ADVERSE EVENTS
As of August 2020, the FDA Adverse Event Reporting System (FAERS) shows 36,678 adult and child adverse event reports related to PEG 3350 products, including 217 deaths. The number of reports rose from 2,257 in 2012, when our FDA Citizen petition was filed.
In response to our petition, the FDA reviewed 167 pediatric reports - 47 of those were serious…
"FAERS received 167 pediatric reports associated with the use of PEG-containing products. Of these reports, we identified 47 non-fatal cases that reported the following events:
neurological/psychiatric (37), metabolic acidosis (3), renal failure (1), aspiration pneumonia (3), and hyponatremia (3). In addition, five of the cases reported fatal outcomes attributable to, or concurrent with, one or more of the following events: renal failure (1), metabolic acidosis with hyponatremia and cerebral edema (1), seizure (1), unknown cause (1), and colonic perforation (1)."
https://www.dropbox.com/s/vnm3y2oah9po97m/Partial_Approval_and_Denial_Response_Letter_from_FDA_CDER_to_Empire_State_Consumer_Project.pdf?dl=0&fbclid=IwAR3LppeJgR73sL2GfrUJoBgw7XuZgv51Vs33MoDCI4ml1iGSv92nlDHmOr0
Due to the serious safety concerns raised in our FDA Citizen Petition, in 2013, the FDA agreed to study the effects of polyethylene glycol 3350 laxative use in children and issued a grant to the Children's Hospital of Philadelphia (CHOP) to conduct the study (now to be completed in 2021).
ESCP submitted the petition in 2012 on behalf of parents who say their children have been harmed by polyethylene glycol 3350 drug products. The Parents Against Miralax Facebook group, now over 44,000 members is a group of parents sharing the same shocking stories of neuropsychiatric and other adverse events acknowledged by the FDA in 2009. In a split decision, the FDA felt that “no action was required” at that time:
FDA Drug Safety Oversight Board Meeting, June 18, 2009
Public Summary
“The Executive Director updated the Board on risk communications [Public Health Advisories (PHAs), Early Communications about Ongoing Safety Reviews (ECs), and Information for Healthcare Professionals (HCP)] posted and in development since the May 21, 2009 meeting.
The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body’s acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.
PEG is a laxative that increases the amount of water in the intestinal tract to stimulate bowel movements. There are currently 19 PEG products, prescription and over-the-counter (OTC), in the US approved for use as either as a bowel preparation prior to colonoscopy or for the treatment of constipation. All products approved for use prior to colonoscopy are prescription products with one product approved for use in children 6 months and older. There is only one PEG product available over-the-counter and it is indicated for short term use (up to 7 days) in adults and children 17 years of age or older with occasional constipation. The Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition has formulated PEG product guidelines for long-term use in the management of pediatric constipation; however, this indication is not FDA approved.
The Board discussed whether the adverse event reports constituted a safety signal and what if any action should be taken for the prescription and over-the-counter preparations used. The Board was assisted by Andrea Gropman, MD who served as the Board’s guest expert in pediatric neurology.
Dr. Andrea Gropman is a child neurologist and clinical geneticist at the National Institutes of Neurological Disorders and Stroke at the National Institutes of Health and the Children’s National Medical Center in Washington, DC.
Some of the issues highlighted by the Board are:
1. PEG is a long-chain polymer of ethylene oxide commercially available in molecular weights of 300 g/mole to 10,000,000 g/mole. Many products contain an average molecular weight of 3350 g/mole and thus are given the name PEG-3350. PEG-3350 products exist in a stable powder form. Approved products instruct patients to dissolve the PEG-3350 powder in a liquid and use immediately. The approved products have been tested under these conditions and are stable. It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.
2. PEG products that are available over-the-counter can be used without medical oversight.
3. There is a perception that PEG is safe because it is minimally absorbed from the stomach and intestines. However, little is known about whether absorption in children differs from adults, especially in children who are constipated, have underlying intestinal disease, or are very young.
