PEG solution in colon cleansing: two identically designed, randomized, controlled, parallel group multicenter phase III trials. Gastrointest Endosc 2001; 54: 705-13 110. Khashab M, Rex DK. Efficacy and tolerability of a new formulation of sodium phosphate tablets and a reduced sodium phosphate dose, in colon cleansing: a single-center open-label pilot trial. Aliment Pharmacol Ther 2005; 21: 465-8 111. Balaban DH, Leavell Jr BS, Oblinger MJ, et al. Low-volume preparation for colonoscopy: randomized, endoscopist-blind trial liquid sodium phosphate versus tablet sodium phosphate. Am J Gastroenterol 2003; 98: 827-32 112. Rex DK, Chasen R, Pochapin MB. Safety and efficacy of two reduced regimens of sodium phosphate tablets for preparation before colonoscopy. Aliment Pharmacol Ther 2002; 16: 93744

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113. Rex DK, Schwartz H, Goldstein M, et al. Safety and coloncleansing efficacy of a new residue-free formulation of sodium phosphate tablets. Am J Gastroenterol 2006; 101: 2594-604 114. Lichtenstein GR, Grandhi N, Scmalz M, et al. Clinical trial: sodium phosphate tablets are preferred and better tolerated by patients compared to polyethylene glycol solution plus bisacodyl tablets for bowep preparation. Aliment Pharmcol Ther 2007; 26: 1361-70 115. Johanson JF, Popp Jr JW, Cohen LB, et al. A randomized multicenter study comparing safety and efficacy of sodium phosphate tablets with 2L polyethylene glycol solution plus bisacodyl tablets for colon cleansing. Am J Gastroenterol 2007; 102: 2238-46 116. Rex DK, Imperial TF, Latinovich DR, et al. Impact of bowel preparation on efficacy and cost of colonoscopy. Am J Gastroenterol 2002; 97: 1696-700 117. Zmora O, Lebedyev A, Hoffman A, et al. Laparoscopic colectomy without mechanical bowel preparation. Int J Colorectal Dis 2006: 21; 683-7 118. Zmora O, Wexner SD. Bowel preparation for colonoscopy. Clin Colon Rectal Surg 2001; 14: 309-15 119. Graney MJ, Graney CM. Colorectal surgery from antiquity to the modern era. Dis Colon Rectum 1980; 23: 432-41 120. Hughes ESR. Asepsis in large bowel surgery. Ann Roy Coll Surg Engl 1972; 51: 347-56 121. Brownson P, Jenkins S, Nott D, et al. Mechanical bowel preparation before colorectal surgery: results of a prospective randomized trial [abstract]. Br J Surg 1992; 79: 461-2 122. Burke P, Mealy K, Gillen P, et al. Requirement for bowel preparation in colorectal surgery. Br J Surg 1994; 81: 907-10 123. Santos Jr JCM, Batista J, Sirimarco MT, et al. Randomized trial of mechanical bowel preparation in patients undergoing elective colorectal surgery. Br J Surg 1994; 81: 1673-6 124. Miettinen RP, Laitinen ST, Makela JT, et al. Bowel preparation with oral polyethylene glycol electrolyte solution vs no preparation in elective open colorectal surgery. Dis Colon Rectum 2000; 43: 669-77 125. Bucher P, Gervaz P, Soravia C, et al. Randomized clinical trial of mechanical bowel preparation versus no preparation before elective colorectal surgery. Br J Surg 2005; 92: 409-14 126. Mahajna A, Krausz M, Rosin D, et al. Bowel preparation is associated with spillage of contents in colorectal surgery. Dis Colon Rectum 2005; 48: 1626-31 127. Ram E, Sherman Y, Weil R, et al. Is mechanical bowel preparation mandatory for elective colon surgery? A prospective study. Arch Surg 2005; 140: 285-8 128. Slim K, Panis Y, Chipponi J. Meta analysis of randomized clinical trials of colorectal surgery with or without mechanical bowel preparation. Br J Surg 2004; 91: 1125-30


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129. Bucher P, Mermillod B, Morel P, et al. Does mechanical bowel preparation have a role in preventing postoperative complications in elective colorectal surgery? A meta-analysis. Swiss Med Wkly 2004; 134: 69-74 130. Zmora O, Wexner SD, Hajjar L, et al. Trends in preparation for colorectal surgery: survey of the members of the American Society of Colon and Rectal Surgeons. Am Surg 2003; 69: 150-4 131. Platell C, Barwood N, Makin G. Randomized clinical trial of bowel preparation with a single phosphate enema or polyethylene glycol before elective colorectal surgery. Br J Surg 2006; 93: 427-33 132. Bretagnol F, Alves A, Ricci A, et al. Rectal cancer surgery without mechanical bowel preparation. Br J Surg 2007; 94: 1266-71 133. Jung B, Pahlam L, Nystron PO, et al, for the Mechanical Bowel preparation Study Group. Multicentre randomized clinical trial of mechanical bowel preparation in elective colonic resection. Br J Surg 2007; 94: 689-95 134. Keighley MRB. A clinical and physiological evaluation for bowel preparation for elective colorectal surgery. World J Surg 1982; 6: 166-74 135. Bleday R, Braidt J, Ruoff K, et al. Quantitative cultures of the mucosal-associated bacteria in the mechanically prepared colon and rectum. Dis Colon Rectum 1993; 36: 844-9 136. Baum ML, Anish DS, Chalmers TC, et al. A survey of clinical trials of antibiotics prohpylaxis in colon surgery: evidence against further use of no-treatment controls. N Engl J Med 1981; 305: 795-9 137. Song F, Glenny AM. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomized controlled trials. Br J Surg 1998; 85: 1232-41 138. Stone HH. Basic principles in use of prophylactic antibiotics. J Antimicrob Chemother 1984; 14: 33-7 139. Qureshi WA, Zuckerman MJ, Adler DG, et al. ASGE guideline: modifications in endoscopic practice for the elderly [online]. Gastrointest Endosc 2006; 63 (4): 566-9 140. Qureshi WA, Rajan E, Adler DG, et al. ASGE guideline: guidelines for endoscopy in pregnant and lactating women [online]. Gastrointest Endosc 2005; 61 (3): 357-62

Correspondence: Dr Steven D. Wexner, Department of Colorectal Surgery, Cleveland Clinic Florida, 2950 Cleveland Clinic Boulevard, Weston, FL 33331, USA. E-mail: [email protected]

Drugs 2008; 68 (4)

Drugs 2008; 68 (4): 439-447 0012-6667/08/0004-0439/$53.45/0

ADIS DRUG PROFILE


Nelarabine Mark Sanford and Katherine A. Lyseng-Williamson Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 6. Nelarabine: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446

Abstract ▲ Nelarabine is an anticancer prodrug of arabinofuranosylguanine (ara-G), which is metabolized in cells to the cytotoxic metabolite ara-G triphosphate (araGTP). ▲ Ara-GTP competes with deoxyguanosine triphosphate for incorporation into DNA. Once incorporated, it inhibits DNA synthesis and leads to high molecular weight DNA fragmentation and cell death. ▲ In paediatric and adult patients with T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma, nelarabine induced a complete response, with or without complete haematological recovery, in approximately one-fifth of patients who had not responded to, or had relapsed following treatment with, two or more prior chemotherapy regimens. ▲ The median overall survival time was 13.1 and 20.6 weeks in paediatric and adult patients, with corresponding 1-year survival rates of 14% and 29%. ▲ Treatment-emergent adverse events were common, but non-haematological events were mostly of mild or moderate severity. ▲ Neurological events, which may be severe and irreversible, were the most likely adverse events to limit treatment.

