pera Safety of Polyethylene Glycol 3350 for the Treatment of Chronic Constipation in Children Dinesh S. Pashankar, MD, MRCP; Vera Loening-Baucke, MD; Warren P. Bishop, MD Objectives: To assess the clinical and biochemical safety profile of long-term polyethylene glycol 3350 (PEG) therapy in children with chronic constipation and to assess pediatric patient acceptance of PEG therapy. Design: Prospective observational study Setting: Pediatric clinics ata referral center. Patients: Eighty-three children (44 with chronic con- stipation, 39 with constipation and encopresis) receiv ing PEG therapy for more than 3 months, Main Outcome Measures: Clinical adverse effects re lated to PEG therapy and acceptance and compliance with PEG therapy. Serum electrolyte levels, osmolality, albu- rin levels, and liver and renal function test results were measured. Results: Av the time of evaluation, the mean duration of PEG therapy was 8.7 months, and the mean PEG dose was 0.75 g/kg daily. There were no major clinical ad- verse elfects, All blood test results were normal, except for transient minimal alanine aminotransferase cleva- don tntelated to therapy in 9 patients. All children pre ferred PEG to previously used laxatives, and daily com- pliance was measured as good in 90% of children. Conelustons: Long-term PEG therapy is safe and is well accepted by children with chronic constipation with and without encopresis. Arch Pediatr Adolesc Med. 2003;157:661-664 ONSTIPATION IS a com- mon problem in the pe diatric population, This symptom accounts for 3% of outpatient visits to gen- Recent studies? in adults have ré ported short-term efficacy of PEG with- ‘utany major clinical adverse elfects. Poly- ethylene glycol has been approved by the Food and Drug Administration for the From the Divisions of Gastroenterology (Drs Pashankar and Bishop) and General Peshatics (Dr Loening-Baucke), Department of Petre, University of low, lowa City cxal pediatric clinics and up to 25% of vis- its to pediatric gastroentetology clinics Treatment regimens vary widely and in- clude dietary and behavioral modifica. tion, counseling, and the use of various laxatives and stool softeners Polyethylene glycol 3350 (PEG) isa relatively new osmotic laxative. Polyeth- ylene glycol is a component of the PEG- electrolyte lavage soliton that has been used in large volume to cleanse the gas- twointestinal tract for diagnostic and st- sical procedures in children Polyethyl- ene glycol 3350 isa nontoxic and highly soluble compound that is minimally’ ab- sorbed inthe gastrointestinal tact." Due to these properties, PEG acts as an os- rmolic agent, increasing fecal water con ten." Polyethylene glycol 3350 without electrolytes i supplied as a powder (M raLax; Braintree Laboratories, Braintree, Mass) that is palatable when dissolved in a beverage stch as water oF juice (©2003 American Med short-term (reatment of constipation in adults, Three small pediatric studies*"™ have reported short- and long-term ell cacy of PEG, Polyethylene glyeol is widely used in clinical practice for children with constipation, but, to our knowledge, there are no data on the long-term safety pro- file of this relatively new laxative in chil- dren or in adults, Therefore, the aim of our study was to assess the biochemical and clinical safety profile of long-term PEG tweatment ina large cohort of children. We also assessed pediatric patient accep- tance of long-term PEG therapy Les PATIENTS All children older than 2 years with chronic constipation who were teated daily with PEG for more than 3 months were eligible for the study. The patients were enrolled at fol- 1 Association, All rights reserved.aobitin PE pte Geo 250 (rar rantee tatomaras Sane tal SM tat te ena ean (uns unles oterviendcated low-up lini visits from May 1, 2001, o September 30,2002. None ofthe children from our 2 previous studies"* wee in- cluded. The dlagnosis of chronic Constipation was based on Symptoms oft feast 3 month’ duration, including a least 2 ofthe ollowing symptoms hard stole, panfl defecation, en- opress or ewer than 3 bowel movements per week, Patents ‘with constipation were exchided if they had history of Hirscheprung disease, anorectal malformations, or any $s tem ilfess potentially lading to constipation. “Thc study was approved bythe inaitonal review board ofthe University of lowa Collegeof Medicine, lowa Ci. In- formed consent Was obtained from parents of al patients nd assent was obtained from children older than 7 yeas. PEG THERAPY Following the diagnosis of