4. Children are receiving adult doses of PEG in some cases.
5. Children may be more susceptible to variations in PEG product quality.
6. Effects of large doses of PEG given over a long duration (e.g weeks or longer) is not known.”
https://docs.google.com/document/d/1YDLD6PhkSyu3iwaLxaId13z7cBxUus8SPRNkpqilDz8/edit?usp=sharing
PEG laxatives are not approved for use in children, and are not approved for more than seven days use in adults for occasional constipation. Many children are prescribed multiple daily adult doses by doctors off-label, often for months or years at a time, some beginning in infancy. The medical community is convincing parents that PEG is safe for children while television ads describe the products as working ‘naturally’ with no adult warnings or warnings against use in children. Some products have fold-out labels with age warnings on the innermost panel that is not opened until after purchase. Off-label prescribing to children has become normalized, so that doctors do not question the possible effects on children, despite the urgent claims of parents.
Although PEG 3350 laxatives have been studied for their effectiveness in producing a bowel movement, no study has ever been conducted on neuropsychiatric effects in children and no study has ever been done on the long term use of these products in children. The study being conducted in response to our petition is limited in scope and does not include research into the effects of PEG 3350 on the gut microbiome or nutrient absorption and depletion, which may be likely contributors to neuropsychiatric events in children.
The FDA New Drug Approval (NDA) for Miralax shows a number of severe adverse events, including death:
www.accessdata.fda.gov/drugsatfda_docs/nda/2006/022015s000_MedR_Part3.pdf
This FDA document, updated in 2016 shows that the FDA acknowledged years ago that Miralax causes seizures (45th page): http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000OtherR.pdf
Doctors at the National Taiwan University Hospital in Taipei have concluded “that bowel preparation with PEG lavage solution may be associated with severe renal complications, and that physicians should be aware of possible adverse effects when administering the agent.” http://www.ntuh.gov.tw/pmr/lists/list14/attachments/164/10253009-200903-37-1-45-50-a.pdf
Researchers at Copenhagen University Hospital in Denmark have concluded that Immediate-type Hypersensitivity Reactions (HSRs) do occur with PEG use, and that doctors have no knowledge of PEG and do not suspect it as a cause of hypersensitivity reactions.
https://documentcloud.adobe.com/link/track?uri=urn%3Aaaid%3Ascds%3AUS%3Ad9b8bccb-71f2-4370-9c9f-60dfab5a728d
This study shows significant decrease in mean potassium, blood urea nitrogen, and carbon dioxide levels in children after taking PEG 3350 mixed with Gatorade..
https://www.sciencedirect.com/topics/medicine-and-dentistry/macrogol-3350
A study published in Diseases of the Colon and Rectum, shows that polyethylene glycol bowel preparation is associated with “significant morphologic alterations in the large bowel, including loss of superficial mucous, loss of epithelial cells and inflammatory changes in the lamina propria.https://documentcloud.adobe.com/link/track?uri=urn%3Aaaid%3Ascds%3AUS%3Afc609b73-83c2-4af0-bc41-6057b2dd0e16
In 2005, Eric Brodsky, M.D., a medical reviewer, reviewed serum electrolyte data submitted in the pivotal clinical trials for NuLYTELY. Hyponatremia occurred in 22% of patients who used NuLYTELY prior to colonoscopy and this incidence increased to 31-36% when serum sodium levels were checked two to three days following the bowel cleansing.
pg.18 - https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/022015s000_MedR_Part2.pdf
Systemic exposure potential of PEG - “As noted in section 1.2 of the original Clinical Pharmacology review (signed in DARRTS 09/18/2012), sponsor did not assess the systemic exposure of PEG3350 following the recommended dosing regimen. Limited information from the literature has been presented in the NDA in this regard to address the systemic exposure potential of PEG3350. Information on the systemic exposure potential for and is currently unavailable in the literature. Previously published findings on PEG absorption have primarily relied upon fecal assay of PEG3350 which is often variable. The lower limit of detection for PEG3350 plasma assay was also very high in these older studies making systemic exposure determination difficult. It is our understanding that more sensitive and specific assays for systemic exposure assessment are now feasible (e.g. Pelham et al, 2006) and therefore can be developed to assess systemic uptake of this widely used product and to characterize/rule-out systemic exposure of smaller molecular weight byproducts."
Pg. 3 -
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000ClinPharmR.pdf
Our FDA petition calls for an investigation into the effects of PEG 3350 on children and a boxed warning on PEG 3350 products. The boxed warning was not granted at the time, but the FDA decided to update the labeling of prescription PEG 3350 bowel preparations with more stringent warnings and precautions for patients with certain health conditions. Our request for a Drug Safety Communication issued to doctors was denied, pending the results of the study, which, according to the FDA, has been delayed due to technical difficulties in producing the blood tests. Meanwhile, the effects of chronic PEG 3350 use on the microbiome and nutrition in children are not being studied.