Features and properties of intravenous nelarabine (GW506U78; 506U78; Arranon®; Atriance®) Approved indication T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma that has not responded to, or has relapsed following treatment with, two or more prior chemotherapy regimens Mechanism of action Prodrug of arabinofuranosylguanine (ara-G); inhibits DNA synthesis resulting in cell death Dosage and administration (cycle length 21 days) Paediatric patients

650 mg/m2/day infused over 1 h for 5 consecutive days

Adult patients

1500 mg/m2/day infused over 2 h on days 1, 3 and 5

Pharmacokinetic profile (mean values in adults after a single 1500 mg/m2 intravenous dose given over 2 h) Peak plasma concentration (µmol/L)

Nelarabine: 13.9 Ara-G: 115

Area under the plasma Nelarabine: 13.5 concentration-time curve Ara-G: 571 from time zero to infinity (µmol • h/L) Plasma elimination half- Nelarabine: ≈30 life (min) Ara-G: ≈180 Most common treatment-emergent neurological adverse events in clinical trials Paediatric patients (affecting >5%)

Headache, peripheral neuropathy, somnolence, hypoaesthesia, seizures

Adult patients (affecting >15%)

Somnolence, dizziness, peripheral neuropathy, hypoaesthesia

440

Sanford & Lyseng-Williamson

OCH3 N

N H2N HO

N

N O HO

OH

Nelarabine

Acute leukaemias are a heterogeneous group of disorders that can be broadly grouped according to abnormal blast cell lineage into T- or B-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia.[1] Lymphoblastic lymphoma (LBL) is classified as a non-Hodgkins lymphoma, but can also be considered a variant of acute lymphoblastic leukaemia.[2] T-cell lineage malignancies are rare. T-cell ALL (T-ALL) makes up about 15–20% of child and 25% of adult ALL, which has an incidence of 1–1.5 per 100 000 population.[2,3] T-cell LBL (TLBL) is diagnosed in 80% of patients with LBL, but these account for 2

0.12–2

≤0.03

≤0.03

0.015–0.25

0.25–1

0.015–0.12

0.015–0.12

0.008–0.03

80.1–94.4

90.9–91

≤0.06–1 ≤0.03 to >2

S (%)

CIP MIC90 (mg/L)

a

71–94.2

NR

0.06

β-lactamase positive (5151)

NR

0.06

>99.5–100

β-lactamase negative (269)

Moraxella catarrhalis (10 088)c 0.03–0.06

100

≤0.06

H. parainfluenzae (112)c 95–100

99.9–100

0.015–0.06

β-lactamase positive (4606)

99.6 to >99.9

0.015–0.06

β-lactamase negative (14 669)

99.7–100

94–94.5

0.25–1

Enterobacter cloacae (427)

S (%)

LEV MIC90 (mg/L)

Species (no. of isolates)

Table II. In vitro antibacterial activity of levofloxacin (LEV) and other quinolones against Gram-negative bacteria that are the causative pathogens for community-acquired pneumonia (CAP), acute bacterial sinusitis (ABS), complicated urinary tract infections (cUTI) and acute pyelonephritis (AP), and are indicated for treatment in the US with levofloxacin 750 mg or 500 mg once daily for 5 or 10 days. Dataa are from surveillance studies (1997–2005)[2-4,16,18,28-31] and recent studies (2002–2006)[1,5,6,15,31,32] conducted worldwide[1,16,18,31] and in North America[2-6,15,28-30,32] comparing the activity of antibacterial agents against clinical isolates.b Data from older studies have been used where small numbers of isolates were tested in recent studies[23,24]

Levofloxacin: A Review 541

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542

levofloxacin and gatifloxacin were 1 and 0.5 mg/L, with corresponding susceptibilities of 97.4% and 97.7%.[2] Fluoroquinolone-resistant isolates of S. pneumoniae (n = 30) had levofloxacin and ciprofloxacin MIC90 values that were 32-fold higher than those of fluoroquinolone-susceptible isolates (n = 29), with the MIC90 values increasing from 0.5 to 16 mg/L (levofloxacin) and from 2 to 64 mg/L (penicillin-susceptibility status not reported).[15] Levofloxacin shows variable activity against S. aureus. Levofloxacin had MIC90 values of 0.25–4 mg/L against meticillin/oxacillin-susceptible S. aureus isolates (within susceptible or intermediate breakpoint guidelines), whereas meticillin/ oxacillin-resistant S. aureus isolates exhibited levofloxacin resistance with MIC90 values of >4 to ≥64 mg/L (table I).[5,6,16,17] The proportion of meticillin/ oxacillin-susceptible S. aureus isolates susceptible to levofloxacin was high (87.6–96.2%), as was susceptibility to ciprofloxacin, gatifloxacin and moxifloxacin (>95.6% of isolates). However, only 18.5–23.1% of the meticillin/oxacillin-resistant isolates were shown to be susceptible to levofloxacin and the other fluoroquinolones (table I).[5,6,16,17] In a small study, the MIC90 values of levofloxacin and ciprofloxacin were 64- and 256-fold higher (0.25 to 16 mg/L and 0.5 to 128 mg/L) against fluoroquinolone-resistant isolates of S. aureus (n = 19) compared with fluroquinolone-susceptible isolates of S. aureus (n = 16).[15] The in vitro activity of levofloxacin was limited against E. faecalis (MIC90 of 8 to ≥32 mg/L in vancomycin-susceptible and -resistant strains), as was the in vitro activity of other fluoroquinolones; the proportion of susceptible vancomycin-susceptible isolates was relatively low for levofloxacin (65%) and ciprofloxacin (46%) [table I]. Levofloxacin has shown good in vitro activity (MIC90 and proportion of susceptible isolates) against a range of other Gram-positive bacteria, such as S. pyogenes (1 mg/L, 99.9%)[2,3] and β-haemolytic streptococci (0.5–1 mg/L, 99.1–100%),[25] but has limited activity against coagulase-negative staphylococci (>4 mg/L, 54.1%).[16] © 2008 Adis Data Information BV. All rights reserved.

