Colyte Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

Colyte^® (PEG 3350 and Electrolytes) is indicated for:

• bowel cleansing prior to colonoscopy or barium enema x-ray examination or surgical procedures requiring a clean colon.
• the treatment of constipation

CONTRAINDICATIONS

Colyte^® 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. For a complete listing, see the Dosage Forms, Composition and Packaging section of this prescribing information.

WARNINGS AND PRECAUTIONS

General

• Use of Colyte^® is not recommended when abdominal pain, nausea, or vomiting are present
• Unconscious or semiconscious patient should be observed during the administration of Colyte^® 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 Colyte^® for more than 1 week, unless recommended by a physician.
• The safety of long term use of PEG plus electrolytes, like Colyte^®, is unknown.

No additional flavorings or ingredients may be added to the solution.

Colyte^® 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 polyethylene glycol (PEG) containing-products.

Advise all patients to hydrate adequately before, during, and after the use of Colyte^®.

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 Colyte^® 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

Colyte^® should be used with caution in patients with ulcerative colitis (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 Colyte^®, 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 Colyte^®.

When a large volume of Colyte^® 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 Colyte^® should be discontinued.

There is a potential risk of Ischemic colitis with co-exposure to osmotic laxatives

(PEG 3550/Macrogol) such as Colyte^®, 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), Colyte^® 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.

Special Populations

Pregnant Women: Animal reproduction studies have not been conducted with Colyte^®, and it is also not known whether Colyte^® can affect reproductive capacity or harm the fetus when administered to a pregnant patient. Colyte^® 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 Colyte^® is administered to a nursing woman.

Pediatrics: Safety and effectiveness of Colyte^® 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.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most frequent adverse reactions, occurring in up to 50% of patients taking 4 L of Colyte^® 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 Colyte^®:

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 (see Warnings and Precautions).

DRUG INTERACTIONS

Drug-Drug Interactions

Colyte^®, as any other laxatives, should not be taken within two (2) hours of another medicine because the desired effect of the other medicine may be reduced.

There is a potential risk of Ischemic colitis with co-exposure to osmotic laxatives

(PEG 3550/Macrogol) such as Colyte^®, 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.

Drug-Food Interactions

When Colyte^® is used for a bowel preparation, no food, except clear liquids, should be taken at least 3 hours prior to administration.

Patients should adequately hydrate before, during, and after the use of Colyte^®.

DOSAGE AND ADMINISTRATION

General considerations

No additional ingredients, e.g. flavouring, should be added to the solution.

Keep refrigerated during treatment, for optimal storage and to improve the taste.

Recommended Dose and Dosage Adjustment

Prior to gastrointestinal examination or procedure

Patients should fast at least 3 hours prior to administration. No foods except clear liquids should be permitted prior to examination after Colyte^® administration. Colyte^® can be administered orally or by nasogastric tube.

Oral: The recommended adult oral dose is 240 mL of Colyte^® solution every 10 minutes. Rapid drinking of each portion is preferred rather than drinking small amounts continuously.

Nasogastric Tube: Colyte^® is administered at a rate of 20 to 30 mL/minute (1.2 to 1.8 L/hour).

The first bowel movement should occur approximately 1 hour after the start of Colyte^® administration. Administration of Colyte^® should be continued until the fecal discharge is clear. Lavage is usually complete after the ingestion of 3 to 4L of Colyte^® solution. The unused portion should be discarded. A 1-hour waiting period after the appearance of clear liquid stools should be allowed prior to examination to complete bowel evacuation.

Constipation

240 to 480 mL/day (equivalent to a PEG dose of 14 to 28 g/day, plus electrolytes) orally for a week or less or as recommended by a physician. Do not take any type of laxatives for more than one week, unless your physician has ordered a special schedule for you.

