Dig Dis Sci (2014) 59:1231–1234 DOI 10.1007/s10620-014-3097-3

ORIGINAL ARTICLE

Granisetron Transdermal System Improves Refractory Nausea and Vomiting in Gastroparesis Kellie Simmons • Henry P. Parkman

Received: 20 July 2013 / Accepted: 25 February 2014 / Published online: 11 March 2014 Ó Springer Science+Business Media New York 2014

Abstract Background Symptoms of gastroparesis include nausea and vomiting, which can markedly diminish quality of life. Nausea and vomiting can also make treatment with oral antiemetics problematic. Aim Our aim was to determine whether treatment-resistant nausea and vomiting in patients with gastroparesis improve after granisetron transdermal patch (GTP) therapy. Methods In an open-label pilot study, patients with gastroparesis and symptoms of nausea and vomiting refractory to conventional treatment were treated with GTP. After 2 weeks, patients were asked to assess their therapeutic response using the Clinical Patient Grading Assessment Scale (CPGAS; ?7 = completely better; 0 = no change; -7 = very considerably worse). Responders were defined as CPGAS score [0, non-responders as B0. Results Patients (n = 36) were treated with GTP. Of these 36 patients, one patient discontinued treatment due to the GTP not adhering to the skin. Of the remaining 35 patients, 18 improved, 15 remained the same, and two worsened. The average CPGAS score was ?1.8 ± 0.4 (SEM) (P \ 0.05 vs 0). Of the 18 patients with improvement, the average CPGAS score was ?3.7 ± 0.3 (SEM), corresponding to ‘‘somewhat’’ to ‘‘moderately better’’ improvement in nausea/vomiting. Side effects occurred in nine patients: four developed constipation, three patients had skin rash, and two reported headaches.

K. Simmons  H. P. Parkman (&) GI Section, Section of Gastroenterology, Department of Medicine, Temple University School of Medicine, Temple University Hospital, 3401 N. Broad Street, Philadelphia, PA 19140, USA e-mail: [email protected]

Conclusions GTP was moderately effective in reducing refractory symptoms of nausea and/or vomiting from gastroparesis in 50 % of patients. Mild side effects were reported by 25 % of patients. GTP may be an effective treatment for nausea and vomiting in gastroparesis, and further study is warranted. Keywords Vomiting

Granisetron  Gastroparesis  Nausea 

Abbreviations GTP Granisetron transdermal patch GES Gastric emptying scintigraphy CPGAS Clinical Patient Grading Assessment Scale GCSI Gastroparesis Cardinal Symptom Index GCSI-DD GCSI daily diary SEM Standard error of the mean SD Standard deviation

Introduction Gastroparesis is a chronic, symptomatic disorder characterized by delayed gastric emptying [1]. It is commonly associated with long-standing diabetes or post-gastric surgery, particularly with surgery for stomach ulcers. Idiopathic gastroparesis represents another common form. Symptoms of gastroparesis can be debilitating, causing frequent hospitalizations and diminished quality of life. The major symptoms of gastroparesis include nausea, early satiety, bloating, and vomiting. Nausea is among the most commonly reported symptoms in gastroparesis. Nausea and vomiting, in particular, have a main impact on decreasing quality of life [2]. Treatment of gastroparesis involves the use of prokinetic agents and antiemetic agents [3]. Prokinetic agents are used

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to accelerate gastric emptying and include metoclopramide, a dopamine type 2 receptor antagonist. Antiemetic agents are also used to reduce nausea and vomiting and include prochlorperazine and promethazine [4]. Perception of gut stimulation is mediated by serotoninergic (5-HT) receptors on intrinsic nerves and extrinsic sensory pathways that project to the nodose and dorsal root ganglia. 5-HT3 mechanisms are involved in vomiting in a range of emetic stimulation; this has been primarily studied in chemotherapy-induced nausea and vomiting. 5-HT3 receptors are on vagal afferents projecting to the brainstem, as well as to the area postrema, nucleus tractus solitaries, and dorsal motor nucleus of the vagus, and may activate during emetic stimulation [5]. Serotonin 5-HT3 receptor antagonists, such as ondansetron and granisetron, are being used to treat nausea and vomiting from a variety of causes, including gastroparesis. Little data are available on the use of 5-HT3 antagonists for treatment of nausea and vomiting in gastroparesis. Oral treatment with medications is problematic in gastroparesis as nausea and vomiting can prevent oral ingestion and delayed gastric emptying can delay absorption, resulting in unpredictable efficacy [1, 3]. The granisetron transdermal patch (GTP; SancusoÒ, ProStrakan, Inc., Bridgewater, NJ, USA) releases 3.1 mg of granisetron per 24 h for up to 7 days and is approved for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy for up to 5 consecutive days [6]. The transdermal route is potentially appealing for drug delivery in gastroparesis as patients may have significant nausea and vomiting precluding oral ingestion of antiemetic or prokinetic agents for treatment. The aim of this open-label pilot study was to explore whether treatment-resistant nausea and vomiting symptoms in patients with gastroparesis improve with treatment with GTP.

