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Introduction

ATC Class:A06AG07

VA Class:IR100

AHFS Class:

Associated Monographs

Cathartic, laxative, and purgative are terms describing drugs that promote evacuation of the intestine; the difference between the terms is largely one of degree.

Uses

[Section Outline]

GI Conditions !!navigator!!

Although there are few valid indications for laxatives, these drugs are self-prescribed and overused by a large portion of the population. Constipation usually is best avoided or relieved with proper diet (high fiber content such as bran), adequate fluid intake, prompt response to the defecation reflex, and exercise. The normal frequency of bowel movements varies from once daily to 1-2 times weekly. If constipation (i.e., decreased frequency of bowel movements with prolonged and difficult passage of stools) occurs, the cause should be identified carefully before initiating laxative use. Use of laxatives in infants and children should be avoided; childhood constipation is best treated by counseling the parents regarding acceptable variations in the frequency of bowel movements.

When laxatives are indicated, the mildest effective laxative should be used. Rectal suppositories or enemas are routinely used to empty the colon prior to surgery or radiologic or colonoscopic procedures but, except for these uses, should not be used when oral laxatives are effective. Single-ingredient laxative products facilitate necessary dosage adjustment and usually are as effective as and safer than combination products. Combinations of two different types of laxatives may be desirable in some patients such as those with both painful and infrequent bowel movements, but there is no rationale for combinations containing more than 2 laxatives. Most clinicians consider fixed combinations of laxatives with other drugs (e.g., belladonna alkaloids, other antimuscarinics, bismuth salts, vitamins, minerals, trace elements) unsafe and irrational.

Most clinicians consider bulk-forming laxatives to be the laxatives of choice for the initial treatment of most cases of simple constipation which is usually caused by a low-fiber and/or low-fluid diet; use of saline or stimulant laxatives for simple constipation is seldom necessary or desirable. If a stimulant laxative is used, most clinicians prefer senna or cascara (preparations containing cascara sagrada are no longer commercially available in the US) derivatives or dehydrocholic acid to the other stimulant laxatives. Aloin, aloe (preparations containing aloe extract or aloe flower extract are no longer commercially available in the US), and castor oil are avoided because they reportedly produce violent purgation, and phenolphthalein (laxatives containing phenolphthalein are no longer commercially available in the US) is avoided because it causes fixed skin eruptions.

Bulk-forming laxatives, stool softeners, or mineral oil are preferred to other laxatives in patients with conditions in which straining at defecation should be avoided (e.g., myocardial infarction, vascular diseases, diseases of the anus or rectum, hernias, recent rectal surgery). Oral stool softeners or mineral oil are preferred to bulk-forming laxatives to ease evacuation of feces in patients with constipation associated with hard, dry stools. Many clinicians consider the stool softeners to be the treatment of choice in childhood constipation associated with hard, dry stools and to be safer and more efficacious than mineral oil for conditions in which straining at defecation is to be avoided.

Bulk-forming and stimulant laxatives have been used to treat constipation that occurs following prolonged bed rest or hospitalization. These laxatives have also been used to treat constipation resulting from diminished colonic motor response in geriatric patients but, because this type of constipation is frequently due to psychological or physical laxative dependence, the bulk-forming laxatives are preferred.

Bulk-forming, hyperosmotic, stimulant, and mild saline laxatives (e.g., oral magnesium hydroxide or milk of magnesia) and stool softeners have been used to treat constipation occurring during pregnancy or the puerperium, but bulk-forming laxatives or stool softeners are usually preferred. Because the anthraquinone and diphenylmethane stimulant laxatives may be distributed into milk, other laxatives usually are used for postpartum constipation.

Mineral oil or stool softeners may be administered orally or rectally for the treatment of constipation associated with stricture of the colon or to soften fecal impactions. Some clinicians consider stool softeners to be safer and more efficacious than mineral oil for these purposes. After softening impacted feces with a stool softener or mineral oil, stimulant or saline laxatives may be administered rectally to evacuate the impacted colon. Alternatively, phosphate-containing saline enemas may be administered rectally to promote evacuation of fecal impactions after manual disimpaction.

Stimulant laxatives are used to treat constipation occurring secondary to idiopathic slowing of transit time, to constipating drugs, or to irritable bowel or spastic colon syndrome. They have also been used to treat constipation in patients with neurologic constipation.

Saline laxatives have been used to eliminate parasites and toxic anthelmintics prior to and/or after therapy with some anthelmintics (e.g., quinacrine hydrochloride). Because oral or rectal preparations of sodium phosphate and sodium biphosphate apparently do not destroy osmotically sensitive trophozoites of Entamoeba histolytica or Giardia lamblia, these preparations have been used to facilitate collection of stool samples for parasitic examination. However, most clinicians agree that with the newer anthelmintics use of laxatives to eliminate parasites or the anthelmintic is not necessary, may complicate identification of the parasite, and may be harmful to the patient.

Oral saline (usually magnesium citrate or sodium phosphates) and/or oral stimulant laxatives (usually castor oil, bisacodyl, or standardized senna fruit extract) are used to empty the bowel prior to surgery or radiologic, proctoscopic, or sigmoidoscopic procedures. These laxatives are usually supplemented with administration of rectal evacuants, such as saline, stimulant, or soapsuds enemas, immediately before radiologic procedures. Polyethylene glycol 3350 electrolyte solutions also are used to empty the bowel prior to colonoscopy and barium enema radiologic examinations.245,246,247,248,252,253 The American Society of Colon and Rectal Surgeons (ASCRS), American Society for Gastrointestinal Endoscopy (ASGE), and Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) recommend the use of polyethylene glycol 3350 electrolyte solutions in patients with electrolyte or fluid imbalances (e.g., those with renal or liver insufficiency, congestive heart failure, liver failure, or advanced liver disease with ascites).251,259 These experts also recommend use of polyethylene glycol 3350 electrolyte solutions for colonic cleansing in infants and children.251 Glycerin and sorbitol also have been used before these procedures, but these laxatives do not always entirely empty the colon. Bisacodyl tannex has been added to barium sulfate enemas to aid in coating the intestinal mucosa and enhance colonic evacuation prior to radiologic examination of the colon. Bisacodyl and mineral oil enemas are used to cleanse the colon postoperatively. Bisacodyl suppositories may be used to cleanse the colon in pregnant women prior to delivery if they are given at least 2 hours before onset of the second stage of labor.

