Unproven Laxative Widely Used for Childhood Constipation

Last year, an article in The New York Times drew attention to the widespread use of polyethylene glycol 3350 (PEG-3350, sold under the brand name MIRALAX), an over-the-counter laxative commonly given to children with constipation.[1]

Though never approved for pediatric use, it has gained widespread popularity among parents of small children due to its ability to provide a quick fix to bothersome, often distressing, bouts of childhood constipation. The drug is now a staple in many American households.[2] Many parents keep their children on it for years, often because the child has become dependent on the easily administered elixir.[3] Yet PEG-3350 has not been studied in children for periods longer than a year, and concerns have arisen regarding the drug’s long-term safety.

Off-label use in children

PEG-3350 is an “osmotic” laxative, which means that it works by drawing water into the colon to soften the stool and facilitate defecation.[4] First approved by the Food and Drug Administration (FDA) in 1999 as a prescription laxative and later granted over-the-counter status in 2006,[5] it is indicated for use only in adults and children 17 and older.[6]

Following its initial approval, the original label for PEG-3350 warned that “MIRALAX should not be used by children.”[7] This warning, though strong and unambiguous, was buried deep within the product’s label and thus could not be expected to deter physicians or parents from using the drug in children. (The label now simply says, “Children 16 years of age or under: Ask a doctor.”[8])

In its first seven years on the market, when PEG-3350 was available only by prescription, physicians were behind its widespread use. Despite its off-label status for children, 75 percent of pediatricians reported prescribing PEG-3350 (the most popular medication choice to treat constipation) in a 2006 survey.[9] (A low response rate of 37 percent may have biased the survey, overestimating the scale of pediatric prescribing.[10]) In 2006, more than 9 million prescriptions were written for PEG-3350 for both adults and children.[11]

One reason for pediatricians’ willingness to use the drug may be that they are more accustomed than other physicians to off-label prescribing because so few drugs are FDA-approved for use in children.

“The dilemma among people who take care of kids is they are so used to drugs coming out and people sort of figuring out how to use it in kids, and not having quality studies, they are almost too willing to accept things without enough evidence,” said Dr. Leo Heitlinger, a spokesman for the American Academy of Pediatrics, in an interview with The New York Times.[12]

With the drug available over-the-counter beginning in 2006, parents were able to medicate their children without ever consulting with a physician, despite the label’s instructions to do so.[13]

For their part, many parents, faced with a constipated child, do not need much convincing to resort to pharmacologic therapy. Mary’s story (her last name was withheld upon request), relayed by The New York Times, is probably typical and explains why the drug has become so popular with parents. Following a pediatrician’s advice, the mother began PEG-3350 on her 3-year-old daughter out of exasperation.

“You’re begging her, promising her anything,” Mary told The New York Times.[14] She then came across what she dubbed the “magic powder”: a capful of PEG-3350 diluted in juice, which seemed to solve the problem in the short term.

However, when Mary tried to wean her daughter off the laxative, the constipation returned. Despite her wish to discontinue the drug, two years later, she found it necessary to give her daughter half a capful every other day to maintain regularity.

One pediatrician told The New York Times that long-term dependence on a laxative is not uncommon and that when parents like Mary try to wean their children off the laxative, “the underlying work isn’t done, so they become constipated again.”[15]

Thus, according to the lead author of a 2006 survey of pediatricians on laxative use (as cited in The New York Times), “it’s definitely not unheard of that kids are on it for years.”[16]

Uncertain safety record

It may not hurt to give a laxative to children in the short term, such as during travel (except in children with kidney or heart problems, for whom any laxative could be dangerous without a physician’s guidance[17]). But little is known about the effects of long-term use in children.

A 2012 systematic review analyzed all randomized controlled trials of osmotic laxatives, such as PEG-3350, and another variety known as “stimulant” laxatives (which work by actively stimulating the intestinal cells to secrete water and electrolytes into the colon[18]) in children with constipation.[19] Eighteen trials comprising 1,643 children 18 and under were analyzed, nine of which were deemed at “high risk for bias” due to a lack of blinding or incomplete or selective reporting of results.[20]

Adverse events observed across all trials included abdominal pain, diarrhea, nausea and headache.[21] In the trials of all formulations of PEG, including PEG-3350[22], only one serious adverse event was reported,[23] but the individual studies were small (averaging 89 subjects per trial).[24] All but two lasted just 12 weeks or less, with none following subjects for more than a year.[25] Thus, rarer and more chronic adverse effects would probably not have been captured in these studies. The review’s authors concluded that, while “PEG appears safe and well tolerated [for short-term use] … [f]urther research is needed to investigate the long term use of PEG for childhood constipation.”[26]

In both adults and children, chronic laxative use can cause imbalances in the acidity of the blood, known as metabolic acidosis (excess of acid) or alkalosis (deficiency of acid), often accompanied by abnormal levels of vital electrolytes, such as potassium.[27] Severe cases of metabolic acidosis can result in death and neurological side effects, such as seizures, while electrolyte imbalances can cause potentially fatal heart rhythm disturbances,[28] especially in those with kidney disease.[29]