Treatment for two to four days may be required to produce a bowel movement. If no bowel movement is achieved after 4 days, patients should consult their physicians

Reconstitution of the solution

Colyte^® powder 278 g bottle: To prepare Colyte^® solution, add lukewarm tap water until half full, replace cap tightly and mix well. Fill the bottle the rest of the way to the fill line (total volume 4 L). Replace cap tightly and mix well until all ingredients have completely dissolved. Do not use cold water.

OVERDOSAGE

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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Polyethylene glycol 3350 (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 Colyte^® (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 Colyte^® are used for constipation relief. It may take about 2 to 4 days to produce a bowel movement.

Pharmacokinetics

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.

STORAGE AND STABILITY

Store Colyte^® powder at room temperature, between 15 ^oC and 30 ^oC.

Once reconstituted, the solution should be used within 48 hours after mixing if stored at room temperature. If kept refrigerated (between 2 ^oC and 8 °C), use within 30 days. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Colyte^® Powder for oral solution

Each 278 g bottle of Colyte^® powder, to be dissolved in 4 L of water, contains the following medicinal ingredients:

Polyethylene glycol 3350 : 240 g

Sodium chloride : 5.84 g

Potassium chloride : 2.98 g

Sodium bicarbonate : 6.72 g

Sodium sulfate (anhydrous) : 22.72 g

Non-medicinal ingredients: (alphabetical) magnasweet 185, pineapple flavour and sodium saccharin.

When reconstituted with 4 L of water, the solution contains :

Sodium: 125 mEq/L

Potassium: 10 mEq/L

Bicarbonate: 20 mEq/L

Sulfate: 80 mEq/L

Chloride: 35 mEq/L

Polyethylene glycol 3350: 17.9 mEq/L

The osmolarity of a prepared solution of PEG/Electrolytes ranges from 235-305 mOsmol.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Drug Substance	Polyethylene Glycol 3350	Sodium Sulfate	Sodium Bicarbonate	Sodium Chloride	Potassium Chloride
Proper name:	Polyethylene Glycol	Sodium Sulfate	Sodium bicarbonate	Sodium Chloride	Potassium Chloride
Chemical name:	Ethanol, 2,2'-(oxybis(2,1-ethanediyloxy)bis-	Bisodium sulfate; Dibasic sodium sulfate	Bicarbonate of soda; Carbonic acid, monosodium salt	Sodium chloride	Potassium chloride
Molecular formula:	HO(C2H4O)nH	Na2SO4	NaHCO3	NaCl	KCl
Structural formula:

CLINICAL TRIALS

Constipation

Polyethylene glycol and electrolytes solutions (PEG-ELS) are described as part of the medications commonly used for the treatment of constipation. The maximal recommended dose is 17-36 g once or twice a day.

Study demographics and trial design

Table 2- Summary of patient demographics for clinical trials of polyethylene glycol and electrolyte solutions (PEG-ELS) in the treatment of chronic constipation

Study results

A double-blind, placebo-controlled, cross-over study by Andorsky and Goldner assessed the effectiveness of a PEG-ELS for the treatment of chronic constipation. 32 patients were instructed to drink 240 mL or 480 mL of PEG-ELS or placebo daily during 5 consecutive days, then received the same volume of the second treatment (PEG-ELS or placebo) after a 2-day washout period. Daily number of bowel movements and stool consistency were recorded. The two-factor analysis of variance results confirmed that PEG-ELS was superior to placebo with regard to the mean stool frequency (7.75 ± 4.55 vs. 4.88 ± 2.62, p < 0,01) and the mean stool consistency (2.56 ± 1.17 vs. 1.91 ± 0.94, p < 0.05). Furthermore, PEG-ELS 480 mL per day was superior to all other groups with regard to the measured variables. Side effects reported with the PEG-ELS solution included cramping, gas, nausea, and loose stools; side effects did not lead to treatment cessation. The finding that PEG-ELS resulted in significant effects on both stool frequency and stool consistency further supports its efficacy in the treatment of constipation.