Sorbitol is used orally or rectally to facilitate the passage of sodium polystyrene sulfonate through the intestinal tract, to prevent constipation caused by the resin, and, by acting as a hyperosmotic laxative, to aid in potassium removal; sorbitol also improves the palatability of the resin.

Bisacodyl has been used to facilitate flushing of colostomies, but the value and safety of the drug as compared to irrigations have not been established.

Semisynthetic celluloses and psyllium bulk-forming laxatives have been used to increase the bulk of stools in patients with chronic, watery diarrhea; subjective improvement has been noted in these patients but the total water content of the stool has been unchanged. Bulk-forming laxatives and dietary bran have also been used, with some success, to reduce intraluminal and rectosigmoid pressure, and pain in patients with diverticular disease. One manufacturer suggests that stool softeners may be useful in the treatment of ulcerative colitis or diverticulitis.

Malt soup extract, in conjunction with other therapy such as proper diet and hygiene, has been used in the treatment of pruritus ani; however, evidence that the drug is effective for this condition is lacking. Bulk-forming laxatives have also been used in the management of obesity but their effectiveness in this condition is questionable.

Other Uses !!navigator!!

Saline laxatives are also used, after inducing emesis or performing gastric lavage, to hasten removal of some poisons from the GI tract, but should not be used after poisonings with ingested acids or alkalies. Magnesium laxatives should not be used to remove poisons producing CNS depression or renal function impairment.

Some manufacturers have suggested that oral phosphate saline laxatives may be useful for the symptomatic relief of gallbladder disorders, but their effectiveness in these conditions has not been proven.

When used as an adjunct to dietary therapy, oral psyllium hydrophilic mucilloid (3.4 g 3 times daily before meals as a sugar-free preparation) has produced modest reductions in serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B concentrations and the ratio of LDL cholesterol to high-density lipoprotein (HDL)-cholesterol in adults with mild to moderate hypercholesterolemia.212,213

Dosage and Administration

[Section Outline]

Administration !!navigator!!

Laxatives are usually administered orally and in conjunction with adequate fluid intake. Rectal suppositories or enemas may be used when oral laxatives are not effective or to prepare for surgery, or radiologic or colonoscopic procedures.

Suppositories should be moistened with lukewarm water before being inserted high into the rectum and retained in the rectum for as long as possible. Before administering laxative enemas, the patient should lie on his left side with knees bent or should kneel on the bed with the head and chest lowered and forward until the left side of the face is resting on the surface of the bed. With steady pressure, the enema nozzle should be inserted into the rectum, with the nozzle toward the navel, and the container squeezed until the entire dose is expelled. Enema fluids, if properly introduced, usually provide adequate evacuation if retained until definite lower abdominal cramping is felt.

Dosage !!navigator!!

Laxatives should be used as infrequently as possible, at the lowest effective dosage level, and usually for periods not exceeding one week; laxatives should be used for longer periods only under the management of a physician and as part of a carefully planned therapeutic regimen.

Cautions

[Section Outline]

When used in appropriate dosages for a limited period of time (one week or less), most laxatives are relatively free from adverse effects such as diarrhea, GI irritation, and fluid and electrolyte depletion. Stimulant laxatives are the laxatives most likely to produce these adverse effects. Chronic use or overdosage of laxatives may produce persistent diarrhea, hypokalemia, loss of essential nutritional factors, and dehydration.

Because magnesium, potassium, or sodium accumulation may occur in patients with renal disease, laxative products containing more than 50 mEq of magnesium, 25 mEq of potassium, or 1 mEq of sodium per dose should be used by these patients only under the supervision of a physician who should monitor electrolytes. Although no information is available on the amount of sodium absorbed following ingestion of carboxymethylcellulose sodium, this drug usually contains 2.7-4 mEq of sodium per gram. Congestive heart failure has occurred following indiscriminate use of saline laxatives containing sodium. Use of carboxymethylcellulose sodium and sodium-containing saline laxatives should be restricted in patients on low-sodium diets. Use of sodium-containing saline laxatives should also be restricted in those with congestive heart failure, edema, or cirrhosis.

Because standardized senna fruit extract and some psyllium preparations contain large amounts of sugar, the caloric value of these preparations should be considered in patients with diabetes mellitus.

All laxatives are contraindicated in patients with acute abdominal pain, nausea, vomiting, or other symptoms of appendicitis or undiagnosed abdominal pain. Stimulant laxatives are contraindicated in patients with intestinal obstruction. Bulk-forming laxatives are not useful when prompt or thorough bowel evacuation is necessary (e.g., poisonings, radiologic examination, bowel surgery) and are contraindicated in patients with partial obstruction of the bowel or dysphagia. Patients should consult their clinicians if sudden changes in bowel habits persist for longer than 2 weeks or if use of a laxative for one week has no effect. Polyethylene glycol 3350 electrolyte solutions are contraindicated in patients with GI obstruction, gastric retention, bowel perforation, toxic colitis, toxic megacolon, or ileus.245,246,247,252,253 Sodium phosphates are contraindicated in patients with biopsy-proven acute phosphate nephropathy,283 GI obstruction,281,283 gastric bypass or stapling surgery,283 bowel perforation,281,283 toxic colitis, toxic megacolon,283 congestive heart failure,275,281 history of kidney disease275 or clinically important renal function impairment,275,281 paralytic ileus,281 active inflammatory bowel disease,281 imperforate anus,281 decreased intravascular volume275 or dehydration,275,281 uncorrected electrolyte abnormalities,275 or known hypersensitivity to sodium phosphate salts or any ingredient in the formulation.281,283 (See Sodium Phosphates Preparations under Cautions: Saline Laxatives.)

Bulk-forming Laxatives !!navigator!!