constipation, PEG therapy was tally prescribed at the dose of 0. gk per day, based on our previous study" andall othe laxative treatments were stopped Zecording to manufacturers directions, parents were it~ Sttucted to disolve 17 gof PEG powder in 240 mL of water or ‘ther beverage and to give the prepared solution in 2 divided doses, Families were allowed ttt choice of beverage to suit tach child’ preference. Parents were asked to adjust the dose OT PEG solution as requited to yield 2 soft painless stools per day. Over ime, parents were instructed to gradually decrease the dowe of PEG If symptoms of constipation and encopresis showed improvement. STUDY DESIGN Athetime ofevaluation, parents wer interviewed uingasruc- tured questionnaire and were asked about the dose of PEG given, redication compliance, beverage sed to prepare PEG, and case fofmixing. Children were asked sbout liking tne medication and prelerence compared with laxatives used in the pas. Parents ‘vere asked about any posible adverse ellets of PEG, and par tila about excessively loose or Frequent stools, abdoms nal pain, flatulence, boating nd naveen. Parents were asked bot overall improvement in bowel movement pater regard- ing too frequency and consistency with PEG therapy Following the interview and physical examination, 4 of blood ws obtained lor measurement of levels of hemoglobin, be- snatocit, serum clectrolytes chiding sod, potassium, chlo- eepguNtED) TECH PEDIATR ADOTESC MED VOLS JURY 105 (©2003 American Med ‘Downloaded From: https:/jamanetwork.com/ on 08/24/2023 de, and carbon dioxide), blood urea nitrogen, serum creat- tine, molly, bun, agperatesminotransteree, and alanine ‘mninotranferce (ALT), Rell of blood tes were considered abnormal they were outside (even by 1 pont the age-and so ‘ppepmte irene ange abled our hoa ihe ‘ils weresbnonmal the blod tes were repeated within 8 weeks wwe the patent continued vo receive therapy. (es A total of 83 children (#4 with constipation and 39 with constipation and encopresis) were enrolled in the study. ‘The patient characteristics are given in the Table. Pre- vious therapy for constipation was attempted in 68 chil- dren (82%), and 37 of them had received multiple medi cations, The previous treatment regimens included mill, of magnesia in 64 patients (77%); mineral oil, 19 (23%); frequent suppositories or enemas, 17 (20%); senna, 16 (19%); fiber in various forms, 11 (13%); docusate so- dium, 7 (8%); and others. At the time PEG therapy was started, patients were symptomatic, and most were tak- ing laxatives either inconsistently or in inadequate doses, PEG SAFETY Clinical adverse effects of PEG therapy were minor and ac- ceptable over the mean duration of 8.7 months (range,3-30 months) of PEG therapy. Eight patients (10%) reported fre- quent watery stools sometime during therapy. The diar- thea disappeared with reduction of the dose, Other ad- verse effects reported were bloating or flatulence in 5 children (6%) and abdominal pain in 2 children (2%). ‘Thirst fatigue, and nausea alter receiving PEG solution on an empty stomach were reported in 1 patient each (1%). None of the patients stopped treatment due to adverse ef fects, and all were willing to continue PEG therapy. The general physical examination findings revealed no new si nificant abnormalities compared with the pretreatment ex- amination in all children, ‘The laboratory evaluation results, including mea- sures of hemoglobin, hematocrit, serum electrolytes, blood urea nitrogen, serum creatinine, serum albumin, and os- molality, were normal in all patients. Ten patients did not have serum osmolality measured. Nine patients (119) hhad a slightly elevated ALT level (<1.5 times the upper limit of normal; range, 31-45 U/L). Bight of these pa- tients had ALT levels remeasured within 8 weeks, 7 of whom were sill receiving PEG therapy. Seven of these 8 patients had values in the reference range, while had a slightly elevated ALT level (<1.2 times normal; 28 U/L). ‘Three patients (4%) had an elevated aspartate amino- transferase level (<1.5 times normal; range, 42-52 U/L), and all had normal values when remeasured while still receiving PEG therapy, The dose and duration of PEG therapy were not significantly different in the patients with abnormal values compared with those with labors- tory values in the reference range PATIENT ACCEPTANCE Polyethylene glycol was mixed in any beverage to suit the child's preference. Forty-one children used fruit juice (40%); 1 Association, All rights reserved.Chronic