Anderson & Perry

2.1.2 Gram-Negative Aerobic Bacteria

In general, levofloxacin shows good in vitro activity against Gram-negative bacteria. Levofloxacin has good activity against the common respiratory tract pathogens Haemophilus influenzae, H. parainfluenzae and Moraxella catarrhalis (including βlactamase positive isolates of H. influenzae and M. catarrhalis), and the urinary tract pathogens Klebsiella pneumoniae, Enterobacter cloacae and Proteus mirabilis. The activity of levofloxacin is variable against the urinary tract pathogen Escherichia coli and Pseudomonas aeruginosa (table II). In a number of in vitro studies, levofloxacin displayed good activity against isolates of H. influenzae, H. parainfluenzae and M. catarrhalis, with MIC90 values of ≤0.06 mg/L and susceptibility rates of approximately 100%; similarly, ciprofloxacin, gatifloxacin and moxifloxacin displayed good activity against isolates of H. influenzae and M. catarrhalis (table II). Levofloxacin was also highly active against β-lactamase negative and positive isolates of H. influenzae and M. catarrhalis. Isolates of P. mirabilis were also susceptible to levofloxacin (MIC90 ≤2 mg/L; 91.6% susceptible isolates) and some of the other fluoroquinolones (MIC90 0.12 to >4 mg/L; 85.9% susceptible isolates) [table II]. The activity of levofloxacin against isolates of E. coli varied, with MIC90 values ranging from ≤0.06 mg/L (susceptible) to >8 mg/L (resistant). The percentage of E. coli isolates susceptible to levofloxacin was 80.4–94.5%, similar to the susceptibility rates of ciprofloxacin and gatifloxacin (table II). Levofloxacin was generally active against isolates of K. pneumoniae (table II); levofloxacin had limited activity against 61 isolates of extendedspectrum β-lactamase (ESBL)-producing K. pneumoniae (MIC90 of >8–32 mg/L).[6,26] Similar results were seen in 100 wild-type ESBL isolates of K. pneumoniae or E. coli, where the MIC90 of levofloxacin was >16 mg/L.[27] E. cloacae, a causative pathogen for complicated UTI, showed a high susceptibility to levofloxacin, with an MIC90 of ≤1 mg/L and a susceptibility rate of 94%. Levofloxacin was generally less active against isolates of P. aeruginosa, with MIC90 values ranging from 0.5 mg/L to 64 mg/L; susceptibility rates were 71–94% (table II). Drugs 2008; 68 (4)

Levofloxacin: A Review

543

Table III. In vitro antibacterial activity of levofloxacin (LEV) and other quinolones against atypical bacteria that are causative pathogens for community-acquired pneumonia (CAP) and acute bacterial sinusitis and are indicated for treatment in the US with levofloxacin 750 mg or 500 mg once daily for 5 or 10 days. Data are from studies (2000–2007) conducted worldwide comparing the activity of antibacterial agents against clinical isolates alone or clinical isolates plus either isolates from environmental sources[36] or reference organisms[37-39] Species MIC90 (mg/L) References (no. of isolates) LEV CIP GAT MOX Chlamydophila pneumoniae 0.25–1 NT NT NT 35,38-40 (42)a Legionella pneumophila 0.008–0.5 0.016–1 0.008 0.008–0.06 5,6,15,35-37 (499) Mycoplasma pneumoniae 1–2 2–4 0.125 0.125 15,35,41-44 (428)a,b a Causative pathogen for CAP and is indicated for treatment with LEV 750 mg once daily for 5 days (US). b Some isolates of M. pneumoniae may have been used in more than one study, but details have not been reported.[41-44] CIP = ciprofloxacin; GAT = gatifloxacin; MIC90 = minimum concentration required to inhibit 90% of isolates; MOX = moxifloxacin; NT = not tested.

In the SENTRY antimicrobial surveillance programme, levofloxacin has shown generally good in vitro activity (MIC90 and proportion of susceptible isolates) against a range of other Gram-negative bacteria such as Stenotrophomonas maltophilia (4 mg/L, 86%),[33] ceftazidime-resistant Serratia spp. (n = 43) and ‘all’ ceftazidime-resistant Enterobacteriaceae (n = 1471) including ceftazidime-resistant Citrobacter spp. (n = 122) [>4 mg/L, 68.5–76.2%];[34] however, the activity of levofloxacin was limited against ceftazidime-resistant Acinetobacter spp. (n = 500) [>4 mg/L, 19.6%].[34] 2.1.3 Atypical Bacteria

Levofloxacin has good activity against the atypical organisms Chlamydophila pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae with MIC90 values of ≤2 mg/L (table III). In a study of 146 isolates of L. pneumophila from North America and Europe, the MIC90 of levofloxacin was 0.003 mg/L, with an MIC range of 0.008–0.03 mg/L in the US (n = 86).[35] Against 41 isolates of M. pneumoniae, levofloxacin had an MIC90 of 1 mg/ L worldwide, and two macrolide-resistant isolates were inhibited by levofloxacin at 0.25 mg/L; against six isolates of C. pneumoniae in the US, the MIC range of levofloxacin was 0.25–0.5 mg/L.[35] 2.1.4 Other Bacteria

Levofloxacin has shown limited activity against bowel-colonizing anaerobic bacteria including Bacteroides spp. and Clostridium difficile.[9] Like most other antibacterial agents, levofloxacin has been associated with C. difficile diarrhoea, which © 2008 Adis Data Information BV. All rights reserved.

may vary in severity from mild diarrhoea to fatal colitis (see section 5).[10] 2.2 Bactericidal Activity and Postantibiotic Effects

The bactericidal activity of levofloxacin is concentration dependent[45] and the minimum bactericidal concentration (MBC) of levofloxacin was ≤4 × the MIC against the majority of isolates for a number of causative pathogens of respiratory tract infections and UTIs.[39-44] The MBC of levofloxacin at which 90% of isolates were killed (MBC90) was 1–4 × the MIC against the majority of M. pneumoniae isolates tested in several studies (MBC of ≤0.5–1 mg/L).[39-44] Against E. coli, E. cloacae, K. pneumoniae and P. aeruginosa, the MBC of levofloxacin was 1–2 × the MIC (≤0.06–4 mg/L); the mutant prevention concentration, the concentration of an antibacterial required to inhibit first-step resistant organisms, was 4–16 × the MIC (0.5–16 mg/L) with only K. pneumoniae being within 4 × the MIC.[32] Levofloxacin has a postantibiotic effect (PAE) of 2–4.5 hours depending on the pathogen (reviewed by Croom and Goa).[9] The PAE of levofloxacin against pneumococci was up to 4.5 hours at 10 × the MIC and a postantibiotic sub-MIC effect of up to 16 hours against S. pneumoniae specifically has also been demonstrated; other bacteria that levofloxacin has demonstrated a PAE against include meticillinsusceptible S. aureus, K. pneumoniae, L. pneumophila and anaerobes.[9] Against erythromycin-resistant and -susceptible strains of L. pneumophila, Drugs 2008; 68 (4)

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Anderson & Perry

levofloxacin demonstrated a mean PAE of 2.59 and 2.14 hours at 4 × the MIC; in Legionella spp. other than L. pneumophila, the mean PAE of levofloxacin was 3.24 hours.[36] 2.3 Resistance