Adverse effects occur rarely with the use of bulk-forming laxatives. Rare cases of allergic reactions and urticaria have been associated with the use of karaya. Bowel and/or esophageal obstruction, swelling or blockage of the throat, choking, or asphyxiation has occurred when insufficient liquid was administered with some of these laxatives;214,215,216,217,218,219,220,221 some of these effects probably result from formation of a viscous, semi-solid mass rather than the emollient gel or viscous solution that results when sufficient fluid is added to these laxatives.215 Therefore, at least one full glass (250 mL) of liquid should be administered with each dose of bulk-forming laxatives.214,215,217,218 Patients should be informed of the symptoms of esophageal obstruction and instructed to contact their physician if chest pain and/or pressure, regurgitation, vomiting, or difficulty in swallowing and/or breathing occur.215,217,218 Bulk-forming laxatives should not be used in individuals with esophageal obstruction, problems of the throat, or those who have difficulty in swallowing.215,217,218

Potentially severe hypersensitivity reactions, including rhinoconjunctivitis, acute bronchospasm, and anaphylaxis, can occur in susceptible individuals (e.g., those with psyllium sensitivity or suffering from respiratory disorders) following inhalation of psyllium dust particles.222,223 Therefore, inhalation of psyllium hydrophilic mucilloid particles should be avoided.222,223 To minimize exposure and, therefore, sensitization to airborne particles of psyllium, one manufacturer suggests that health-care personnel dispense powdered psyllium preparations with a spoon rather than pouring them directly from the container into the glass for administration.224 In some cases, reassignment of health-care personnel to areas (e.g., nongeriatric units) where use of bulk powder formulations of psyllium was minimal has been necessary.222,223

Hyperosmotic Laxatives !!navigator!!

Adverse effects occur rarely following rectal administration of glycerin or sorbitol. Glycerin may produce rectal discomfort, irritation, burning or griping, cramping pain and tenesmus. Hyperemia of the rectal mucosa with minimal amounts of hemorrhage and mucus discharge may also occur. These adverse effects occur less frequently following rectal administration of sorbitol. Diarrhea frequently occurs with the dosages of sorbitol used as adjuncts to sodium polystyrene sulfonate therapy.

Polyethylene glycol 3350 electrolyte solutions (oral or nasogastric) may produce malaise, nausea,245,246,247,248,252,253,259 abdominal distention,245,246,248 abdominal fullness and/or bloating,245,246,247,248,252,253,259 abdominal cramps,245,246,247,248,253 vomiting,245,246,247,248,253,259 anal irritation,245,246,247,248,253 and thirst.248 Generalized tonic-clonic seizures associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia) have been reported following use of polyethylene glycol 3350 electrolyte solutions for bowel cleansing in patients without a history of seizures.248 Such neurologic effects resolved with correction of fluid and electrolyte abnormalities.248 Polyethylene glycol 3350 electrolyte solutions (Golytely®, Colyte®, MoviPrep®) should be used with caution in patients with severe ulcerative colitis.245,247,248,252,253 In addition, polyethylene glycol 3350 electrolyte solutions should be used with caution in patients receiving drugs that increase the risk of electrolyte abnormalities (e.g., diuretics, angiotensin-converting enzyme [ACE] inhibitors).248 Consideration should be given to measuring electrolyte, BUN, and creatinine concentrations before and after colonoscopy in patients receiving such drugs and in those with known or suspected hyponatremia.248 Since MoviPrep® contains sodium ascorbate and ascorbic acid, the drug should be used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, especially those with an active infection, with a history of hemolysis, or those taking concomitant drugs known to precipitate hemolytic reactions. If severe bloating, distention, or abdominal pain occurs in patients receiving therapy with polyethylene glycol 3350 electrolyte solutions, administration should be slowed or temporarily discontinued until symptoms subside. If GI obstruction or perforation is suspected, appropriate tests should be performed to rule out these conditions before administration of polyethylene glycol 3350 electrolyte solution.245,246,247,248,252

If rectal bleeding, nausea, bloating, cramping, or abdominal pain worsens, or the patient experiences diarrhea or requires more than 7 days of use of polyethylene glycol 3350 solution (MiraLAX®) for the treatment of constipation, the drug should be discontinued and a clinician notified.244

Mineral Oil !!navigator!!

Adverse effects associated with the proper use of mineral oil are few. Seepage of mineral oil from the rectum may occur following oral or rectal administration, particularly when high doses are given. Seepage may cause soiling of the skin and clothing, anal irritation, and pruritus ani; impair normal rectal reflex mechanisms; and increase infection of anorectal lesions and interfere with their healing. Seepage of mineral oil may be minimized by reducing dosage.

Infrequently, aspiration of orally administered mineral oil may occur, particularly in young children and geriatric or debilitated patients, causing lipid pneumonitis.

Rarely, and only with chronic, oral use of plain mineral oil, absorption of fat-soluble vitamins, including provitamin A and vitamins A, D, and K, may be impaired. Hypoprothrombinemia and hemorrhagic disease of the newborn has occurred when mineral oil was chronically administered orally to pregnant women. Clinically important malabsorption of fat-soluble vitamins can be minimized by administering mineral oil on an empty stomach and limiting use of the drug to periods of less than 1 week.

Systemic absorption of mineral oil has caused foreign-body granulomatous reactions or paraffinomas, particularly in mesenteric lymph nodes and in the liver and spleen. Tissue depositions of mineral oil have simulated neoplasms and, in rare instances, carcinomas have been associated with industrial exposure to unrefined mineral oils or injection of refined mineral oil in animals and humans.

Oral administration of mineral oil is contraindicated in children younger than 6 years of a in bedridden, geriatric, debilitated, or pregnant patients; and in patients with esophageal or gastric retention, dysphagia, or hiatal hernia.

Saline Laxatives !!navigator!!

Saline laxatives generally do not produce serious adverse effects except when used for prolonged periods or when overdoses are administered. The bitter taste of magnesium sulfate, which may cause nausea, can be masked by mixing the drug with lemon juice. Common adverse effects associated with sodium phosphates preparations include dehydration, abdominal pain, bloating, nausea, vomiting, headache, and dizziness.229,233,234 Rectal discomfort and burning sensations have occurred occasionally in patients receiving carbon dioxide-releasing suppositories, because of inadequate moistening of the suppository prior to insertion and/or the sudden stretch reflex caused by expanding gas.

Dehydration may result from repeated administration of hypertonic solutions of saline laxatives but can be avoided by administering the laxatives with sufficient fluid. Serious, potentially life-threatening electrolyte disturbances may occur with long-term use or overdosage of saline laxatives.