constipation is a common problem in children and requires long-term treatment with laxatives. Pol ‘lene glycol 3350 isa newly available laxative that is widely used in children. Recent studies eport efficacy of PEG, bt dats om its long-term use and safety are lacking. ‘This study reports lack of major clinical adverse clfects and biochemical abnormalities in large cohort fof children receiving PEG 3350 therapy over the long- term, The sty also reports good patient acceptance and ‘compliance with PEG therapy. Polyethylene glycol 3350 should be considered as a favorable therapeutic option for children with chronic constipation with or without ‘encopresis because of ts safety and elfcacy over the long term and good patient acceplance 1, cow's milk (13%);0, water (1196);8, uit punch (10%); and other beverages were also used to prepate the PEG so- lution. All caretakers found it easy to prepare the PEG so- lution. The PEG solution was liked by 78 children (03%) All 68 children who had used other therapies preferred PEG. tw other laxatives. Daily compliance, assessed by parent re- call and diary, was good in 75 patients (90%) during the mean duration of 8.7 months of therapy. Seventy-eight (01%) of 83 caretakers reported definite improvement in bowel movement patter with PEG therapy’ ee Constipation with or without encopresis is oflen a chronic problem in children. In one long-term study from the United States," 37% of children continued to have symp- toms of constipation 3 to 12 years after initial diagnosis. In another study from aly." constipation persisted in 52% of children 5 years after intial diagnosis, Adequate doses of laxatives and treatment compliance are the most important factors for successful resolution of chronic con- stipation."' Long-lerm treatment is required for chil- dren with chronic constipation, as relapse is common al- {er premature discontintation of laxalives."! Therefore, thet and acceptable to children over the long-term, In our study, long-term PEG therapy did not have any major clinical adverse effects, The most common clint cal adverse effect was excessively loose oF frequent stools, that resolved with reduction of the PEG dose. Other ad- verse ellects were minimal and acceptable. Polyethyl- ‘ene glycol does not ferment by colonic bacterial flora and, therefore, does not cause excessive gas production that leads to flatulence or bloating.* Polyethylene glycol elec- trolyte solution-induced acute pancreatitis has been re- ported in an adult patient with intestinal dysmouility fol- lowing rapid ingestion of a large volume (4 L) of the solution. The mechanism was thought to be due to duo- denal distention and reflux of duodenal contents into the pancreatic duct and not the effect of PEG on the pan- ‘creas. No patient in our study had severe acute abdomi- nal pain or any features suggesting acute pancreatitis. “Although we did not conduct laboratory tests in the patients prior to starting PEG therapy, patients recelv- fs a need for an ideal laxative that is sale, effect (©2003 American Med ing long-term PEG therapy did not have any adverse ef- fects on renal function, electrolyte levels, serum albu- rin levels, and osmolality. Thus, long-term PEG therapy does not adversely alfect fluid and electrolyte balance de- spite improvement in stool frequency and consistency Nine patients had minor elevations of ALT levels, and 3 patients had minor elevation of aspartate aminotransfer- ase levels at one point during the study. The elevation was only a few points above the reference range for our laboratory and completely resolved in all but 1 patient when remeasured while still receiving therapy. No symp- toms or signs of liver disease were present in these pa- tients. A recent study" on liver funetion tests indicates no need for further evaluation if mildly elevated levels of aminotransferase are within the reference range on re- testing, Due to these reasons, we believe that the tran- siently abnormal ALT levels were clinically insignifi- cant and unrelated to PEG treatment. Although we did not see any major adverse effects in our study, the up- per limit of the 95% confidence interval of point esti- mate of zero for adverse ellects is approximately 49% in a sample size of 83 patients. Therefore, a study of a larger number of patients followed up for a longer duration of treatment would be required to ensure the absence of rare adverse effects Short-term PEG therapy in adults (2 weeks) and chi dren (3 days) has shown no significant change in labora- tory