Resistance to antibacterial drugs in S. pneumoniae has become a major problem in the US for more than a decade.[46] Nevertheless, although there are reports of the emergence of fluoroquinolone resistance among S. pneumoniae,[46] the incidence of levofloxacin-resistant organisms has remained stable to date, with the level of levofloxacin resistance in S. pneumoniae remaining ≤1% worldwide.[1-4,19,20] The primary cause of reduced susceptibility of bacteria (particularly S. pneumoniae) to fluoroquinolones is at least one mutation in the parC and parE genes that code for DNA topoisomerase IV and/or gyrA and gyrB genes that code for DNA gyrase.[47,48] A secondary fluoroquinolone resistance mechanism is active drug efflux, which results from a mutation in the efflux regulatory genes mexR and nfxB.[47,49] In the PROTEKT surveillance programme (worldwide) between 1999 and 2000, 35 levofloxacin-resistant isolates of S. pneumoniae were identified and 33 of these isolates had a mutation in one each of the genes coding for topoisomerase IV and DNA gyrase.[48] In levofloxacin-intermediate S. pneumoniae isolates, only one or no mutation was identified in the DNA gyrase or topoisomerase IV genes; when a mutation was detected, it was usually in the parC gene.[48] Similarly, in the SENTRY surveillance programme (1997–2005), fluoroquinolone-resistant isolates of β-haemolytic Streptococcus spp. showed significant mutations in the parC and/or gyrA gene; in strains with lower MIC values, a mutation in parC was the only one identified.[25] A study in which an in vitro pharmacodynamic model simulating the concentration of levofloxacin or moxifloxacin in the epithelial lining fluid (ELF) after once daily administration of 500 mg or 400 mg found that all five isolates of S. pneumoniae containing the first-step parC mutation showed levofloxacin resistance within 48 hours (≥16-fold increase in MIC) and four of the isolates had acquired a secondstep mutation (gyrA mutations in these cases).[50] © 2008 Adis Data Information BV. All rights reserved.

The two isolates that were exposed to moxifloxacin showed no change in resistance.[50] When S. pneumoniae isolates were exposed to simulated concentrations from an ≈750 mg dose of levofloxacin, two of the four isolates containing parC mutations showed phenotypic resistance at 48 hours (≥16-fold increase in MIC) and one of these isolates acquired a second-step gyrA mutation.[50] The acquisition of a second-step mutation in the above simulation appeared to be associated with an area under the concentration-time curve (AUC) : MIC ratio of ≤256; this suggests that to prevent levofloxacin resistance from being acquired in isolates with a first-step parC mutation, the AUC : MIC ratio target should be ≥200 (section 2.4).[50] Another study simulating a range of free AUCs (fAUCs) of levofloxacin, gatifloxacin, gemifloxacin and moxifloxacin, demonstrated that fAUC : MIC ratios of ≤82 and ≤86 for levofloxacin were associated with a first-step parC mutation and second-step gyrA mutation in S. pneumoniae; these resistance breakpoints for levofloxacin were significantly (all p ≤ 0.001) higher than those for gatifloxacin (51 and ≤60), gemifloxacin (34 and 37) and moxifloxacin (≤24) [post hoc analysis].[51] As the fAUC : MIC ratio increased for each fluoroquinolone, a delay in the development of first- or secondstep mutations was seen.[51] In the TRUST (US, 1998–2002),[19,20] PROTEKT (US and Canada, 1999–2002)[2-4] and SENTRY (worldwide, 1999–2005)[1] surveillance programmes (n = 71 973), the overall levofloxacinresistance rate in S. pneumoniae isolates was ≤1%; in penicillin-resistant isolates, the rate of levofloxacin resistance was 0.9–2.7%.[1,4,19] From 2000 to 2005, the proportion of S. pneumoniae isolates (collected from patients with ABS) in the TRUST surveillance programme that were found to be resistant to levofloxacin changed from 0% to 0.5%.[52] During the same period, the resistance of these isolates to amoxicillin/clavulanic acid increased from 6.5% to 12.9%, clindamycin resistance increased from 12.1% to 18.6% and penicillin resistance increased 27.4% to 28.9%.[52] Of the 339 of 847 isolates that were found to be resistant to two or more drugs, 0.9% displayed levofloxacin resistance while 83.2% and 81.7% were resistant to azithromycin or cefuroxime.[52] Other data from 2004 to Drugs 2008; 68 (4)


2006[53] suggest that the rate of levofloxacin resistance in S. pneumoniae isolates in the US has decreased from 1.1% to 0.6% accompanied by shifts in the serotype and the possibility that different mechanisms for fluoroquinolone resistance (mechanisms other than mutations in the quinolone-resistance determining region) are emerging. No levofloxacin-resistant isolates of H. influenzae or M. catarrhalis were identified in large, worldwide surveillance studies reported between 1998 and 2005.[1-4,18,28,29] However, surveillance studies have identified resistance to levofloxacin in E. coli (5.1–15.4%), P. aeruginosa (24.7%) and meticillin/oxacillin-susceptible and -resistant strains of S. aureus (3.4–10.1% and 76.6–79.2%).[16,17,30] 2.4 Pharmacodynamic/Pharmacokinetic Relationships

The most common pharmacodynamic parameters for predicting the in vivo antibacterial activity of fluoroquinolones and the potential for resistance to emerge is the AUC : MIC ratio and the Cmax : MIC ratio, although the AUC : MIC ratio has been suggested as being the preferred option as it includes the parameter of exposure over time.[54-56] A review of pharmacological parameters from a number of clinical trials has suggested that an AUC : MIC ratio of 30–50 predicts a bacteriostatic effect, with values of >100–250 indicating a bactericidal effect (>250 indicates rapid bactericidal action); failing to reach the higher pharmacodynamic targets could increase selection pressure on mutants with the first-step parC mutation (section 2.3).[56] In one study simulating levofloxacin concentrations in ELF, it appeared that an AUC : MIC ratio of ≥200 was necessary to maintain bactericidal activity and prevent levofloxacin resistance from being acquired in S. pneumoniae isolates with a first-step parC mutation (section 2.3).