Magnesium Sulfate Preparations

Symptoms of hypermagnesemia, including muscle weakness, ECG changes, sedation, and confusion, may occur when plasma magnesium concentrations exceed 1.5-2.2 mEq/L. When plasma magnesium concentrations exceed 4 mEq/L, deep tendon reflexes become depressed and at 12-15 mEq/L, respiratory paralysis may occur. Complete heart block occasionally occurs when plasma magnesium concentrations are elevated. In patients with impaired renal function, oral or rectal administration of 30 g (243 mEq magnesium) or greater of magnesium sulfate has been fatal. If hypermagnesemia occurs, urinary excretion of magnesium may be increased by administration of diuretics (e.g., furosemide, ethacrynic acid, ammonium chloride).

Sodium Phosphates Preparations

Overdosage

Overdosage has been reported in adults and pediatric patients receiving nonprescription (over-the-counter, OTC) sodium phosphates preparations (i.e., oral solution, enema) for self-medication of occasional constipation.279

In 1998, following reports of inadvertent overdosage and death associated with the use of large-size containers of sodium phosphates oral solution, FDA limited the container size of the drugs to no more than 90 mL when used as a nonprescription laxative.274 In addition, FDA required that the product information of nonprescription oral and rectal sodium phosphates preparations contain warning and direction statements to inform patients that exceeding the recommended dosages in a 24-hour period can be harmful.274 According to a subsequent FDA review of the safety of oral sodium phosphates preparations, use of more than 45 mL (usually 90 mL or more) of sodium phosphates oral solution in a 24-hour period and/or use in patients at increased risk for electrolyte abnormalities has been associated with severe electrolyte abnormalities, dehydration, metabolic acidosis, renal failure, tetany, and death.231

Between 1957 and August 2013, a total of 54 cases of serious adverse effects associated with oral or rectal sodium phosphate laxative preparations, including severe dehydration, electrolyte abnormalities (e.g., hypernatremia, hyperphosphatemia, hypocalcemia), acute kidney injury, cardiac arrhythmias, and/or death, have been identified in the FDA Adverse Event Reporting System (AERS) and the medical literature.279 Nearly half (12/25) of adult cases and 3% (1/29) of pediatric cases resulted in a fatal outcome.279 The remaining nonfatal cases were life-threatening in more than two-thirds of affected adults and in all of the affected children; these included acute deterioration in respiratory status, mental status, and heart function; dialysis; suspected bowel perforation requiring surgery; abdominal distention requiring surgery; and residual neurologic defects.279 The severity of reported adverse events was similar regardless of whether the drugs were administered orally or rectally.279

In the 50 cases (27 pediatric, 23 adult) for which the administered dose was reported, the majority of adverse events occurred in patients who received higher than recommended dosages in a 24-hour period (i.e., a single dose that was larger than recommended or more than one dose in a day) or in patients at increased risk of developing sodium phosphate-induced toxicity (e.g., those with dehydration, kidney disease, acute colitis, or delayed bowel emptying or receiving concomitant therapy with drugs that affect renal function [e.g., diuretics, angiotensin converting-enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]).279 Forty percent (11/27) of the pediatric cases for which the dose was reported occurred in young children for whom FDA has not proposed a safe and effective dose (9 cases in children younger than 2 years of age receiving a rectal preparation, and 2 cases in children younger than 5 years of age receiving an oral preparation); these children received doses comparable to those recommended on the label for use in adults or older children.279 The duration of sodium phosphates use in the majority of the overdose cases was 1-2 days.279

In light of these findings, FDA issued a drug safety communication in 2014, warning patients of possible harm from exceeding the recommended dosages of nonprescription sodium phosphates preparations.279 The agency stated that the maximum recommended oral or rectal dosage of nonprescription sodium phosphates preparations should not be exceeded, and that additional doses are not recommended within 24 hours, even in patients who do not have a bowel movement after receiving a dose.279 FDA also stated that clinicians should be cautious in recommending use of nonprescription sodium phosphates preparations in patients older than 55 years of a patients with hypovolemia, decreased intravascular volume, kidney disease, decreased bowel transit time, or active colitis; and patients receiving drugs that affect renal perfusion or function (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIAs).279 FDA recommended that serum electrolytes and renal function be assessed in patients who may be at increased risk of serious adverse effects, including those who have retained a rectal dose for more than 30 minutes, who are vomiting, or who may have signs of dehydration.279 Nonprescription sodium phosphates preparations should not be used concomitantly with other laxatives containing sodium phosphate.279 Patients should be advised to discontinue sodium phosphates therapy and to immediately seek medical attention if symptoms of kidney injury (e.g., drowsiness; sluggishness; decreased urine; swelling of the ankles, feet, or legs) occur.279

Nonprescription sodium phosphates oral solution should not be used for self-medication of occasional constipation in children 5 years of age or younger, and nonprescription sodium phosphates enema should not be used for such self-medication in children 2 years of age or younger.275,279 Sodium phosphates preparations should not be used for self-medication of occasional constipation for longer than 3 days.279

Serious Adverse Effects Associated with Oral Sodium Phosphates

Electrolyte abnormalities (e.g., hyperphosphatemia, hypernatremia, hypocalcemia, hypokalemia) resulting in prolongation of the QT interval, generalized tonic-clonic seizures, and/or loss of consciousness have been reported rarely with sodium phosphates preparations.229,234 Renal failure, acute phosphate nephropathy, and nephrocalcinosis, often resulting in permanent renal impairment and sometimes requiring long-term dialysis, also have been reported rarely in patients receiving oral sodium phosphates preparations (i.e., oral solution, OsmoPrep® tablets) for bowel cleansing prior to colonoscopy or other procedures.229,230,232,234,269,283 Onset of kidney injury occurred from several days to several months after use of the oral sodium phosphates preparation.269,283 Although certain patients (e.g., patients older than 55 years of a patients with hypovolemia, increased bowel transit time, bowel obstruction, active colitis, or kidney disease; patients receiving drugs that affect renal perfusion or function, such as diuretics, ACE inhibitors, angiotensin II receptor antagonists, and possibly NSAIAs) appear to be at increased risk of developing acute phosphate nephropathy,229,234,269,270,283 this adverse effect has occurred in patients without identifiable risk factors; however, FDA states that the possibility that some of these patients were dehydrated prior to or did not drink sufficient fluids after ingestion of oral sodium phosphates preparations cannot be ruled out.269 Death secondary to substantial fluid shifts, severe electrolyte abnormalities, and cardiac arrhythmias also has occurred in patients with renal impairment, patients with bowel perforation, and patients who misused or administered overdosages of sodium phosphates preparations prior to colonoscopy.229,234 Prolonged use or overdosage of phosphate laxatives may result in inorganic phosphate poisoning, which reduces plasma calcium concentrations; acidosis also may occur.