Dig Dis Sci (2014) 59:1231–1234 Table 1 Summary of baseline characteristics in gastroparesis patients with treatment-refractory nausea and vomiting Age, years (SD)

43.6 ± 16.7 years

Female/male, n (%)

32 (88.9 %)/4 (11.1 %)

Etiology, n (%)

Diabetic 8 (22.2 %) Post-surgical 1 (2.8 %) Idiopathic 27 (75.0 %)

Gastric emptyinga, % retention ± SD

53.6 ± 21.1 % retention at 2h 23.4 ± 21.5 % retention at 4h

Main symptomsb, n (%)

Nausea 31 (86.1 %) Vomiting 17 (47.2 %) Abdominal pain 8 (22.2 %)

a

Gastric emptying using 4-h scintigraphy was obtained in 27 patients

b

Some patients reported more than one main symptom

emptying was assessed with the 4-h Egg BeatersÒ (ConAgra Foods, Omaha, NE, USA) gastric emptying scintigraphy (GES) [7, 8]. Delayed gastric emptying is defined as [60 % retention at 2 h and/or [10 % retention at 4 h [8]. Gastric emptying was not used as criteria for this study because there is a poor correlation between gastric emptying and symptoms, and some patients were treated prior to obtaining a gastric emptying test [9]. Following 2 weeks of treatment, patients were asked to assess their therapeutic response using the Clinical Patient Grading Assessment Scale (CPGAS), reporting if their symptoms of nausea and vomiting improved, stayed the same, or worsened with treatment on a scale of ?7 = completely better; 0 = no change; and -7 = very considerably worse [10]. Responders were defined as those with a score of [0 and non-responders with a score of B0. Patients were also asked whether they experienced any side effects with treatment. Statistical Analysis

Methods Patients being seen at Temple University Hospital Gastroenterology section for gastroparesis and who had symptoms of nausea and vomiting refractory to conventional antiemetic treatment participated in this open-label study. For this study, patients were identified as having gastroparesis if they had typical symptoms of gastroparesis with past negative upper endoscopy. During an outpatient office visit, potential treatment options were discussed for their persistent symptoms, including the use of GTP. Patients who participated were given a prescription for GTP with directions to change the patch to a new one every 7 days. Patients could continue their current antiemetic and/or prokinetic medications. In most patients, gastric

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Descriptive variables are listed as percentages or means and SEMs, where appropriate. Student’s t tests were used to determine significant differences.

Results A total of 36 patients with refractory nausea and vomiting from gastroparesis were treated with GTP. Table 1 summarizes the baseline characteristics. The average age was 43.6 ± 16.7 (SD) years. There were 32 females and four males. Eight patients had diabetes, and one patient had post-gastric surgery. Overall, GES was performed at our institution in 27 of the 36 patients. The average gastric emptying showed 53.6 ± 21.1 % retention at 2 h and

Dig Dis Sci (2014) 59:1231–1234

Fig. 1 Clinical response to the granisetron transdermal patch in patients with gastroparesis with treatment-refractory nausea and vomiting, as assessed by the Clinical Patient Grading Assessment Scale (CPGAS). Responses of the CPGAS range from ?7 (completely better) to 0 (no change) and to -7 (completely worse)