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It was also suggested that the lower pharmacodynamic targets may have predicted microbiological efficacy in studies using wild-type S. pneumoniae isolates, but that these targets may be insufficient in isolates already containing a mutation.[50] Similarly, another in vitro pharmacodynamic study indicated that an AUC : MIC ratio of ≈100 resulted in the maximal bactericidal effect for levofloxacin and moxifloxacin against various strains of S. pneumoniae, S. aureus, K. pneumoniae and E. coli.[57] However, in several studies[55,58,59] simulating a levofloxacin dose of 750 mg, an AUC : MIC ratio target of >30 was determined as being predictive of the likelihood of levofloxacin having in vivo activity against S. pneumoniae that would potentially be great enough to show a microbiological and/or clinical effect in patients without increasing resistance selection. This lower ratio was used based on prior animal, in vitro and clinical studies that suggested that an AUC : MIC ratio of >25–34 (based on freedrug concentrations) was required to predict bacterial eradication for community-acquired infections caused by S. pneumoniae, in comparison the required AUC : MIC ratio for Gram-negative bacteria such as P. aeruginosa was higher (AUC : MIC ratio of >100–125).[58-61] A recent in vitro pharmacodynamic trial on levofloxacin has also indicated that a lower AUC : MIC ratio against S. pneumoniae is required compared with that needed for Gram-negative bacteria, but further studies are required to determine the optimal drug exposure.[57] In three studies using Monte Carlo simulations,[55,58,59] levofloxacin 750 mg once daily resulted in an AUC from time zero to 24 hours (AUC24) : MIC ratio ≥30 being achieved in high proportions of S. pneumoniae isolates from the overall patient population (including patients with CAP)[58,59] in both the plasma and ELF (table IV); in

Table IV. The probability (%) of once-daily levofloxacin 750 mg attaining the pharmacodynamic target of area under the plasma concentration-time curve from time zero to 24 hours : minimum inhibitory concentration ratio ≥30 against Streptococcus pneumoniae isolates in Monte Carlo simulationsa Compartment All pts Elderly pts Younger pts Plasma 97–99[55,58] 98.1[58,59] 89.9–90.1[58,59] ELF 98.4[59] 98.6[59] 94.1[59] a Monte Carlo simulations were carried out using S. pneumoniae susceptibility data from the Canadian Respiratory Organism Susceptibility Study[58,59] or pharmacodynamic data from the Surveillance Network 2002 database[55] and demographic data from hospitalized pts with CAP.[58,59] CAP = community-acquired pneumonia; ELF = epithelial lining fluid; pts = patients.


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one study, as the ratio approached 70 in the plasma, the probability of target attainment remained ≈90%, but from a ratio of 70 upwards, the probability showed a steep decline.[55] In elderly (aged ≥65 years) and younger patients (aged 1 in the Monte Carlo simulation, although inflammation would likely have altered the penetration of levofloxacin into ELF.[71] After receiving a lower dosage of levofloxacin (500 mg once daily for 3 days), Cmax and AUC24 values for levofloxacin were significantly higher in the polymorphonuclear leukocytes than in plasma (both p < 0.01) in healthy volunteers.[73] After a Drugs 2008; 68 (4)

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single 500 mg oral dose of levofloxacin, the paranasal sinuses mucosa : plasma ratio was 2.56 at tmax and the concentration of levofloxacin in the paranasal sinuses mucosa was generally higher than the MIC90 against the most common causative pathogens for upper respiratory tract infections (0.008–2 mg/L), including penicillin-susceptible, -intermediate and -resistant isolates of S. pneumoniae (section 2.1).[72] 3.2 Metabolism and Elimination

Levofloxacin is mainly eliminated via the kidneys, with 75–87% of the dose excreted unchanged in the urine within 48–72 hours of taking oral levofloxacin 500 or 750 mg,[10,64,65] and 88%) were observed in both levofloxacin treatment groups at the test-of-cure (day 17–24 of the study) visit (table VI). The noninferiority of levofloxacin 750 mg once daily for 5 days to levofloxacin 500 mg once daily for 10 days was established (upper limit of the 2-sided 95% CI for © 2008 Adis Data Information BV. All rights reserved.

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the between-group difference in the clinical success rate 90% to detect the difference for the population that included all patients with complicated UTI or AP,[75] but the power dropped to 75% (modified ITT population) and 85% (microbiologically evaluable population) in the analysis of patients with AP.[76] The most common pathogen identified at baseline was E. coli, which was isolated in 424 patients with complicated UTI or AP. Of the 76 patients (12.3%) who had Gram-positive pathogens isolated from their samples, E. faecalis was isolated in 37 of them (the most commonly isolated Gram-positive pathogen).[75] Levofloxacin 750 mg once daily for 5 days was at least as effective as ciprofloxacin 400 mg or 500 mg twice daily for 10 days in the treatment of adults with complicated UTI or AP.[75,76] At the post-therapy visit (day 15–22, extended from the predetermined day 19) of the complicated UTI and AP study,[75] levofloxacin was noninferior to ciprofloxacin according to the microbiological © 2008 Adis Data Information BV. All rights reserved.

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eradication rate (primary endpoint) in both the overall co-primary modified ITT and microbiologically evaluable populations table VII. At the end-of-therapy visit (day 11 ± 1 of the study), the overall microbiological eradication rate was not significantly different between levofloxacin and ciprofloxacin recipients in the overall modified ITT population (79.8% vs 77.5%; 95% CI –8.8, 4.1) and the overall microbiologically evaluable population (88.3% vs 86.7%; 95% CI –7.4, 4.2). The E. coli eradication rate in the modified ITT population (levofloxacin versus ciprofloxacin) was 80.1% (165 of 206) versus 73.1% (158 of 216); in the corresponding groups, E. faecalis was eradicated in 61.9% (13 of 21) versus 75% (12 of 16) of patients.[75] In 12 patients with levofloxacin-resistant E. coli, the overall eradication rate was 33.3% and in 21 patients with ciprofloxacin-resistant E. coli the eradication rate was 19% at the posttherapy visit. In both primary analysis populations, microbiological eradication occurred in a significantly smaller proportion of patients with a catheter compared with patients without a catheter (95% CI –26.6, –3.3), and a significantly greater proportion of levofloxacin recipients with catheters showed microbiological eradication compared with ciprofloxacin recipients with catheters.[75] The rate of clinical success at the post-therapy visit was not significantly different between levofloxacin or ciprofloxacin recipients in either the overall modified ITT population (95% CI –7.2, 5.3) or the overall microbiologically evaluable population (95% CI –3.9, 7.8) [table VII]. At the end-oftherapy visit, the clinical success rates in the modified ITT and microbiologically evaluable populations (levofloxacin vs ciprofloxacin recipients) were 82.6% versus 78.5% (95% CI –10.4, 2.1) and 91.3% versus 87.1% (95% CI –9.6, 1.2).[75] In the analysis of patients with AP,[76] levofloxacin was at least as effective as ciprofloxacin at the post-therapy visit (primary endpoint) with noninferiority established in each patient population within this strata as it was in the overall patient population (table VII). The microbiological eradication rates in levofloxacin versus ciprofloxacin recipients at the end-of-therapy visit in the modified ITT population (83% vs 78.6%; 95% CI –15.5, 6.7) and microbiologically evaluable population (91.3% vs 86.8%; Drugs 2008; 68 (4)


