The Reference Listed Drug (RLD) is Mira LAX® (Polyethylene Glycol 3350 Powder for solution 17 g) was approved in the United States in October 6, 2006 (NOC 11523-7268-3) for treatment of occasional constipation (irregularity). The maximum daily dose is 17 g/day, based on individual patient response and tolerability.

Mechanism of Action:
Polyethylene Glycol 3350 is an Osmotic laxative that causes water to be retained in the stool. In vitro studies showed indirectly that PEG 3350 was not fermented into hydrogen or methane by the colonic micro flora. It does not appear to have any effect on the active absorption or secretion of glucose or electrolytes. PEG 3350 is generally produces a bowel movement within 1 or 3 days and relieves occasional constipation (irregularity).
Special populations
Pregnant Women: Animal reproduction studies have not been conducted with Polyethylene glycol, and it is also not known whether Polyethylene glycol can affect reproductive capacity or harm the fetus when administered to a pregnant patient. Polyethylene glycol should be given to a pregnant patient only if clearly needed.
Nursing Women: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Polyethylene glycol is administered to a nursing woman.
Pediatrics: Safety and effectiveness of Polyethylene glycol in children have not been established.
Geriatrics (> 60 years of age): There are isolated reports of serious post-marketing events following the administration of large volumes of PEG-based products for colon preparation in patients over 60 years of age (acute pulmonary edema after vomiting and aspirating the PEG based solution, asystole, esophageal perforation, and upper GI bleeding from a Mallory-Weiss tear).
Caution is required in patients with renal and cardiac dysfunction in whom fluid and electrolyte shifts are of extra risk.
Monitoring and Laboratory Tests
Repeated or prolonged use of PEG-based products may result in electrolyte imbalance; monitoring of serum electrolytes including phosphate level is advised.

Polyethylene glycol is contraindicated in patients with: • ileus • gastric retention • bowel perforation • gastrointestinal obstruction • toxic colitis • toxic megacolon • hypersensitivity to this drug or to any ingredient in the formulation or component of the container.

General
• Use of Polyethylene glycol is not recommended when abdominal pain, nausea, or vomiting are present
• Unconscious or semiconscious patient should be observed during the administration of Polyethylene glycol via nasogastric tube.
• A laxative should not be taken within 2 hours of another medicine because the desired effect of the other medicine may be reduced.
For use in the treatment of constipation:
• Patients presenting with complaints of constipation should have a thorough medical history and physical examination to detect associated metabolic, endocrine and neurogenic conditions, and medications. A diagnostic evaluation should include a structural examination of the colon.
• Do not take Polyethylene glycol for more than 1 week, unless recommended by a physician.
• The safety of long term use of PEG plus electrolytes, like Polyethylene glycol, is unknown.
No additional flavorings or ingredients may be added to the solution.
Polyethylene glycol may result in a potential interactive effect when used with starch-based
food thickeners. The PEG ingredient counteracts the thickening effect of starch, effectively liquefying preparations that need to remain thick for people with swallowing problems. This warning applies to all PEG containing-products.
Advise all patients to hydrate adequately before, during, and after the use of Polyethylene glycol.
Cardiac Arrhythmias
There have been rare reports of serious cardiac arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing Polyethylene glycol for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy ECGs should be considered in patients at increased risk of serious cardiac arrhythmias.
Gastrointestinal
PEG should be used with caution in patients with UC.
Patients suffering from UC or from an acute exacerbation of inflammatory bowel disease have not been studied. Patients with impaired gag reflex and patients prone to regurgitation or aspiration should be observed during the administration of Polyethylene glycol, especially if it is administered via nasogastric tube. If gastrointestinal obstruction or perforation is suspected, appropriate studies should be performed to rule out those conditions before administration of PEG.
When a large volume of PEG is used for colon preparation, if a patient experiences severe bloating, distension or abdominal pain, administration of the solution should be slowed or temporarily discontinued until the symptoms abate. When used for the treatment of constipation, if diarrhea occurs, the use of Polyethylene glycol should be discontinued. There is a potential risk of Ischemic colitis with co-exposure to osmotic laxatives (PEG 3550/Macrogol) such as Polyethylene glycol, and stimulant laxatives (e.g., bisacodyl). If patients develop severe abdominal pain and/or rectal bleeding, immediate evaluation and close medical attention should be provided.
Immune
Cases of urticaria, rhinorrhea, dermatitis and anaphylactic reactions have been reported with PEG-based products which may represent allergic reactions.
Neurologic
Use of a 4 L volume of PEG-based colon preparation products have resulted in reports of generalized tonic-clonic seizures in patients with no prior history of seizures. Electrolyte abnormalities, such as hyponatremia and hypokalemia, as well as severe vomiting and excessive beverage consumption have been associated with these cases. A correction of fluid and electrolyte abnormalities resolved the neurologic irregularity. Therefore, in patients with known or suspected hyponatremia, or in patients using concomitant medications that increase the risk of electrolyte abnormalities (such as diuretics), Polyethylene glycol should be used with caution. In these patients, baseline and post-colonoscopy laboratory tests (sodium, potassium, calcium, creatinine, and BUN) should be monitored.
Renal
The close monitoring of patients with impaired renal function should be performed, especially if severe vomiting occurs. Measurement of electrolytes (sodium, potassium, calcium,) and BUN and creatinine is desirable. Mild hypokalemia was reported in a patient treated for constipation during 1 month who concurrently received diuretics. Hyperphosphatemia was reported during long term treatment with PEG-products.