Regulatory Actions in 2008 Involving Oral Sodium Phosphates

Because of continued reports of acute renal injury in patients receiving oral sodium phosphates preparations for bowel cleansing, in 2008 FDA required the manufacturer to add a boxed warning to the labeling of OsmoPrep®, an oral sodium phosphates preparation available by prescription only.269,283

Because acute phosphate nephropathy also had been reported following use of nonprescription oral sodium phosphates preparations (i.e., oral solutions) as bowel cleansing regimens (i.e., at dosages higher than those used for relief of constipation), FDA stated that these preparations should be used for bowel cleansing only when a prescription for such use has been issued by a clinician.269,270 In response to FDA's announcement, at least one manufacturer (i.e., Fleet Laboratories) ceased distribution and initiated a voluntary recall of some of its nonprescription oral sodium phosphates preparations used for bowel cleansing (i.e., Fleet® Phospho-soda® Oral Saline Laxative, Fleet® Phospho-soda® EZ-PREP® Bowel Cleansing System) effective December 12, 2008.271,272,273 Health-care professionals were advised to cease recommending oral sodium phosphates preparations for bowel cleansing and to remove them from pharmacy shelves;271,272 patients requesting a nonprescription oral sodium phosphates preparation for bowel cleansing should be advised to consult their clinician for an alternative bowel cleansing preparation (i.e., one available by prescription only).272

Because nonprescription oral sodium phosphates preparations had not been associated with acute kidney injury when used as laxatives (i.e., for relief of constipation), FDA concluded that these preparations should continue to be available over-the-counter for such use.269,270

Subsequent Regulatory Actions Involving Oral Sodium Phosphates

Despite efforts to inform healthcare professionals and consumers about the risks associated with the use of sodium phosphates oral solution for bowel cleansing, FDA reported in 2011 that the agency continued to receive reports of acute kidney injury following administration of usual recommended dosages of the drugs for self-medication (i.e., approximately 60 g of sodium phosphates [dibasic sodium phosphate and monobasic sodium phosphate salts] administered as two 45-mL doses given 12 hours apart, or approximately 50 g of sodium phosphates administered as a 45-mL dose initially, followed by a 30-mL dose 12 hours later).282

A review of reports received from 1969-2005 revealed 33 reports of acute kidney injury (i.e., chronic kidney failure requiring hospitalization or dialysis, end-stage kidney disease requiring transplantation) associated with the use of nonprescription sodium phosphates oral solution for bowel cleansing; in most cases, acute kidney injury occurred within the recommended dosages for self-medication for bowel cleansing, including the lower-dose regimen (i.e., approximately 50 g of sodium phosphates administered as a 45-mL dose initially, followed by a 30-mL dose 10-12 hours later).282 Seizures, serious cardiac events, and death also have been reported with nonprescription sodium phosphates oral solution, although most of these cases occurred following use of dosages higher than those recommended for self-medication for bowel cleansing.282

As a result of these findings, FDA has tentatively concluded that the usual recommended dosage of nonprescription oral sodium phosphates for self-medication for bowel cleansing based on professional labeling in an OTC monograph poses an unacceptable risk of serious adverse events.282 Therefore, in February 2011, the agency issued a proposed rule amending the tentative final monograph on nonprescription laxative drug products to classify the individual sodium phosphate salts (i.e., dibasic sodium phosphate, monobasic sodium phosphate) as not generally recognized as safe (GRAS) for bowel cleansing.282 In the proposed rule, FDA also suggested that the professional labeling for sodium phosphates (which discusses use of the drugs as part of a bowel cleansing regimen) be removed from the 1985 tentative final monograph for over-the-counter laxative drug products.282 In response to FDA's proposed rule, some manufacturers have removed the indication for bowel cleansing from labeling of nonprescription sodium phosphates preparations.275

Precautions and Contraindications Involving Use of Oral Sodium Phosphates for Bowel Cleansing

FDA states that use of prescription-only oral sodium phosphates preparations as bowel cleansing regimens should be avoided in patients younger than 18 years of a these agents should be used with caution as bowel cleansing regimens in patients older than 55 years of a patients with dehydration, kidney disease, delayed bowel emptying, or acute colitis; and patients receiving drugs that may affect renal perfusion or function (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists, possibly NSAIAs).230,232,269

Furthermore, the manufacturer of sodium phosphates tablets (OsmoPrep®) states that these preparations (which are intended for use in cleansing the bowel prior to colonoscopy) should be used with caution in patients with renal disease or renal impairment (creatinine clearance less than 30 mL/minute), congestive heart failure, ascites, unstable angina, gastric retention, ileus, pseudo-obstruction of the bowel, severe chronic constipation, severe active ulcerative colitis, acute exacerbation of chronic inflammatory bowel disease, or hypomotility syndrome.229,234,283 Sodium phosphates tablets also should be used with caution in patients with a history of acute phosphate nephropathy or inflammatory bowel disease, known or suspected electrolyte disturbances (e.g., dehydration), an increased risk of arrhythmias (i.e., history of cardiomyopathy or uncontrolled arrhythmias, recent history of myocardial infarction, evidence of prolonged QT interval), or a history or an increased risk of seizures (e.g., those receiving drugs that lower the seizure threshold [e.g., tricyclic antidepressants], those in alcohol or benzodiazepine withdrawal, those with known or suspected hyponatremia).229,234 Electrolyte abnormalities (e.g., hypernatremia, hyperphosphatemia, hypokalemia, hypocalcemia) should be corrected prior to initiation of oral sodium phosphates therapy for bowel cleansing.229,234

Patients receiving oral sodium phosphates preparations for bowel cleansing should receive instructions on preparation for the procedure and be informed of symptoms of acute phosphate nephropathy (e.g., malaise; lethargy; drowsiness; decreased amount of urine; swelling of the ankles, feet, and legs).269,270 Patients should be advised not to exceed recommended dosages and to avoid use of additional laxatives, particularly sodium phosphate-based preparations.229,230,232,234,269 Patients also should be advised to drink sufficient quantities of clear fluids before, during, and after bowel cleansing.269