95% CI –14.2, 5.4) were close to those assessed at the post-therapy visit. Similar proportions of levofloxacin or ciprofloxacin recipients were deemed to have clinical success at the post-therapy visit in the modified ITT population (86.2% vs 80.6%; 95% CI –16.0, 4.9) and the microbiologically evaluable population (92.5% vs 89.5%; 95% CI –12.0, 6.0) [table VII], and at the end-of-therapy visit (85.1% vs 80.6% [95% CI –15.1, 6.1] and 93.8% vs 88.2% [95% CI –14.6, 3.4]) in the corresponding populations.[76] The resolution or improvement of symptoms was not significantly different between either treatment group at the end-of-therapy or post-therapy visits. At the end-of-therapy visit, flank pain, costovertebral angle tenderness and fever was resolved or improved in 82.4% versus 78.9% (95% CI –14.8, 7.9), 84.1% versus 81.3% (95% CI –14.1, 8.4) and 85.7% versus 80.8% (95% CI –16.9, 7.0) of levofloxacin versus ciprofloxacin recipients, respectively. By the post-therapy visit, the corresponding proportions were 89% versus 85.3% (95% CI –13.3, 5.9), 90.2% versus 90.1% (95% CI –9.0, 8.8) and 92.9% versus 85.9% (95% CI –16.8, 2.8).[76] Of the patients with complicated UTI or AP who were classified as having clinical success at the posttherapy visit, 8.7% and 8.6% of levofloxacin or ciprofloxacin recipients were deemed to have had a clinical relapse at a follow-up visit on day 38–45,[75] including one patient with AP in each treatment group.[76] One limitation of this study was the potential for the assessment of clinical and microbiological response to favour the longer-course active treatment as the timing of the post-therapy (and end-of-therapy) visit was the same during the study regardless of the length of active treatment (i.e. on day 15–22 of the study). Another limitation was the high threshold set for the uropathogen colony count in the inclusion criteria, which would cause more severely infected patients to be enrolled in the study and therefore could potentially cause the efficacy of either active drug to be underestimated.[75] © 2008 Adis Data Information BV. All rights reserved.

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5. Tolerability Levofloxacin 750 mg once daily for 5 days is generally well tolerated in patients with respiratory infections or UTIs.[75,76,82] Tolerability data are from a pooled analysis of clinical trials with analyses comparing once-daily levofloxacin 750 mg for 5 days with once-daily levofloxacin 500 mg for 10 days in patients with certain respiratory tract infections,[82] as well as the randomized clinical trial in patients with complicated UTI or AP[75,76] receiving levofloxacin 750 mg once daily for 5 days or ciprofloxacin 400 mg or 500 mg twice daily for 10 days, reported in section 4. The pooled analysis[82] included trials of similar design, although they did not need to be head-tohead comparisons of the two levofloxacin treatment regimens, and contained two of the randomized clinical trials[45,74] reported in section 4. In a pooled analysis of patients with respiratory infections receiving the levofloxacin 750 mg regimen (n = 1141) or 500 mg regimen (n = 3268), 45.5% and 49% of patients had a treatment-emergent adverse event (all body systems).[82] The specific treatment-emergent adverse events (occurring in ≥2% of levofloxacin recipients) in both dosage regimens included nausea, headache, diarrhoea, insomnia, constipation, abdominal pain, dizziness, dyspepsia and vomiting; only the incidence of diarrhoea (4.6% vs 6.5%; p < 0.05) and abdominal pain (1.6% vs 3.1%; p < 0.05) was significantly different between the levofloxacin 750 mg and 500 mg regimens. The incidence of drug-related adverse events (deemed by the clinical investigator as definitely, very likely or probably related to levofloxacin therapy) were similar between both levofloxacin treatment regimens (8% vs 7.6%), with headache (0.5% vs 0.1%; p < 0.05) being the only adverse event to show a significant difference between the levofloxacin 750 mg and 500 mg regimens, and nausea and diarrhoea the only adverse events to be reported by >1% of patients. The incidence of specific drugrelated adverse events in patients receiving the levofloxacin 750 mg regimen in the pooled analysis are presented in figure 2. In patients with respiratory tract infections, one case each of asterixis, paralysis, laryngeal oedema and hepatic necrosis (clinically important adverse Drugs 2008; 68 (4)

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500 mg 750 mg

10 9 8

8 7.6

Patients (%)

7 6 5 4 3 2

1.8

2 1.4 1.4

1

Al

lb

a

0

0.6 0.5 0.3 0.6 0.5 0.3 0.3 0.2

rrh

ia

ea

da

ch

se

0.6 0.2 0.1

D

N

au H

od

y

sy

st

em

s

0

e oe In a s C om on ni a Ab st do ipa tio m in al n pa D in iz zi D nes ys s pe ps Vo ia m iti ng

* 0.5 0.1

Fig. 2. Tolerability of intravenous and/or oral levofloxacin. Incidence of the most common drug-related adverse events occurring in patients with respiratory infections receiving levofloxacin 750 mg once daily for 5 days (n = 1141) or 500 mg once daily for 10 days (n = 3268) in a pooled analysis.[82] * p < 0.05 vs 500 mg.

events) were reported with the 750 mg dosage regimen of levofloxacin; however, these were not deemed to be related to drug treatment.[82] Moderate to severe photosensitivity/phototoxicity reactions can be associated with the use of quinolones after exposure to the sun or UV light.[10] Although fluoroquinolones can potentially prolong the QT interval, there were no cases of torsade de pointes in any clinical or postmarketing trials.[10,82] Like most other antibacterial agents, levofloxacin has been associated with C. difficile diarrhoea, which may vary in severity from mild diarrhoea to fatal colitis.[10] Tendon effects, including ruptures of the hand, Achilles tendon and shoulder, sometimes resulting in prolonged disability, have been observed in patients receiving levofloxacin and other quinolones.[10] Sensory or sensorimotor axonal polyneuropathy, resulting in weakness, paresthesias and other symptoms, have been observed (rarely) with quinolones, including levofloxacin. Treatment with levofloxacin should be discontinued if symptoms of neuropathy occur.[10] In addition, there have been reports of convulsions and toxic psychoses in recipients of quinolones, including levofloxacin.[10] Serious hypersensitivity, occasionally fatal, has also © 2008 Adis Data Information BV. All rights reserved.