It is well known in the medical community that a small fraction of adverse events are reported; the FDA cites literature that estimates 1-10%. In Attention must be paid: adverse event reporting needs improvement, the authors write, “ As of 2005, only half of the newly discovered adverse drug reactions were detected and documented within 7 years of drug approval…it takes a median of 11 years to identify a serious adverse drug reaction…it took 81 years to identify aspirin-associated Reye’s Syndrome…Of 33,171 warfarin-associated hospitalizations and 67,200 hemorrhage cases, a reporting rate of 1.07% and 1.02% was calculated (for patients aged 65 or older), respectively. Of 13,363 hospitalizations associated with clopidogrel and ticlopidine, a 0.9% reporting rate was calculated. The 9-year reporting rate for venous thromboembolism associated with thalidomide was calculated to be 2.3%. https://www.openaccessjournals.com/articles/attention-must-be-paid-adverse-event-reporting-needs-improvement.pdf
Whether due to lack of awareness, confusion over the process, or physician discouragement, most consumers do not file adverse event reports. The same is true for doctors. These unreported adverse events cannot be dismissed and, in the case of PEG 3350, could be measured by any researcher willing to survey members of the Parents against Miralax Facebook group of over 40,000 members.
After news of our petition was published in the New York Times, adverse events rose exponentially. We were told by the FDA that many of the reports were industry filings. The industry entries were also missing patient ages and outcomes. As one analysis of the media coverage states, “as members of the medical profession, the authors may have some inherent bias against interference of caregivers in the medical decision making process.” https://onlinelibrary.wiley.com/doi/10.1002/ygh2.336
That parent involvement in children’s medical decision making can in any way be seen as interference speaks to the hubris parents are witnessing when voicing concerns over PEG 3350 use. Parents are the core of children’s medical decision making, not an interference in it – parents, not doctors being the primary decision makers. To blame rather than credit media coverage for increased consumer awareness is to discredit parents and to ask the informed to join the legions of disempowered healthcare consumers who do not feel comfortable questioning the judgment of doctors. News reports validate patient experiences; they do not create them.
In response to our petition, the FDA reviewed 167 pediatric reports - 47 of those were serious…
"FAERS received 167 pediatric reports associated with the use of PEG-containing products. Of these reports, we identified 47 non-fatal cases that reported the following events:
neurological/psychiatric (37), metabolic acidosis (3), renal failure (1), aspiration pneumonia (3), and hyponatremia (3). In addition, five of the cases reported fatal outcomes attributable to, or concurrent with, one or more of the following events: renal failure (1), metabolic acidosis with hyponatremia and cerebral edema (1), seizure (1), unknown cause (1), and colonic perforation (1)."
https://www.dropbox.com/s/vnm3y2oah9po97m/Partial_Approval_and_Denial_Response_Letter_from_FDA_CDER_to_Empire_State_Consumer_Project.pdf?dl=0&fbclid=IwAR3LppeJgR73sL2GfrUJoBgw7XuZgv51Vs33MoDCI4ml1iGSv92nlDHmOr0
Due to the serious safety concerns raised in our FDA Citizen Petition, in 2013, the FDA agreed to study the effects of polyethylene glycol 3350 laxative use in children and issued a grant to the Children's Hospital of Philadelphia (CHOP) to conduct the study (now to be completed in 2021).
ESCP submitted the petition in 2012 on behalf of parents who say their children have been harmed by polyethylene glycol 3350 drug products. The Parents Against Miralax Facebook group, now over 44,000 members is a group of parents sharing the same shocking stories of neuropsychiatric and other adverse events acknowledged by the FDA in 2009. In a split decision, the FDA felt that “no action was required” at that time:
FDA Drug Safety Oversight Board Meeting, June 18, 2009
Public Summary
“The Executive Director updated the Board on risk communications [Public Health Advisories (PHAs), Early Communications about Ongoing Safety Reviews (ECs), and Information for Healthcare Professionals (HCP)] posted and in development since the May 21, 2009 meeting.
The Drug Safety Oversight Board discussed reports of metabolic acidosis, metabolic acidosis with increased anion gap, and neuropsychiatric adverse events in children using polyethylene glycol (PEG) products. Metabolic acidosis is a disturbance in the body’s acid-base balance and causes too much acid in the blood. In some situations, metabolic acidosis can be a mild, chronic condition; however, it may lead to shock or death in severe cases. Neuropsychiatric adverse events may include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings.