IV hydration in a hospital setting may be used to support frail patients who are unable to drink an appropriate volume of fluid or who do not have adequate assistance at home.229,230,232,234,269 The fluid intake volume necessary to minimize electrolyte abnormalities and to lower the risk of acute phosphate nephropathy is not known; furthermore, it is not known whether fluid intake should be individualized based on weight, age, gender, concomitant drug therapy, or medical conditions.232 However, some data indicate that use of an electrolyte or carbohydrate-electrolyte replacement solution may help minimize electrolyte abnormalities and hypovolemia associated with bowel cleansing with oral sodium phosphates preparations.269

The manufacturer states that sodium phosphates tablets are contraindicated in patients with biopsy-proven acute phosphate nephropathy, GI obstruction, gastric bypass or stapling surgery, bowel perforation, toxic colitis, toxic megacolon, or known hypersensitivity to sodium phosphate salts or any ingredient in the formulation.283

FDA recommends that baseline and postprocedural (e.g., postcolonoscopy) laboratory measurements, including serum concentrations of electrolytes (e.g., potassium, sodium), phosphate,231 calcium, creatinine, and BUN, be obtained in patients who may be at increased risk of acute phosphate nephropathy, including those with vomiting and/or manifestations of dehydration.230,231,232,269 FDA also recommends monitoring of the glomerular filtration rate in smaller, frail patients.269 In addition, the manufacturers of sodium phosphates tablets recommend that baseline and postprocedural laboratory measurements also be considered in patients with a history of renal impairment, history of acute phosphate nephropathy, known or suspected electrolyte disorders, seizures, arrhythmias, cardiomyopathy, prolonged QT interval, recent history of myocardial infarction, or known or suspected hyperphosphatemia, hypocalcemia, hypokalemia, or hypernatremia.229,234 In addition, baseline and postprocedural ECGs should be considered in patients at high risk of serious cardiac arrhythmias.229,234

Precautions and Contraindications Involving Use of Oral Sodium Phosphates for Occasional Constipation

When oral sodium phosphates solution is used for self-medication for the relief of occasional constipation, patients should be advised to drink sufficient quantities of fluids and should be advised not to exceed recommended dosages.235 The manufacturer states that use of oral sodium phosphates solution for self-medication of occasional constipation should be avoided in patients with a history of kidney disease or clinically important renal function impairment, congestive heart failure, decreased intravascular volume, dehydration, or uncorrected electrolyte abnormalities and in children younger than 5 years of age.235,275 Patients should be advised to consult their clinician before initiating self-medication with oral sodium phosphates solution if they are under a clinician's care for any medical condition, if their dietary sodium intake is restricted, or if they are receiving therapy with other prescription or nonprescription drugs.235

Precautions and Contraindications Involving Sodium Phosphates Enemas

Because dehydration, hypocalcemia, hyperphosphatemia, hypernatremia, hypokalemia, and acidosis may occur following administration of sodium phosphates rectal solutions, these preparations should be used with caution in patients with cardiac disease, colostomy, or preexisting electrolyte disturbances (e.g., patients receiving diuretics) and in those receiving drugs that may affect serum electrolyte concentrations (e.g., diuretics).200,203,207,210,236,237 If fluid or electrolyte disturbances occur or if sodium phosphates rectal solutions are retained, fluid and electrolyte balance should be restored promptly as necessary;200,201,202,203,204,205,206,207,208,209 serum concentrations of calcium, phosphorus, chloride, and sodium should be monitored.200,201,202,203,204,205,206,207,208,209 Children with anatomic abnormalities of the colon or with abnormal colonic motility (e.g., megacolon) appear to be at particular risk of developing marked, potentially life-threatening fluid and electrolyte disturbances and altered acid-base balance during therapy with phosphate laxatives.200,201,202,203,204,205,206,210

Sodium phosphates rectal solutions are contraindicated in patients with congestive heart failure, clinically important renal function impairment, known or suspected GI obstruction, congenital or acquired megacolon, paralytic ileus, perforation, active inflammatory bowel disease, imperforate anus, dehydration, or increased absorption capacity or decreased elimination capacity; sodium phosphates rectal solutions also are contraindicated in children younger than 2 years of age and patients with known hypersensitivity to sodium phosphate salts or any ingredient in the formulation.200,203,205,236,237,281

The manufacturer states that patients should be advised to consult their clinician before initiating self-medication with sodium phosphates rectal solutions for the relief of occasional constipation if they have kidney disease or if their dietary sodium intake is restricted.236,237 Recommended dosages of sodium phosphates rectal solutions should not be exceeded.236,237

Stimulant Laxatives !!navigator!!

In therapeutic oral doses, all stimulant laxatives may produce some degree of abdominal discomfort, nausea, mild cramps, griping, and/or faintness. Rectal administration of bisacodyl suspensions or suppositories may cause irritation and a sensation of burning of the rectal mucosa and mild proctitis. Some clinicians state that stimulant laxative suppositories or enemas should not be used in patients with abdominal cramps, anal or rectal fissures, or ulcerated hemorrhoids. Aloe (preparations containing aloe extract or aloe flower extract are no longer commercially available in the US), aloin, and castor oil reportedly cause excessive irritation of the colon, and violent purgation usually accompanies administration of therapeutic doses. Castor oil may rarely cause pelvic congestion.

With long-term use or overdosage of stimulant laxatives, electrolyte disturbances including hypokalemia, hypocalcemia, metabolic acidosis or alkalosis, abdominal pain, diarrhea, malabsorption, weight loss, and protein-losing enteropathy may occur. Electrolyte disturbances may produce vomiting and muscle weakness; rarely, osteomalacia, secondary aldosteronism, and tetany may occur. Pathologic changes including structural damage to the myenteric plexus, severe and permanent interference with colonic motility, and hypertrophy of the muscularis mucosae may occur with chronic use. “Cathartic colon” with atony and dilation of the colon, especially of the right side, has occurred with habitual use (often for several years) and often resembles ulcerative colitis.