been reported (rarely) in recipients of quinolones, including levofloxacin (see the manufacturer’s prescribing information for further details[10]). The safety profile of levofloxacin has not been shown to differ between elderly and younger adult patients in phase III clinical trials.[10] Pooled analyses of clinical trials in patients with ABS (n = 389) or CAP (n = 379) receiving the levofloxacin 750 mg regimen, showed that the tolerability profiles of these specific patient populations were generally similar to that of the overall patient population, in regards to the type and incidence of specific adverse events.[82] The incidence of treatment-emergent and drug-related adverse events in patients with ABS or CAP was also similar between the levofloxacin 750 mg and 500 mg regimens. Patients with ABS receiving the levofloxacin 750 mg regimen had a significantly lower incidence of treatment-emergent insomnia or abdominal pain, and a significantly higher incidence of treatmentemergent vomiting or treatment-emergent and drugrelated dry mouth (all p < 0.05), than those receiving the levofloxacin 500 mg regimen. The incidence of adverse events in patients with CAP were also similar between the treatment regimens, with the exception of a higher (p < 0.05) incidence of treatmentemergent insomnia in those receiving the levofloxacin 750 mg regimen than those receiving the 500 mg regimen.[82] The type and incidence of adverse events in the two clinical trials[45,74] reported in section 4 and used in the pooled analysis, are similar to the overall results of the pooled analysis.[82] In patients with complicated UTI or AP who were evaluable for safety analysis, treatment-emergent events were experienced by 35.5% and 33.1% of patients receiving levofloxacin (n = 543) or ciprofloxacin (n = 559) [95% CI –7.9, 3.3].[75] In patients with AP, 43.8% and 39.2% of levofloxacin (n = 146) or ciprofloxacin (n = 166) recipients experienced treatment-emergent adverse events (95% CI –11.2, –0.6).[76] Common adverse events (≥2% of recipients) were the same as those reported in patients with respiratory infections (headache,[75,76] nausea[75,76] and diarrhoea[75]) and there were no significant differences between the treatment groups (statistical analysis not reported).[75] Discontinuing therapy because of adverse events occurred in 4.4–4.8% (treatment emergent) and Drugs 2008; 68 (4)


1.5–1.6% (drug related) of patients with respiratory infections.[82] In patients with CAP,[45] 7% (18 of 256) and 8.3% (22 of 265) of patients discontinued treatment with the levofloxacin 750 mg or 500 mg regimen because of adverse events. Serious treatment-emergent or drug-related adverse events were reported in 5.3% versus 6.5% and 0.4% versus 0.2% of patients with respiratory infections receiving the 750 mg or 500 mg dosage regimens of levofloxacin.[82] In one clinical trial,[45] 9.8–14% of patients with CAP reported one or more serious adverse event (which included any treatment-emergent adverse event that resulted in a fatality, was life-threatening, resulted in or prolonged hospitalization, resulted in a permanent or significant disability, was a congenital anomaly or was assessed as being medically important); the most common serious adverse event in these patients was their CAP becoming worse (3.4–3.5% of levofloxacin recipients). In patients with complicated UTI or AP, 0.18% of levofloxacin and 0.71% of ciprofloxacin recipients experienced serious adverse events, including a treatment-related allergic reaction to levofloxacin; four ciprofloxacin recipients experienced a worsening of their infection after receiving one to four doses of medication.[75] In the AP analysis, serious adverse events were reported in 3.42% of levofloxacin and 3.6% of ciprofloxacin recipients; in the levofloxacin treatment group these included unintended pregnancy, noncardiac chest pain, renal calculus, pelvic inflammatory disease and urinary retention with subsequent urosepsis, and all were deemed to be unrelated to the drug treatment.[76] There were no deaths in the CAP clinical trial[45] and neither of the deaths (one each in the levofloxacin or ciprofloxacin treatment group) in the complicated UTI or AP trial[75] were deemed to be related to treatment. 6. Dosage and Administration Levofloxacin (in various dosages and treatment durations) is indicated in the US for the treatment of adults aged ≥18 years with a range of infections.[10] Intravenous and/or oral levofloxacin 750 mg once daily for 5 days is currently approved for the treatment of ABS, CAP, complicated UTI and AP caused by susceptible strains of causative pathogens © 2008 Adis Data Information BV. All rights reserved.

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in patients with normal renal function (CLCR ≥50 mL/min [3 L/h]).[10] The micro-organisms that cause ABS, CAP, complicated UTI and AP and that are approved for treatment with levofloxacin 750 mg once daily for 5 days are listed in table VIII; this list of pathogens may differ from the list of causative pathogens that are approved for treatment with a lower dose, longer course of levofloxacin (e.g. levofloxacin 500 mg once daily for 10 days). Intravenous levofloxacin must be administered slowly as an infusion over a minimum period of 60–90 minutes, depending on the dose.[10] Levofloxacin tablets or oral solution are usually given at a dosage of 250, 500 or 750 mg once daily and the tablet formulation of levofloxacin can be taken with or without food; however, the oral solution should be taken 1 hour prior to or 2 hours after eating. Sufficient hydration should be maintained in patients receiving intravenous or oral levofloxacin to prevent highly concentrated urine from being formed. Levofloxacin and agents such as magnesium- or aluminium-containing antacids, sucralfate, metal cations, zinc-containing multivitamins or didanosine should be taken ≥2 hours apart.[10] Patients with impaired renal function taking levofloxacin 750 mg once daily for 5 days require the following dosage adjustments: CLCR 20–49 mL/ min, 750 mg every 48 hours; CLCR 10–19 mL/min or patients on haemodialysis or chronic ambulatory Table VIII. Approved indications in the US and the associated causative pathogens that are approved for treatment with intravenous and/or oral levofloxacin 750 mg once daily for 5 days[10] Acute bacterial sinusitis Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis Community-acquired pneumonia S. pneumoniae (excluding multi-drug-resistant strainsa), H. nfluenzae, H. parainfluenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae Complicated urinary tract infections Escherichia coli, K. pneumoniae, Proteus mirabilis Acute pyelonephritis E. coli b a Strains that are resistant to two or more of the following antibacterials: penicillin, second generation cephalosporins and cotrimoxazole (trimethoprim plus sulfamethoxazole). b Including cases with concurrent bacteraemia.

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peritoneal dialysis, 750 mg initial dose then 500 mg every 48 hours (section 3). No studies have been carried out in patients with reduced hepatic function; however, no dosage adjustment is expected to be necessary because of the limited metabolism of levofloxacin (section 3). Data from patients aged ≥65 years who participated in phase III clinical trials showed no difference between elderly and younger patients in regards to the safety or effectiveness of levofloxacin, although elderly patients may be more sensitive to levofloxacin, particularly the effect of the drug on the QT interval.[10] Thus, caution is warranted in the concomitant use of levofloxacin with drugs that are also known to prolong the QT interval such as class IA or class III antiarrhythmics in this age group. Also, as there is an increased risk of severe tendon disorders in elderly patients when receiving fluoroquinolones, which is further increased with concomitant steroid therapy, caution is warranted in the use of levofloxacin in the elderly, particularly if they are receiving corticosteroids.[10] The risk of CNS stimulation and convulsive seizures may be increased when an NSAID is administered concomitantly with a quinolone (including levofloxacin).[10] Clinically significant effects, such as symptomatic hyperglycaemia and hypoglycaemia, have been reported with levofloxacin usually in patients with diabetes mellitus receiving concomitant hypoglycaemic agents/insulin. Thus, blood glucose monitoring is recommended in these circumstances.[10] Postmarketing data suggest that levofloxacin may increase the prothrombin time when warfarin is administered concomitantly, so anticoagulation and evidence of bleeding should be monitored in patients receiving the two drugs concurrently.[10] Because other quinolones, when administered concomitantly with theophylline, have been associated with decreasing theophylline metabolism, monitoring and dosage adjustment of theophylline may be required when used in conjunction with levofloxacin.[10] Similarly, some quinolones administered in conjunction with ciclosporin have resulted in higher serum concentrations of ciclosporin; however, these changes were not clinically significant.[10] © 2008 Adis Data Information BV. All rights reserved.