PEG is a laxative that increases the amount of water in the intestinal tract to stimulate bowel movements. There are currently 19 PEG products, prescription and over-the-counter (OTC), in the US approved for use as either as a bowel preparation prior to colonoscopy or for the treatment of constipation. All products approved for use prior to colonoscopy are prescription products with one product approved for use in children 6 months and older. There is only one PEG product available over-the-counter and it is indicated for short term use (up to 7 days) in adults and children 17 years of age or older with occasional constipation. The Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition has formulated PEG product guidelines for long-term use in the management of pediatric constipation; however, this indication is not FDA approved.
The Board discussed whether the adverse event reports constituted a safety signal and what if any action should be taken for the prescription and over-the-counter preparations used. The Board was assisted by Andrea Gropman, MD who served as the Board’s guest expert in pediatric neurology.
Dr. Andrea Gropman is a child neurologist and clinical geneticist at the National Institutes of Neurological Disorders and Stroke at the National Institutes of Health and the Children’s National Medical Center in Washington, DC.
Some of the issues highlighted by the Board are:
1. PEG is a long-chain polymer of ethylene oxide commercially available in molecular weights of 300 g/mole to 10,000,000 g/mole. Many products contain an average molecular weight of 3350 g/mole and thus are given the name PEG-3350. PEG-3350 products exist in a stable powder form. Approved products instruct patients to dissolve the PEG-3350 powder in a liquid and use immediately. The approved products have been tested under these conditions and are stable. It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.
2. PEG products that are available over-the-counter can be used without medical oversight.
3. There is a perception that PEG is safe because it is minimally absorbed from the stomach and intestines. However, little is known about whether absorption in children differs from adults, especially in children who are constipated, have underlying intestinal disease, or are very young.
4. Children are receiving adult doses of PEG in some cases.
5. Children may be more susceptible to variations in PEG product quality.
6. Effects of large doses of PEG given over a long duration (e.g weeks or longer) is not known.”
https://docs.google.com/document/d/1YDLD6PhkSyu3iwaLxaId13z7cBxUus8SPRNkpqilDz8/edit?usp=sharing
PEG laxatives are not approved for use in children, and are not approved for more than seven days use in adults for occasional constipation. Many children are prescribed multiple daily adult doses by doctors off-label, often for months or years at a time, some beginning in infancy. The medical community is convincing parents that PEG is safe for children while television ads describe the products as working ‘naturally’ with no adult warnings or warnings against use in children. Some products have fold-out labels with age warnings on the innermost panel that is not opened until after purchase. Off-label prescribing to children has become normalized, so that doctors do not question the possible effects on children, despite the urgent claims of parents.
Although PEG 3350 laxatives have been studied for their effectiveness in producing a bowel movement, no study has ever been conducted on neuropsychiatric effects in children and no study has ever been done on the long term use of these products in children. The study being conducted in response to our petition is limited in scope and does not include research into the effects of PEG 3350 on the gut microbiome or nutrient absorption and depletion, which may be likely contributors to neuropsychiatric events in children.
The FDA New Drug Approval (NDA) for Miralax shows a number of severe adverse events, including death:
www.accessdata.fda.gov/drugsatfda_docs/nda/2006/022015s000_MedR_Part3.pdf
This FDA document, updated in 2016 shows that the FDA acknowledged years ago that Miralax causes seizures (45th page): http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000OtherR.pdf
Doctors at the National Taiwan University Hospital in Taipei have concluded “that bowel preparation with PEG lavage solution may be associated with severe renal complications, and that physicians should be aware of possible adverse effects when administering the agent.” http://www.ntuh.gov.tw/pmr/lists/list14/attachments/164/10253009-200903-37-1-45-50-a.pdf
Researchers at Copenhagen University Hospital in Denmark have concluded that Immediate-type Hypersensitivity Reactions (HSRs) do occur with PEG use, and that doctors have no knowledge of PEG and do not suspect it as a cause of hypersensitivity reactions.
https://documentcloud.adobe.com/link/track?uri=urn%3Aaaid%3Ascds%3AUS%3Ad9b8bccb-71f2-4370-9c9f-60dfab5a728d
This study shows significant decrease in mean potassium, blood urea nitrogen, and carbon dioxide levels in children after taking PEG 3350 mixed with Gatorade..
