Drug Interactions between amitriptyline / chlordiazepoxide and bisacodyl / polyethylene glycol 3350 / potassium chloride / sodium bicarbonate / sodium chloride

CONTRAINDICATED: The following interaction does not apply to all products containing potassium chloride, including split dose products used for colon preparation prior to colonoscopy. It is applicable to certain oral solid formulations of potassium chloride used primarily for potassium supplementation, and the prescriber should consult the individual product labeling for more specific information and guidance.

Concomitant use of agents with anticholinergic properties (e.g., antihistamines, antispasmodics, neuroleptics, phenothiazines, skeletal muscle relaxants, tricyclic antidepressants, the class IA antiarrhythmic disopyramide) may potentiate the risk of upper gastrointestinal injury associated with oral solid formulations of potassium chloride. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents, thereby creating a high localized concentration of potassium ions in the region of a dissolving tablet or capsule and increasing the contact time with GI mucosa. Solid formulations of potassium chloride have been associated with upper GI bleeding and small bowel ulceration, stenosis, perforation, and obstruction. Deaths have been reported rarely. In clinical studies, short-term coadministration of wax-matrix or microencapsulated formulations of potassium chloride at high dosages in combination with an anticholinergic agent such as glycopyrrolate resulted in more frequent and more serious endoscopic lesions than potassium therapy alone. However, the lesions were not accompanied by bleeding or epigastric symptoms. Some investigators have suggested a higher risk of upper GI lesions with wax-matrix than microencapsulated formulations, although existing data are limited and conflicting.

MANAGEMENT: The use of certain oral solid formulations of potassium chloride is considered contraindicated in patients receiving agents with anticholinergic properties at sufficient doses to exert anticholinergic effects. A liquid formulation of potassium chloride should be considered. Patients prescribed a solid oral formulation should be advised to discontinue potassium therapy and contact their physician if they experience potential symptoms of upper GI injury such as severe vomiting, abdominal pain, distention, and gastrointestinal bleeding.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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ADJUST DOSING INTERVAL: By increasing gastric pH, antacids may reduce the resistance of the enteric coating of bisacodyl tablets, resulting in earlier release of bisacodyl and gastric irritation and dyspepsia.

MANAGEMENT: The administration of antacids and bisacodyl should be separated by at least one hour.

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GENERALLY AVOID: Concomitant use of stimulant laxatives (e.g., bisacodyl, sodium picosulfate) may increase the risk of serious gastrointestinal adverse effects associated with certain osmotic laxatives (e.g., polyethylene glycol (PEG), oral sulfate solution), such as colonic mucosal ulcerations or ischemic colitis. There have been isolated case reports of ischemic colitis occurring with the use of PEG-based bowel cleansing products in combination with higher dosages of bisacodyl (usually greater than 10 mg). Bisacodyl can cause colonic ischemia due to transient reduction in splanchnic blood flow. When administered in conjunction with an osmotic laxative such as PEG, increased intramural pressure secondary to increased peristalsis may lead to ischemic colitis and perforation.

MANAGEMENT: The manufacturers for some osmotic bowel cleansing products recommend avoiding the concurrent use of stimulant laxatives. However, stimulant laxatives, in particular bisacodyl and sodium picosulfate, are sometimes used with PEG in certain bowel cleansing regimens to help reduce dose volume and improve patient tolerability and acceptance. Please consult individual product labeling for specific recommendations and guidance. Patients using osmotic bowel cleansing products and stimulant laxatives who present with sudden abdominal pain, rectal bleeding, or other symptoms of ischemic colitis should be evaluated promptly.

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A number of studies have reported that antacids can delay the gastrointestinal absorption and reduce the peak plasma concentration (Cmax) of some benzodiazepines, including clorazepate, chlordiazepoxide and diazepam, although the overall extent of absorption is generally not affected. The exact mechanism of interaction is unknown, but may involve delayed gastric emptying or cation binding of the benzodiazepine. As a result, benzodiazepine onset of action may be delayed and clinical effects diminished. However, one study reported a significant increase in diazepam absorption during coadministration with aluminum hydroxide, and there was a marginal increase in the onset of sedative effect. Aluminum hydroxide also increased triazolam Cmax and systemic exposure (AUC) in 11 dialysis patients such that their drug levels reached into the range observed for the matched controls. In contrast, another study by the same group of investigators found no significant effect of aluminum hydroxide on temazepam absorption or Cmax in 11 patients with end-stage renal disease. A multi-dose study also failed to find an effect of antacids on the steady-state levels of N-desmethyldiazepam, the active metabolite of clorazepate, although an acidic environment is thought to be necessary for the rapid conversion. Based on available data, the clinical significance of this interaction appears to be minor. As a precaution, patients may consider separating the administration times of benzodiazepines and antacids or other oral medications that contain antacids (e.g., didanosine buffered tablets or pediatric oral solution) by 2 to 3 hours.

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