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Levofloxacin should not be used in paediatric patients aged 100 may be preferable for bactericidal rather than bacteriostatic action. Thus, if patients are suspected of being infected with S. pneumoniae with parC mutations (e.g. they have been treated with fluoroquinolones in the previous 3 months or have had a treatment failure with fluoroquinolones), caution in the use of fluoroquinolones is warranted.[50] The PAE associated with levofloxacin (section 2.2) and fluoroquinolones in general[54] allows high doses of levofloxacin to be administered less frequently than the t1/2β of ≈6–9 hours (section 3.2) would suggest, hence the ability for once-daily administration in the high-dose, short-course levofloxacin regimen. After oral administration levofloxacin is rapidly absorbed into the plasma as well as other body compartments, and the concentration in other tissues (such as ELF, AM, paranasal sinuses mucosa and urine) can exceed that in the plasma (section 3). Greater Cmax and AUC values are achieved with the 750 mg levofloxacin regimen compared with the 250 or 500 mg regimens.[10] Drugs 2008; 68 (4)


Levofloxacin 750 mg once daily for 5 days showed efficacy in the treatment of adults with CAP, ABS, complicated UTI and AP. The efficacy of the levofloxacin 500 mg regimen in the treatment of respiratory infections and UTIs is well established[9] as is the efficacy of ciprofloxacin in UTIs.[99] The levofloxacin 750 mg regimen was at least as effective as levofloxacin 500 mg once daily for 10 days in adults with CAP or ABS according to the primary endpoint of clinical response rate 7–14 days after the end of treatment (section 4.1 and section 4.2). In addition, a significantly (all p ≤ 0.027) higher proportion of patients with CAP had a resolution of fever on day 3 of therapy with the levofloxacin 750 mg regimen compared with the 500 mg regimen,[80,81] including the subgroup of patients infected with atypical pathogens[80] and specifically those infected with M. pneumoniae.[80] Levofloxacin 750 mg once daily for 5 days was also at least as effective as ciprofloxacin 400 mg or 500 mg twice daily for 10 days in adults with complicated UTI or AP according to the primary endpoint of microbiological response (eradication) rate on day 15–22 of the study (section 4.3). Each respiratory and UTI study was powered to determine noninferiority, which was established in each case. No other randomized comparative trials of the high-dose shortcourse regimen of levofloxacin in the indications approved in the US have been published to date. Thus, the efficacy of this regimen of levofloxacin relative to that of other antibacterial drugs used to treat these infections has yet to be established. A potential for bias was present in the studies in patients with CAP, ABS, complicated UTI and AP, which means caution is warranted in generalizing the results from each study to the wider patient population. The enrolment of fewer patients with more severe CAP (PSI stratum I) and a relatively large number of patients with M. pneumoniae infections (less severe presentation) could have resulted in the efficacy of levofloxacin being overestimated in the CAP study.[45] Similarly, the late timing of the test-of-cure visit in the ABS study could potentially make levofloxacin seem more effective as ABS is known to have a high rate of spontaneous resolution.[74] In contrast, the enrolement of more severely infected patients in the complicated UTI and AP study could cause the efficacy of levofloxacin to be © 2008 Adis Data Information BV. All rights reserved.

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underestimated, and the timing of the post-therapy visit (i.e. on day 15–22 of the study regardless of study treatment) could favour the longer 10-day ciprofloxacin regimen over the 5-day levofloxacin regimen.[75] More studies are needed comparing the effectiveness of levofloxacin with other fluoroquinolones in the treatment of CAP, ABS, complicated UTI or AP to accurately place levofloxacin within this class of drugs. The high-dose, short-course levofloxacin regimen has a tolerability profile similar to that of the lower dose, longer course levofloxacin regimen, which has a well characterized tolerability profile;[9,82] in addition, levofloxacin has a similar tolerability profile to that of ciprofloxacin.[9] Levofloxacin is generally well tolerated in patients with respiratory infections or UTIs with the majority of drug-related adverse events being mild to moderate in nature (section 5). In comparison, patients receiving aminoglycoside therapy should be kept under close clinical observation as drugs in that class have the potential to cause ototoxicity and nephrotoxicity.[100] The shorter 5-day course of levofloxacin has an advantage in terms of the potential for compliance over many other agents that can have administration schedules of 7–14 days or longer including other fluoroquinolones (e.g. ciprofloxacin [including extended-release formulation],[99] moxifloxacin,[7] gatifloxacin),[101] macrolides (e.g. clarithromycin[102] and erythromycin[103]), β-lactams (e.g. amoxicillin/ clavulanic acid,[89] cefpodaxime[104] and ceftriaxone[105]) and aminoglycosides (e.g. gentamicin,[106] tobramycin[100] and amikacin[107]). Levofloxacin is administered once daily and can be taken without regard to food (section 2.4), which is a more convenient administration schedule than that for drugs such as ciprofloxacin (standard formulation),[99] amoxicillin/clavulanic acid,[89] clarithromycin,[102] erythromycin,[103] cefpodoxime,[104] gentamicin,[106] tobramycin[100] and amikacin,[107] which may require more frequent administration. With the availability of an intravenous and an oral formulation, levofloxacin is appropriate for use in patients with severe infections who require initial intravenous therapy and who can then move onto the rapidly absorbed, bioequivalent oral formulation (section 2.4) for a Drugs 2008; 68 (4)

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more convenient and cost-effective treatment regimen. The broad spectrum antibacterial profile of levofloxacin means that monotherapy is often a possibility in patients with CAP at times when other agents may require combination therapy, although levofloxacin can be used in combination therapy when necessary. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent bactericidal activity and may reduce the potential for resistance to emerge. In addition, this regimen lends itself to better compliance because of the shorter duration of treatment and the convenient once-daily administration schedule. Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation; importantly, patients can transition between the formulations, which results in more options in regards to the treatment regimen and the potential for patients with varying degrees of illness to be treated. Levofloxacin has good tissue penetration and an adequate concentration can be maintained in the urinary tract to treat uropathogens. Levofloxacin is generally well tolerated and has good efficacy in the treatment of patients with CAP, ABS, complicated UTI and AP. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP, ABS and UTIs is well established, and the high-dose, short-course levofloxacin regimen has been shown to be noninferior to the 10-day regimen in CAP and ABS, and to have a similar tolerability profile. Similarly, the highdose, short-course levofloxacin regimen is noninferior to ciprofloxacin in patients with complicated UTI or AP. Thus, levofloxacin is a valuable antimicrobial agent that has activity against a wide range of bacterial pathogens; however, its use should be considered carefully so that the potential for resistance selection can be minimized and its usefulness in severe infections and against a range of penicillin- and macrolide-resistant pathogens can be maintained. Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.


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Correspondence: Caroline M. Perry, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: [email protected]

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