https://www.sciencedirect.com/topics/medicine-and-dentistry/macrogol-3350
A study published in Diseases of the Colon and Rectum, shows that polyethylene glycol bowel preparation is associated with “significant morphologic alterations in the large bowel, including loss of superficial mucous, loss of epithelial cells and inflammatory changes in the lamina propria.https://documentcloud.adobe.com/link/track?uri=urn%3Aaaid%3Ascds%3AUS%3Afc609b73-83c2-4af0-bc41-6057b2dd0e16
In 2005, Eric Brodsky, M.D., a medical reviewer, reviewed serum electrolyte data submitted in the pivotal clinical trials for NuLYTELY. Hyponatremia occurred in 22% of patients who used NuLYTELY prior to colonoscopy and this incidence increased to 31-36% when serum sodium levels were checked two to three days following the bowel cleansing.
pg.18 - https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/022015s000_MedR_Part2.pdf
Systemic exposure potential of PEG - “As noted in section 1.2 of the original Clinical Pharmacology review (signed in DARRTS 09/18/2012), sponsor did not assess the systemic exposure of PEG3350 following the recommended dosing regimen. Limited information from the literature has been presented in the NDA in this regard to address the systemic exposure potential of PEG3350. Information on the systemic exposure potential for and is currently unavailable in the literature. Previously published findings on PEG absorption have primarily relied upon fecal assay of PEG3350 which is often variable. The lower limit of detection for PEG3350 plasma assay was also very high in these older studies making systemic exposure determination difficult. It is our understanding that more sensitive and specific assays for systemic exposure assessment are now feasible (e.g. Pelham et al, 2006) and therefore can be developed to assess systemic uptake of this widely used product and to characterize/rule-out systemic exposure of smaller molecular weight byproducts."
Pg. 3 -
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000ClinPharmR.pdf
Our FDA petition calls for an investigation into the effects of PEG 3350 on children and a boxed warning on PEG 3350 products. The boxed warning was not granted at the time, but the FDA decided to update the labeling of prescription PEG 3350 bowel preparations with more stringent warnings and precautions for patients with certain health conditions. Our request for a Drug Safety Communication issued to doctors was denied, pending the results of the study, which, according to the FDA, has been delayed due to technical difficulties in producing the blood tests. Meanwhile, the effects of chronic PEG 3350 use on the microbiome and nutrition in children are not being studied.
It is well known in the medical community that a small fraction of adverse events are reported; the FDA cites literature that estimates 1-10%. In Attention must be paid: adverse event reporting needs improvement, the authors write, “ As of 2005, only half of the newly discovered adverse drug reactions were detected and documented within 7 years of drug approval…it takes a median of 11 years to identify a serious adverse drug reaction…it took 81 years to identify aspirin-associated Reye’s Syndrome…Of 33,171 warfarin-associated hospitalizations and 67,200 hemorrhage cases, a reporting rate of 1.07% and 1.02% was calculated (for patients aged 65 or older), respectively. Of 13,363 hospitalizations associated with clopidogrel and ticlopidine, a 0.9% reporting rate was calculated. The 9-year reporting rate for venous thromboembolism associated with thalidomide was calculated to be 2.3%. https://www.openaccessjournals.com/articles/attention-must-be-paid-adverse-event-reporting-needs-improvement.pdf
Whether due to lack of awareness, confusion over the process, or physician discouragement, most consumers do not file adverse event reports. The same is true for doctors. These unreported adverse events cannot be dismissed and, in the case of PEG 3350, could be measured by any researcher willing to survey members of the Parents against Miralax Facebook group of over 40,000 members.
After news of our petition was published in the New York Times, adverse events rose exponentially. We were told by the FDA that many of the reports were industry filings. The industry entries were also missing patient ages and outcomes. As one analysis of the media coverage states, “as members of the medical profession, the authors may have some inherent bias against interference of caregivers in the medical decision making process.” https://onlinelibrary.wiley.com/doi/10.1002/ygh2.336
That parent involvement in children’s medical decision making can in any way be seen as interference speaks to the hubris parents are witnessing when voicing concerns over PEG 3350 use. Parents are the core of children’s medical decision making, not an interference in it – parents, not doctors being the primary decision makers. To blame rather than credit media coverage for increased consumer awareness is to discredit parents and to ask the informed to join the legions of disempowered healthcare consumers who do not feel comfortable questioning the judgment of doctors. News reports validate patient experiences; they do not create them.