Adverse reactions
The most frequent adverse reactions, occurring in up to 50% of patients taking 4 L of Polyethylene glycol solution, are nausea, abdominal fullness and bloating. Abdominal cramps, vomiting and anal irritation occur less frequently. These adverse effects are transient.
The adverse reactions occurring with PEG products used in the treatment of constipation include: nausea, abdominal bloating, cramping, diarrhea and/or gas. High doses may produce diarrhea and excessive stool frequency, particularly in elderly nursing home patients.
Post-Market Adverse Drug Reactions
The following rare adverse events have been reported following administration of 4 L of Polyethylene glycol:
Cardiovascular: bradycardia, acute pulmonary edema, hypotension
Eye: sensitivity to light, painful irritated eyes
Gastrointestinal: rectal bleeding (occult blood in stool), sores in mouth, Ischemic Colitis (when used in conjunction with a stimulant laxative)
General and Administration Site Conditions: chills, loss of appetite
Hematologic: anemia

Metabolism and Nutrition: fluid imbalance, hypoglycaemia
Musculoskeletal and Connective Tissue: muscle pain
Nervous System: headaches, unconscious, coma, seizures, shakes
Psychiatric: confused feeling, disorientation
Respiratory, Thoracic and Mediastinal: aspiration
Skin and Subcutaneous Tissue: oily hair and skin, facial swelling, leg swelling
Isolated cases of urticaria, rhinorrhea and dermatitis have been reported which may represent allergic reactions.
The use of large volume (4 Liter) PEG-based colon preparation has resulted in reports of generalized tonic-clonic seizures

Pregnant Women: Animal reproduction studies have not been conducted with Polyethylene glycol, and it is also not known whether Polyethylene glycol can affect reproductive capacity or harm the fetus when administered to a pregnant patient. Polyethylene glycol should be given to a pregnant patient only if clearly needed.
Nursing Women: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Polyethylene glycol is administered to a nursing woman.

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There are no specific antidotes that are required to be administered in the event of overdose; however, supportive care may be required in order to prevent dehydration and/or electrolyte imbalance.

The pharmacological rationale for the use of Polyethylene Glycol (PEG) in gastroenterology is its inverse relation between molecular mass and intestinal absorbability, with practically no intestinal absorption at molecular masses exceeding 3000, its lack of intestinal enzymatic degradation or bacterial metabolism, and its water binding capacity.

Mechanism of Action
PEG 3350 is an osmotic laxative which causes water to be retained with the stool leading to decrease stool consistency, soften the stools, increase fecal bulk and facilitate bowel movements. Large volume (about 4 L) of PEG 3350 and electrolytes cleanses the bowel by induction of diarrhea. The osmotic activity of PEG 3350, in combination with the electrolyte concentration, result in virtually no net absorption or secretion of ions, such as sodium or potassium, and water. Accordingly, large volumes may be administered over a short period of time without significant changes in fluid and electrolyte balance. Smaller volumes of Polyethylene glycol are used for constipation relief. It takes about 2 to 4 days to produce a bowel movement.
A study was conducted to compare water and a PEG preparation as potential oral contrast media for MRI of the small bowel. Twenty-two healthy volunteers underwent separate MRI examinations after drinking up to two liters of water or PEG preparation. Small bowel images were obtained every 10 minutes for at least two hours using breath-hold single shot half-Fourier imaging, including both thick section projection and thin section images. Examinations were evaluated by two radiologists in consensus, blinded to the volunteer and contrast details, for arrival at the terminal ileum, transit time, and demonstration of small bowel segments. The PEG preparation was significantly better than water at reaching the terminal ileum (PEG 21/22