In 2009, the FDA’s Drug Safety Oversight Board evaluated reports of metabolic acidosis and neurological and psychiatric disturbances in children taking PEG products.[30] Although board members did not report on their conclusions regarding the link between PEG and the adverse events in question, they highlighted the overall lack of evidence on the safety and effectiveness of PEG-3350 in children for long-term use, stating that “effects of large doses of PEG given over a long duration (e.g., weeks or longer) is not known.”[31]

The board also noted that the common perception of PEG-3350 being “safe” is based on data from adults showing that the drug is minimally absorbed through the intestines, but that little is known about whether children absorb the drug more than adults, especially very young children and those with underlying intestinal disease.[32]

Furthermore, because the drug is not approved in children and the label does not contain pediatric dosing information,[33] many children receive “adult” doses.[34]

Official guidelines

In 2006, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHN) released guidelines on the management of childhood constipation,[35] which were subsequently endorsed by the American Academy of Pediatrics.[36]

The guidelines defined childhood constipation as a delay or difficulty in having a bowel movement that persists for two weeks or longer and that causes significant distress to the child and/or parent.[37] Constipation is very common in children and is responsible for almost 5 percent of all visits to the pediatrician and one-quarter of all visits to pediatric gastrointestinal specialists.[38]

In children older than 1 year, constipation is most commonly “functional,” which means that there is no objective underlying physical cause.[39] Cases of “functional” constipation arise when a child avoids defecating for a variety of reasons, including painful bowel movements (often due to hard or bulky stool), changes in diet or daily routines (such as starting school), or stressful life events.[40]

In rare cases, constipation can be one of a number of symptoms of a more serious underlying disease. The presence of fever, abdominal distension, loss of appetite, nausea, vomiting, weight loss or poor weight gain warrants a more thorough investigation.[41] Constipated infants with bloody or malformed, “ribbon-like” stools and swelling of the abdomen may be experiencing a potentially fatal complication of Hirschsprung disease,[42] caused by a narrowing of part of the colon that blocks the normal passage of stool. (This disease is usually detected in the first weeks of life due to a failure to pass the first stool, known as “meconium.”[43])

Once constipation is diagnosed, it is important to first clear any fecal impaction, or backup of old stool in the child’s rectum, if present, with a short course of oral or rectal medication, such as mineral oil or PEG.[44] Once the impaction is cleared, the NASPGHN guidelines recommend dietary changes, specifically an increased fluid intake and a balanced diet high in whole grains, fruits and vegetables,[45] along with behavioral techniques, such as keeping a diary of bowel movements and instituting a reward system.[46]

The NASPGHN guidelines recommend the use of laxatives (with the exception of the long-term use of stimulant laxatives, which they advise against) in constipated children as add-on therapy to behavioral interventions and claim that medication is “most advantageous” until the child is able to maintain regular toilet habits.[47] The guidelines claim that medication may be necessary “for many months” in some children.

Though we agree that the short-term use of laxatives may help some children return to normal bowel habits, we believe that they should be used only as a last resort and only if dietary and behavioral interventions have not worked. Except in rare cases in which the constipation is due to a severe, underlying disease (such as cystic fibrosis[48]), no laxative should be used on a chronic basis. The long-term use of any laxative has the potential to make the child physically or psychologically dependent on the drug to stay regular, and laxatives such as PEG-3350, which have never been approved in children, are to be used cautiously and only after consultation with a pediatrician.

What You Can Do

All children have occasional, temporary changes in their bowel habits. Only changes that persist for more than two weeks warrant treatment, but not necessarily with drugs. While a child’s constipation can be very distressing for both the child and the parents, in most cases, the problem can be resolved by slight changes to the child’s diet and daily routine.

It is better to treat simple, occasional constipation by first ensuring that the child eats a balanced diet, including whole-grain breads and cereals, raw vegetables, raw and dried fruits, and beans, and drinks plenty of water. This type of diet will prevent and treat constipation. Physical activity also can help.

Sometimes, avoiding certain foods can be helpful. For example, some children may be intolerant to cow’s milk, and a short trial of a diet free of cow’s milk may be helpful, though such a trial should not be undertaken until other diet and lifestyle changes fail to alleviate the symptoms.[49]

If behavioral or dietary changes fail to make the child regular, a short-term trial of a laxative may be helpful. However, a pediatrician should always be consulted before starting a child on any drug for constipation. 

References

[1] Saint Louis, C. Drug for adults is popular as children’s remedy. The New York Times. May 25, 2012. http://www.nytimes.com/2012/05/26/us/miralax-a-popular-cure-but-never-approved-for-children.html?pagewanted=all&_r=0. Accessed October 10, 2013.

[2] Ibid.