23.4 ± 21.5 % retention at 4 h. The main symptoms were nausea, vomiting, and abdominal pain. Of the 36 total patients, one patient discontinued treatment due to failure of the GTP to adhere to the skin. Of the remaining 35 patients treated with GTP, 18 patients improved, 15 remained the same, and two patients worsened (Fig. 1). Overall, the average CPGAS score was ?1.8 ± 0.4 (SEM) (P \ 0.05 vs 0). Of the 18 patients who improved, the average CPGAS score was ?3.7 ± 0.3 (SEM), corresponding to ‘‘somewhat’’ to ‘‘moderately better’’ improvement in nausea/ vomiting. Thus, GTS was somewhat to moderately effective in reducing nausea and/or vomiting from gastroparesis in 50 % (18 of 36) of the intent-to-treat population. Various subgroups experienced improvement in nausea and vomiting as assessed by the CPGAS. Both idiopathic and diabetic patients improved (idiopathic 51.9 %, 14 of 27; diabetic 37.5 %, 3 of 8). The one patient with postsurgical gastroparesis also improved. Of patients with documented delayed gastric emptying, 47.1 % (8 of 17) improved, whereas if there was no documented delay in gastric emptying, 60 % (6 of 10) of patients improved. Of the four male patients, two improved (50 %), whereas of the 32 female patients, 16 patients improved (50 %). Side effects occurred in 25 % (9 of 36) of patients: four patients developed constipation, three patients had skin rash, and two patients reported headaches.

Discussion Nausea and vomiting can be particularly distressing to patients with gastroparesis [2, 11]. Nausea has been

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reported in 90 % of patients, including both diabetic and idiopathic patients with gastroparesis [12]. Vomiting is also a significant symptom in gastroparesis, and both nausea and vomiting have a significant impact in decreasing the quality of life in patients with gastroparesis [2, 11]. Effective treatment of nausea and vomiting would be a welcome addition to the treatment options in gastroparesis, a syndrome with a paucity of available treatments [3]. This study examined the outcome of treating refractory symptoms of nausea and vomiting due to gastroparesis with GTP. This was an open-label treatment study, where symptomatic patients with gastroparesis were given a prescription for GTP, and the treatment responses were assessed by patient report. Patients had generally failed prior treatments with other antiemetic agents. GTP was somewhat to moderately effective in reducing nausea and/ or vomiting from gastroparesis in 50 % (18 of 36) of patients. Although limitations of this study include the small size and that it was an open-label exploratory study, this study suggests that GTP may be effective for treating refractory nausea and vomiting in some patients with gastroparesis. Transdermal granisetron is effective in the prevention of nausea and vomiting in patients with cancer who are receiving moderately or highly emetogenic chemotherapy for 3–5 days [6, 13–15]. Transdermal granisetron is similar to oral granisetron in this indication and is generally well tolerated in this indication. Transdermal granisetron provides a convenient option for the prevention of chemotherapy-induced nausea and vomiting, with the potential to improve patient compliance as symptoms may prevent intake of oral antiemetic agents [6]. Granisetron has not yet been studied in gastroparesis. Another 5-HT3 receptor antagonist, ondansetron, has been suggested in case reports to decrease nausea and vomiting in gastroparesis [16, 17]. Ondansetron does not have an effect on gastric emptying [18], but is thought to have its effects on vagal afferent nerves. In this study, therapeutic response was assessed using the modified CPGAS [10]. Patients were asked whether their symptoms of nausea and vomiting improved, stayed the same, or worsened with transdermal granisetron treatment. Patients graded the clinical response of their symptoms to treatment with the following gradations: (?7) = completely better; to (-7) = very considerably worse. Future studies can evaluate the symptomatic responses to specific symptoms of gastroparesis using the Gastroparesis Cardinal Symptom Index (GCSI) [19]. The nine-symptom GCSI (nausea, vomiting, retching, stomach fullness, unable to finish a meal, feeling excessively full after meals, loss of appetite, bloating, belly visibly larger) assesses severity of symptoms over the prior 2 weeks. The onset of improvement with granisetron could be captured using the GCSI daily diary [20, 21].