volunteers [95.45%], water 14/22 volunteers [63.6%], P = 0.04). There was no significant
difference in the mean transit time (water 51 ± 48 minutes, PEG 37.7 ± 22 minutes) or in the
demonstration of the stomach, duodenum, and jejunum, but the PEG preparation was
significantly better at demonstrating the ileum (P = 0.005) and terminal ileum (P = 0.002). It was
concluded that a PEG preparation is significantly better than water as an oral contrast medium
for demonstrating the distal small bowel during breath-hold T2-weighted MRI.i
A study was conducted to evaluate the safety and efficacy of PEG versus lactulose in the
management of HE. This clinical trial included 100 patients with post-hepatitis C cirrhosis who
were admitted with HE. Patients were randomized into two equal groups: group I patients
received lactulose and group II patients received PEG. The clinico-epidemiological
characteristics of patients, Child-Pugh score, and HE scoring algorithm were registered before
and 24 h after administration of the drug. Moreover, any suspected adverse effects were
recorded. All 100 patients received treatment. Three patients died within 24 h of admission and
did not complete the follow-up period. According to intention-to-treat approach, they were
considered as treatment failure. On analysis, 36/50 (72%) patients improved one grade or more
in HE scoring algorithm score after 24 h of lactulose therapy versus 47/50 (94%) of those on
PEG therapy (P<0.05). The time needed for resolution of HE and length of hospital stay were
significantly lower in PEG group versus lactulose group (P<0.001). Both therapies were
tolerated, and no significant adverse events were reported. It was concluded that both lactulose
and PEG were safe and effective in the treatment of HE. PEG significantly decreased the time
needed for resolution of HE and significantly shortened the hospital stay.ii

Absorption:
When used in large doses in gastrointestinal lavages, PEG 3350 has been shown to be absorbed
in only very small amounts. In general, absorption to PEG's of differing molecular weights
declines with increasing molecular weights.
Metabolism and Elimination:
Systemic absorption of PEG 3350 is minimal; once absorbed, the drug is excreted solely by the kidneys. Consistent with previous reports of minimal absorption and maximal excretion in feces, no clinically significant changes from baseline in renal function tests (i.e., estimated glomerular filtration rate and serum creatinine level values) were observed after treatment, indicating that PEG 3350 aqueous solution concentrate does not affect renal function.
PEG 3350 is poorly absorbed through the gastrointestinal track, and not metabolized by the colonic bacteria. Pharmacokinetics of PEG 3350 was evaluated in human volunteers after the oral administration of 17 g doses (as a laxative). Results show minimal absorption (<0.28%), low blood levels, rapid excretion through feces and lack of substantial accumulation of PEG 3350 on multiple dosing regardless of age and gender.
A study was conducted to investigate the absorption of PEG 3350 in patients undergoing routine gut lavage. Urine specimens were collected for 8 hours in 24 patients undergoing bowel cleansing with PEG 3350 for colonoscopy. The urinary excretion of PEG 3350, measured by size exclusion chromatography, ranged between 0.01 and 0.51 % of the ingested amount, corresponding to 5.8 and 896 mg in absolute amounts, respectively. Mean PEG excretion in patients with impaired mucosa such as inflammation or ulceration of the intestine (0.24 % ± 0.19, n = 11) was not significantly higher (p = 0.173) compared to that in subjects with macroscopically normal intestinal mucosa (0.13 % ± 0.13, n = 13). It was concluded that intestinal absorption of PEG 3350 is higher than previously assumed and underlies a strong inter-individual variation. Inflammatory changes of the intestine do not necessarily lead to a significantly higher permeability of PEG.
A study was conducted to determine efficacy, safety, and optimal dose of a laxative, PEG 3350, in children with chronic constipation. Children with chronic constipation (n = 24) were treated with PEG for 8 weeks at an initial dose of 1 g/kg/d. The dose was adjusted every 3 days as required to achieve 2 soft stools per day. A diary was kept to monitor dose, stool frequency and consistency, soiling, and other symptoms. Stool consistency was rated from 1 (hard) to 5 (watery). Subjects were examined for fecal retention. The Student t test and the Fisher exact test were used for data analysis. All 20 children who completed the study found PEG to be palatable and were satisfied with the treatment. There were no significant adverse effects. Weekly stool frequency increased from 2.3 ± 0.4 to 16.9 ± 1.6 (P <.0001) during treatment and stool consistency from 1.2 ± 0.1 to 3.3 ± 0.1 (P <.0001). In 9 children with soiling, weekly soiling events declined from 10.0 ± 2.4 to 1.3 ± 0.7 (P =.003). The mean effective dose was 0.84 g/kg/d (range, 0.27-1.42 g/kg/d). It was concluded that daily administration of PEG at a mean dose of 0.8 g/kg is an effective, safe, and palatable treatment for constipation.iii
A study was conducted to describe the pharmacokinetics of PEG-3350 in humans. A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG-3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 microg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers. Peak PEG-3350 plasma concentrations occurred at 2-4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half-life of about 4-6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG-3350. Mean faecal excretion of the administered dose was 93% in young subjects. It was concluded that orally administered PEG-3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.

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Eulax (Polyethylene Glycol 3350 powder for solution 17g)
The other ingredients are: The drug product formulation contains only active pharmaceutical ingredient

Not applicable

2 Years

Store below 30ºC.

30 Sachets (17 g packet)

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