[3] Gordon M, Naidoo K, Akobeng AK, Thomas AG. Osmotic and stimulant laxatives for the management of childhood constipation. Cochrane Database Syst Rev. 2012 Jul 11;7:CD009118.

[4] Ibid.

[5] Food and Drug Administration. Approval package: Miralax (polyethylene glycol 3350). http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020698a_MiraLax_appltr_prntlbl.pdf. Accessed October 10, 2013.

[6] FDA approval letter. 10/6/2006. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/022015s000ltr.pdf. Accessed October 11, 2013.

[7] Food and Drug Administration. Drug labels: Polyethylene glycol 3350. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/091077s000lbl.pdf. Accessed October 10, 2013.

[8] Food and Drug Administration. Approval package: Miralax (polyethylene glycol 3350). http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020698a_MiraLax_appltr_prntlbl.pdf. Accessed October 10, 2013.

[9] Food and Drug Administration. Drug labels: Polyethylene glycol 3350. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/091077s000lbl.pdf. Accessed October 10, 2013.

[10] Focht DR 3rd, et al. Variability in the management of childhood constipation. Clinical Pediatrics, Philadelphia. 2006 Apr;45(3):251-6.

[11] Ibid.

[12] PR Newswire. Kristalose offers prescription alternative to Miralax and other PEG 3350 products. http://www.prnewswire.com/news-releases/kristaloser-offers-prescription-alternative-to-miralaxr-and-other-peg-3350-products-57163592.html. Accessed October 11, 2013.

[13] Saint Louis, C. Drug for adults is popular as children’s remedy. The New York Times. May 25, 2012. http://www.nytimes.com/2012/05/26/us/miralax-a-popular-cure-but-never-approved-for-children.html?pagewanted=all&_r=0. Accessed October 10, 2013.

[14] Food and Drug Administration. Drug labels: Polyethylene glycol 3350. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/091077s000lbl.pdf. Accessed October 10, 2013.

[15] Saint Louis, C. Drug for adults is popular as children’s remedy. The New York Times. May 25, 2012. http://www.nytimes.com/2012/05/26/us/miralax-a-popular-cure-but-never-approved-for-children.html?pagewanted=all&_r=0. Accessed October 10, 2013.

[16] Ibid.

[17] Gordon M, Naidoo K, Akobeng AK, Thomas AG. Osmotic and stimulant laxatives for the management of childhood constipation. Cochrane Database Syst Rev. 2012 Jul 11;7:CD009118

[18] Ibid.

[19] Ibid.

[20] Ibid.

[21] Ibid.

[22] Ibid.

[23] Ibid.

[24] Ibid.

[25] Ibid.

[26] Ibid.

[27] Uptodate.com. Acid-base and electrolyte abnormalities with diarrhea or ureteral diversion. Updated Sept 23, 2013. Accessed October 14, 2013.

[28] Mayo Clinic. Over-the-counter laxatives for constipation: Use with caution. http://www.mayoclinic.com/health/laxatives/HQ00088. Accessed October 14, 2013.

[29] Medical knowledge.

[30] Food and Drug Adminstration. Drug safety oversight board meeting, June 18, 2009. Public Summary. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm171059.htm. Accessed October 10, 2013.

[31] Ibid.

[32] Ibid.

[33] Food and Drug Administration. Drug labels: Polyethylene glycol 3350. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/091077s000lbl.pdf. Accessed October 10, 2013.

[34] Food and Drug Administration. Drug Safety Oversight Board Meeting, June 18, 2009. Public Summary. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm171059.htm. Accessed October 10, 2013.

[35] Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in infants and children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology and Nutrition. 2006 Sep;43(3):e1-13. http://www.naspghan.org/user-assets/Documents/pdf/PositionPapers/constipation.guideline.2006.pdf. Accessed October 8, 2013.

[36] American Academy of Pediatrics. Practice guideline endorsement: Evaluation and treatment of constipation in infants and children. http://pediatrics.aappublications.org/site/aappolicy/misc/Constipation_in_Infants_and_Children.xhtml. Accessed October 8, 2013.

[37] Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in infants and children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology and Nutrition. 2006 Sep;43(3):e1-13. http://www.naspghan.org/user-assets/Documents/pdf/PositionPapers/constipation.guideline.2006.pdf. Accessed October 8, 2013.

[38] National Institute of Diabetes and Digestive and Kidney Diseases. How common is constipation in children? http://digestive.niddk.nih.gov/ddiseases/pubs/constipationchild/#sup1. Accessed November 1, 2013.

[39] Ibid.

[40] Ibid.

[41] Ibid.

[42] Ibid.

[43] Ibid.

[44] Ibid.

[45] Ibid.

[46] Ibid.

[47] Ibid.

[48] Medical knowledge.

[49] Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in infants and children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology and Nutrition. 2006 Sep;43(3):e1-13. http://www.naspghan.org/user-assets/Documents/pdf/PositionPapers/constipation.guideline.2006.pdf. Accessed October 8, 2013.