Anthraquinone laxatives may discolor colonic mucosa (melanosis coli), but this adverse effect is usually innocuous and reversible. Anthraquinones also produce a pink to red or brown to black discoloration of the urine; phenolphthalein (laxatives containing phenolphthalein are no longer commercially available in the US) colors alkaline urine pink to red. The diphenylmethane and anthraquinone laxatives may be distributed into the milk of nursing women but usually in amounts insufficient to produce a laxative effect. Although specific evidence of carcinogenic potential in humans is not available, danthron-containing preparations were withdrawn from the US market in 1987 because mice and rats developed intestinal and hepatic tumors following chronic administration of high dosages of the laxative. In addition, danthron and other anthraquinone laxatives have been shown to be mutagenic in some in vitro studies.225

Phenolphthalein and dehydrocholic acid rarely have produced hypersensitivity reactions. Phenolphthalein allergy often has been manifested by dermal reactions including polychromatic, fixed skin eruptions with macules and nonspecific rashes, itching, burning, and pigmentation that may last for several months. Phenolphthalein allergy also has produced renal irritation, encephalitis, cardiac arrest, respiratory disturbances, and, rarely, death.

Current evidence indicates that phenolphthalein is potentially genotoxic and carcinogenic in humans.225 FDA reached this conclusion after reviewing animal data demonstrating carcinogenic activity of the drug in rodents and subsequent data indicating that the mechanism of this activity probably was secondary to a genotoxic effect.225 Drug exposures used in the in vivo and in vitro studies showing the carcinogenic and genotoxic effects of phenolphthalein were in the range of those that could occur with human laxative use.225 These findings indicate that chronic use of the drug could result in damage to the human genome (including p53, which is known to be a tumor suppressor gene) and could increase the risk of malignancy; some human cancers have been associated with alterations of the p53 gene.225 As a result, all preparations containing phenolphthalein for self-medication (over-the-counter [OTC] use) are no longer generally recognized as safe and effective.225,227 Therefore, US manufacturers have reformulated phenolphthalein-containing preparations to include other laxatives.225,227

As part of its ongoing review of OTC drug products, the FDA has determined that existing data are insufficient to establish safety and efficacy of aloe and cascara sagrada as stimulant laxatives.228 This determination was made after no comments or data were submitted in response to the FDA's request for mutagenicity, genotoxicity, and carcinogenicity data on these agents.228 Therefore, any OTC drug product containing laxative ingredients derived from aloe (i.e., aloe extract, aloe flower extract) or cascara sagrada (i.e., casanthranol, cascara fluidextract aromatic, or cascara sagrada bark, extract, or fluidextract) is considered by the FDA to be misbranded.228 Effective November 5, 2002, any such OTC drug product introduced or initially delivered for introduction into interstate commerce is considered to be misbranded, and manufacturers are required to reformulate preparations containing aloe or cascara sagrada to delete and/or replace these ingredients.228 In addition, previously marketed OTC products containing aloe or cascara sagrada may not be repackaged or relabeled after this date.228

Hepatotoxicity may result if sufficient tannic acid is absorbed from bisacodyl tannex laxatives. Bisacodyl tannex should be used with caution, if at all, in patients receiving multiple enemas or in those with extensive ulceration of the colon since increased tannic acid absorption may occur.

In general, use of stimulant laxatives should be avoided in children younger than 6-10 years of age. Because the possibility of tannic acid absorption has not been studied adequately in children younger than 10 years of age, bisacodyl tannex is contraindicated in these patients. Castor oil is contraindicated in pregnant or menstruating women. Safe use of bisacodyl tannex during pregnancy has not been established.

Stool Softeners !!navigator!!

Adverse effects associated with the use of stool softeners are rare. Occasionally, mild, transitory GI cramping pains or rashes may occur. Irritation of the throat has occurred following oral administration of docusate sodium solutions. In one study, docusate sodium was found to be toxic to hepatic cells in vitro.

Drug Interactions

By increasing intestinal motility, all laxatives may potentially decrease transit time of concomitantly administered oral drugs and thereby decrease their absorption.

Mineral oil may impair absorption of many orally administered drugs including fat-soluble vitamins (i.e., vitamins A, D, E, and K), carotene, oral contraceptives, and coumarin and indandione derivative anticoagulants. By mixing with nonabsorbable sulfonamides (e.g., phthalylsulfathiazole) in the feces, mineral oil may interfere with antibacterial activity of these drugs. Patients receiving any of these drugs should be discouraged from ingesting more than therapeutic amounts of mineral oil and from taking these drugs concurrently with mineral oil.

Stool softeners (i.e., docusate salts) theoretically may enhance the absorption of many orally administered drugs. Docusate sodium increases the extent of mineral oil absorption and the rate of phenolphthalein (laxatives containing phenolphthalein are no longer commercially available in the US) absorption. Greater intestinal mucosal damage has reportedly occurred following concomitant administration of aspirin and docusate sodium than occurs with aspirin alone. Oral stool softeners should not be administered concurrently with oral mineral oil, and some clinicians recommend that stool softeners not be administered concurrently with any oral drugs having low therapeutic indices.

Magnesium hydroxide, in antacid preparations also containing aluminum hydroxide, has been shown to decrease the rate and extent of chlordiazepoxide, chlorpromazine, dicumarol, digoxin, and isoniazid absorption. The effect of magnesium hydroxide laxative preparations on drug bioavailability is not known.

Cellulose binds orally administered digitalis, nitrofurantoin, and salicylates in the GI tract. Although the clinical importance of these interactions has not been determined for other cellulose derivatives such as methylcellulose, patients taking bulk-forming laxatives concurrently with digitalis, nitrofurantoin, or salicylates should consult their physician or pharmacist before initiating or discontinuing use of these laxatives. Some clinicians recommend that bulk-forming laxatives be administered at least 3 hours after or before administration of these drugs.

Several manufacturers of polyethylene glycol 3350 electrolyte solution suggest that other oral drugs should be administered at least 1 hour before polyethylene glycol 3350 electrolyte solutions.245,246,247,248,252,253

Other Information

[Section Outline]

General

Cathartic, laxative, and purgative are terms describing drugs that promote evacuation of the intestine; the difference between the terms is largely one of degree. Cathartic and purgative are interchangeable terms describing drugs that promote rapid evacuation of the intestine and noticeable alteration of stool consistency. The evacuant action of a laxative is less pronounced, but large doses of a laxative may produce catharsis or purgation. Cathartic, laxative, and purgative drugs will be referred to as laxatives.