evaluation results consisting of electrolyte profile, re- nal function tests, and serum chemistry analysis °"” Postmarketing safety information from the manufacturer reports rare allergic reaction to PEG in the form of rashes, but no other serious adverse effects have been reported in children (John McGowan, BA, Braintree Laboratories, ¢-mail communication, January 29, 2003). Sidies in human voluustecrsindlicaie that systemic absorption of PEG is mint- ‘mal (estimated at 0.00%) and renal excretion is high. There- fore, systemic toxicity of PEG is unlikely." here are several effective medications available for long-term treatment of constipation in children, includ- ing milk of magnesia, lactulose, and mineral oil.’ How- ever, these medications have either poor palatability or adverse elfects such as abdominal pain, flatulence, or anal leakage, which may limit patient acceptance and com- pliance."® Most children in our study had tried other laxs- Lives before, They al preferred PEG to other laxatives be- cause of its palatability. Therefore, compliance with PEG and patient acceplance was excellent. Ellicacy of PEG therapy for children with constipa- lion and encopresis has been reported before." In one study, milk of magnesia was as effective as PEG (679% vs 61%) in children with constipation and encopresis who received these therapies for 12 months.” However, 33% of children refused to take mill of magnesia, whereas none refused PEG.” In another crossover study, PEG therapy was as effective as lactulose for the treatment of const pation in children in a 2-week trial, but PEG was pre ferred by children compared with lactulose." In summary, PEG seems to bea safe medication for long-term treatment of constipation in children, Itshould be considered a favorable option for long-term therapy {or children, particularly because of excellent patient ac- ceplance. 1 Association, All rights reserved.Accepted for publication February 6, 2003. This study was financially assisted by Braintree Labo- ratories. We thank Aliye Ue, MD, Dawyn Sawyer, MPAS, and Judith Heckman, MPAS, for their assistance in the study. This study was presented in partat the American Gas- troenterological Association Meeting: May 20, 2002; San Francisco, Calif. This study was published as an abstract in Gastroenterology (2002:122(suppl):A318). Corresponding author and reprints: Dinesh Pashan- kar, MD, Division of Gastroenterology, 2864 John Pappa- john Pavillion, Children’s Hospital of Iowa, 300 Hawkins Dr, lowa City, 1A 52242 (e-mail: Dinesk-Pashankax@uiowa dw) EES} 1. Bata, Lipa Coletta Consgan innate: ea son and wearart a mada poston sament of the Noch Aree So yor Pei Gastoeteogy and Nutr J Pedi Gatos! Nu ‘ean cic Sandan, Sool Tr SF, Seman A, Zane 8. Safe teary, ‘a eranc ois agen patie pens unergingdgresticeale scopy J Pasi 0B: 119:48152 4 Pio, Mita KA Crk BA eal Absurpion peter lal ater adpinstison ofa PEG alecolte lage sauon. Cn Pham. 1855153 18, 4 Harmer HF, Sana Ana A, Seiler LA, Fran 8 Stuteso smote ar ein teD) HCH PEDIATR ADOLESC MEDVOL 7 OUT 005 ‘hea inca n noma sujet by ngstn of pote gel and eeu Toei nest 10884561082 Seiler LR. Ems Sania aC, Foran JS. Osa lee Gel Saroertsrfgy. 188 4033-01 Dalat epider PH, Ondo RC, ots BE, Cela A random, ceo corre, mulcrar say othe sey and fica at ane py ye gyal nave Ar J Gasol 20005 446-450, Cieyand M8, va DP Ruben RA, sen AM, Crk GE. New petyene iyo nae for weamer of consipaion nuts: a andre, double in past conto shay. South Med J 200 447.6%, ahaa 5, shop WP. cy ad optima dose aly otyns 1 00 ar wens of conspaten an eneoprass ince, J Pea 200 renaze-a2 Loring Bock Poet ene ght witout ool o chlden with cn- Staton a encopresis J Peat Gasroenea A 20023637237 GromseDA Hin.) Ceictild A Comparison of one hol 5350and Tacdose for eats of boi constipation chan Cin Peat (Pi) oz 20520, Losing Suck Coasipatnin cay cithon patent chasers, ea ‘men an og oop. Gat 0663400 Slo A Andres, Graco ale Aue. Lone low ot ‘hen wth vr psi onsipaton. ig Os Se 108430561584 Frana DL, Hore 8 Pleyel ince parents Gasramtst tose 20005278075, Prat. Kapin NM, Eatin of bona tay aus in aeymp- tampons. En ed 200032 126-127 oust Peters, anderson, See Pate Lact Lorne oe agen of PES 350 fr th estat of hla el ipacton, 1 Pea 200 1411-4 ray CE, Pan Jk, MoravskS, Sant Ana CA Fortran 1S, Urry x= ano pene ye 250 and ute ar patiosge ith pethyens iyo decd age sluion Gasoemaaoy. 1085908141018 et ot ple (©2003 American Medical Association, All rights reserved. ‘Downloaded From: https:/jamanetwork.com/ on 08/24/2023