A multicentre, double-blind, randomized, parallel-group study by Chaussade and Minic compared the efficacy and tolerability of standard and maximum daily doses of PEG-ELS (PEG 3350 and electrolytes) and PEG 4000 in the treatment of chronic constipation. Results showed that both doses of PEG-ELS and PEG 4400 were similarly effective in treating the symptoms of constipation (stool frequency and stool consistency were improved when compared to baseline). Diarrhea was observed in 13% of patients treated with low dose of PEG-ELS and 36% after the higher dose. Side effects reported were abdominal distention, flatulence and abdominal pain similarly distributed across all groups. Vital signs were normal in 95% of the patients

A randomized, open-label, parallel-group, multicenter study by Attar et al. compared PEG-ELS to lactulose for treatment of constipation. 115 patients with chronic idiopathic constipation were instructed to take two 13 g sachets of PEG-ELS or two 10 g lactulose sachets, in divided doses. After two weeks of treatment, dosage could be adjusted to 1 to 3 sachets / day. Treatment lasted for 4 weeks. PEG was well tolerated in the young and elderly population and the treatment of constipation was better than lactulose in terms of number of bowel movement, straining and use of suppositories and minienemas.

TOXICOLOGY

Acute Toxicity:

The oral LD₅₀ is >50 g/kg in mice, rats and rabbits.

Rats

Chronic oral toxicity studies were conducted in rats (up to 6 g/kg/day) up to six months duration.

The major target organ of toxicity in the rat appeared to be the kidney (focal or multi focal cytoplasmic vacuolation in cortical tubular epithelial cells in males at 6 g/kg/day).

Dogs

Chronic oral toxicity studies were conducted in dogs (up to 3 g/kg/day) up to nine months duration.

Following oral administration of PEG 3350 for 28-days, the target organs of toxicity appeared to be the lungs (minimal to moderate interstitial fibrosis characterized by thickening of alveolar septa with associated pneumocyte hypertrophy/hyperplasia and the presence of a small number of mononuclear inflammatory cells and alveolar histiocytes; foamy or vacuolated histiocytes in perivascular or peribronchiolar regions characterized as perivascular mononuclear infiltrates), gastrointestinal tract (minimal subacute inflammation or crypt abscesses, hemorrhage and lymphoid hyperplasia in cecum, colon, ileum and/or rectum; lymphoid hyperplasia of the gut-associated lymphoid tissue in females at 3, 6 and 9.3 g/kg/day), testes (hypospermia in the epididymides and seminiferous tubule degeneration or multinucleated spermatids of the testes) and salivary gland (atrophy).

Following 9-month oral administration of PEG 3350 in dogs (up to 3 g/kg/day), the target organs of toxicity appeared to be testes (retarded development) and prostate (lymphocyte infiltrate) in the males and mammary gland (glandular hyperplasia), liver (vacuolation) and gallbladder (lymphocyte infiltrate and epithelial hyperplasia) in females.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenesis

No tumorigenic effect was seen in mice and rats up to 6 g/kg/day. The carcinogenic potential of PEG 3350 has also been examined in CD-J mice (l04 weeks) and Sprague Dawley rats (l04 weeks).

Mutagenesis

PEG 3350 was negative in the Ames test. No clastogenic potential was shown in the chromosome aberration test with human peripheral blood lymphocytes. It was also negative in in vivo oral rat micronucleus test.

Development and reproductive toxicity

Reproduction studies with PEG 3350 have been performed in pregnant rats (oral doses up to 2 g/kg/day) and in pregnant rabbits (oral doses up to 2 g/kg/day) and have revealed no adverse effects on fertility or harm to the fetus.

In pre- and post-natal developmental study in rats up to 2 g/kg/day dose, PEG 3350 did not show any adverse effect on F_l postnatal survival, body weight, developmental landmarks, startle response, motor activity, learning and memory and reproductive performance, intrauterine growth and survival of F₂ fetuses and external and developmental parameters of F₂ fetuses.

REFERENCES

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