Laxatives are usually subdivided into several categories, including the bulk-forming, hyperosmotic, lubricant, saline, and stimulant laxatives and the stool softeners. The bulk-forming laxatives include cellulose derivatives, karaya, malt soup extract, psyllium preparations, and dietary bran. Glycerin, sorbitol, and polyethylene glycol are commonly termed hyperosmotic laxatives. Mineral oil is a lubricant laxative. Laxatives containing magnesium cations or phosphate anions are commonly termed saline laxatives. Anthraquinone laxatives (aloe [preparations containing aloe are no longer commercially available in the US], cascara sagrada [preparations containing cascara sagrada are no longer commercially available in the US], senna), the diphenylmethane derivatives (bisacodyl, phenolphthalein [preparations containing phenolphthalein are no longer commercially available in the US]), castor oil, and dehydrocholic acid are stimulant laxatives. The stool softeners include the calcium, potassium, and sodium salts of docusate.

Laboratory Test Interferences

By discoloring the urine, anthraquinone laxatives and phenolphthalein (laxatives containing phenolphthalein are no longer commercially available in the US) may produce an apparent increase in the urinary excretion of phenolsulfonphthalein (PSP). These laxatives may also give false-positive test results for urinary urobilinogen and for estrogens when measured by the Kober procedure.

Pharmacology

The precise mechanisms of action of the laxatives are not known. Recent evidence indicates that the actions of the various laxatives may be pharmacologically similar but dose dependent and that most laxatives promote defecation by altering intestinal fluid and electrolyte transport. Active ion secretion stimulated by most laxatives may be the driving force for intestinal fluid accumulation and subsequent defecation.

Bulk-forming Laxatives !!navigator!!

Bulk-forming laxatives dissolve or swell in water to form an emollient gel or viscous solution. It is thought that the resulting bulk in the feces promotes peristalsis and reduces transit time. Reductions in fecal pH and in serum cholesterol, and altered composition of fecal bile acids have been observed following administration of some bulk-forming laxatives; some pharmacologists believe these actions may also contribute to the laxative effect of some of these drugs.

Hyperosmotic Laxatives !!navigator!!

When administered rectally, glycerin and sorbitol exert a hygroscopic and/or local irritant action, drawing water from the tissues into the feces and reflexly stimulating evacuation. The extent to which the simple physical distention of the rectum and the hygroscopic and/or local irritant actions are responsible for the laxative effects of some of these drugs is not known. Only extremely high oral doses of sorbitol (25 g daily) or glycerin exert laxative action.

Polyethylene glycol 3350 electrolyte solution is a nonabsorbable solution that passes through the bowel without net absorption or secretion; therefore, substantial fluid and electrolyte shifts are avoided.245,246,247,248,251,253,259 Polyethylene glycol 3350 electrolyte solution osmotically increases intraluminal fluids to induce diarrhea and rapidly cleanse the bowel.245,246,247,248,250

Mineral Oil !!navigator!!

Oral mineral oil appears to lubricate fecal material and the intestinal mucosa by retarding reabsorption of water from the intestinal tract. Increased water retention may secondarily increase the bulk of the stool and hasten evacuation. Mineral oil emulsion reportedly has better wetting properties than does nonemulsified mineral oil and penetration of the feces thus may be enhanced. Rectal enemas of heavy or light mineral oil exert laxative action via a lubricant effect and/or simple physical distention of the rectum.

Saline Laxatives !!navigator!!

It is commonly believed that the action of the saline laxatives results from the hyperosmotic effect of poorly absorbed magnesium or phosphate ions within the small intestine and from the retention of water which indirectly stimulates stretch receptors and increases peristalsis. These mechanisms of action are unproven, and conversely, it has been noted that isosmolarity is present at the ligament of Treitz following ingestion of hyperosmolar meals. The laxative action of magnesium also may be the result of cholecystokinin release or decreased transit time. The effectiveness of phosphate enemas may simply reflect the volume of liquid introduced rectally.

Orally administered saline laxatives act mainly on the small intestine. Saline suppositories or enemas generally promote evacuation of the colon only.

The amount of sodium biphosphate in rectal suppositories containing sodium acid pyrophosphate, sodium bicarbonate, and sodium biphosphate is probably insufficient to exert an effect as a saline laxative, but it is included to facilitate the chemical reaction that produces carbon dioxide (CO2). Rectal suppositories containing potassium bitartrate and sodium bicarbonate also produce CO2. The expanding CO2 promotes laxation by exerting pressure in the rectum.

Stimulant Laxatives !!navigator!!

It has commonly been thought that the stimulant laxatives induce defecation by stimulating propulsive peristaltic activity of the intestine through local irritation of the mucosa or through a more selective action on the intramural nerve plexus of intestinal smooth muscle, thus increasing motility. However, recent studies show that these drugs alter fluid and electrolyte absorption, producing net intestinal fluid accumulation and laxation. Some of these drugs may directly stimulate active intestinal ion secretion. Increased concentrations of cyclic 3',5'-adenosine monophosphate (cAMP), occurring in colonic mucosal cells following administration of stimulant laxatives, may alter the permeability of these cells and mediate active ion secretion thereby producing net fluid accumulation and laxative action.

Stimulant laxatives mainly promote evacuation of the colon; however, castor oil and phenolphthalein (laxatives containing phenolphthalein are no longer commercially available in the US) also directly or reflexly increase activity of the small intestine. Rectal suppositories of some stimulant laxatives reportedly promote laxation by physical distention of the rectum.

With the exception of aloe (preparations containing aloe extract or aloe flower extract are no longer commercially available in the US) and aloin which are reportedly very irritating, the anthraquinone laxatives are considered to be the mild laxatives in the stimulant category. The laxative action of dehydrocholic acid also appears to be relatively mild. The diphenylmethanes have a more pronounced laxative effect. Castor oil produces violent purgation in therapeutic doses.

Stool Softeners !!navigator!!

In vitro studies suggest that the stool softeners soften fecal material and ease defecation by lowering surface tension at the oil-water interface of fecal material, permitting water and lipids to penetrate. Recent in vivo evidence suggests that the laxative properties of these drugs may result from stimulation of electrolyte and water secretion in the colon. Increased concentrations of cAMP, occurring in colonic mucosal cells following administration of these drugs, may alter the permeability of these cells and mediate active ion secretion thereby producing net fluid accumulation and laxative action.

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions October 12, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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