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When used for chemotherapy-induced nausea and vomiting, the most common adverse reaction with GTP is constipation [15]. The GTP may also cause some local skin irritation. In a previous clinical trial, application site reactions were reported, which were generally mild in intensity and did not lead to discontinuation of use [14]. In the present study of patients with gastroparesis, mild side effects were reported by 25 % of patients: four patients developed constipation, three patients had skin rash, and two patients reported headaches. These side effects are similar to those reported with use of granisetron in chemotherapy-induced nausea and vomiting [6]. In summary, this study examined the outcome of treating refractory symptoms of nausea and vomiting due to gastroparesis with the GTP. In this open-label study, GTP was somewhat to moderately effective in reducing nausea and/or vomiting from gastroparesis in half of patients. Mild side effects were reported by a quarter of patients. Thus, GTP may be effective for treating refractory symptoms of nausea and/or vomiting in patients with gastroparesis. Conflict of interest Henry Parkman has served as a consultant and on a product advisory board for ProStrakan, Inc., makers of SancusoÒ. Kellie Simmons has nothing to disclose.

References 1. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127:1592–1622. 2. Cherian D, Parkman HP. Nausea and vomiting in diabetic and idiopathic gastroparesis. Neurogastroenterol Motil. 2012;24:e103. 3. Camilleri M, Parkman HP, Shafi MA, et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108: 18–37. 4. Abell TL, Bernstein RK, Cutts T, et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil. 2006;18:263–283. 5. Hasler WL. Serotonin and the GI tract. Curr Gastroenterol Rep. 2009;11:383–391. 6. Keating GM, Duggan ST, Curran MP. Transdermal granisetron: a guide to its use in preventing nausea and vomiting induced by chemotherapy. CNS Drugs. 2012;26:787–790. 7. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: establishment of international control values. Am J Gastroenterol. 2000;95:1456–1462.

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Dig Dis Sci (2014) 59:1231–1234 8. Abell TL, Camilleri M, Donohoe K, et al. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol. 2008;103: 753–763. 9. Pasricha PJ, Colvin R, Yates K, et al. Characteristics of patients with chronic unexplained nausea and vomiting and normal gastric emptying. Clin Gastroenterol Hepatol. 2011;9:567–576. 10. Parkman HP, Mishra A, Jacobs M, et al. Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters. J Clin Gastroenterol. 2012;46:494–503. 11. Jaffe JK, Paladugu S, Gaughan JP, et al. Characteristics of nausea and its effects on quality of life in diabetic and idiopathic gastroparesis. J Clin Gastroenterol. 2011;45:317–321. 12. Parkman HP, Yates K, Hasler WL, et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol. 2011;9:1056–1064. 13. Schulmeister L. Granisetron transdermal system: a new option to help prevent chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs. 2009;13:711–714. 14. Boccia RV, Gordan LN, Clark G, et al. Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Support Care Cancer. 2011;19:1609–1617. 15. A granisetron patch (Sancuso). Med Lett Drugs Ther. 2008;50:103–104. 16. Amin K, Bastani B. Intraperitoneal ondansetron hydrochloride for intractable nausea and vomiting due to diabetic gastroparesis in a patient on peritoneal dialysis. Perit Dial Int. 2002;22: 539–540. 17. El-Gammal A, Rashed HM, Taylor J, et al. Long term ondansetron therapy is beneficial in patients with chronic nausea and vomiting [abstract]. Gastroenterology. 2000;118:A1170. 18. Nielsen OH, Hvid-Jacobsen K, Lund P, et al. Gastric emptying and subjective symptoms of nausea: lack of effects of a 5-hydroxytryptamine-3 antagonist ondansetron on gastric emptying in patients with gastric stasis syndrome. Digestion. 1990;46:89–96. 19. Revicki DA, Rentz AM, Dubois D, et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther. 2003;18:141–150. 20. Revicki DA, Camilleri M, Kuo B, et al. Evaluating symptom outcomes in gastroparesis clinical trials: validity and responsiveness of the Gastroparesis Cardinal Symptom Index-daily diary (GCSI-DD). Neurogastroenterol Motil. 2012;24:456–463. 21. Maranki JL, Lytes V, Meilahn JE, et al. Predictive factors for clinical improvement with Enterra gastric electric stimulation treatment for refractory gastroparesis. Dig Dis Sci. 2008;53: 2072–2078.

Granisetron transdermal system improves refractory nausea and vomiting in gastroparesis.

Symptoms of gastroparesis include nausea and vomiting, which can markedly diminish quality of life. Nausea and vomiting can also make treatment with o...
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