Cisapride Withdrawal Requires
`Alternative Therapy
`
`Volume III, Number 2 | May/June 2000
`Jodie M. Zalewski, Pharm.D.
`
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`Introduction
`
`Janssen Pharmaceutica, in consultation with the FDA, has decided to stop marketing the prokinetic agent cisapride (Propulsid®) on July 14, 2000 due to the risk of serious cardiac arrhythmias and death associated with this agent. It is well recognized that
`cisapride can prolong the QT interval and lead to a lethal arrhythmia (torsade de pointes), especially when administered to patients at high risk for such an arrhythmia. High risk patients include those with underlying QT prolongation (e.g., congenital or drug-
`induced) and those with electrolyte disturbances.
`Availability
`
`Cisapride will be available only by an investigational limited access program for patients meeting strict inclusion criteria. Only certified physicians will be able to enroll patients into such protocols. Adult patients eligible for the program include those receiving
`cisapride for the management of gastroesophageal reflux disease (GERD), gastroparesis, intestinal pseudo-obstruction, or severe chronic constipation. Other protocols exist for pediatric patients and neonates.
`Alternative Agents
`
`The withdrawal of cisapride leaves medical professionals with the task of prescribing a ppropriate alternative therapy for patients. Treatment must be individualized to each patient's condition. Agents other than prokinetic agents (e.g., proton pump inhibitors)
`may be appropriate in certain situations. Table 1 summarizes alternative prokinetic agents.
`
`Table 1: Alternative Prokinetic Agents
`Drug and Usual
`Adult Dose
`Metoclopramide
`(Reglan®)
`
`10 mg IV or PO
`QID,
`before meals & at
`bedtime
`
`Bethanechol
`(Urecholine®)
`
`25 mg PO QID
`
`Erythromycin
`
`Ethylsuccinate:
`250 mg PO TID,
`before meals
`Lactobionate:
`200 mg IV TID,
`before meals
`
`Mechanism of Action
`
`Adverse Effects
`
`Comments
`
`• Dopamine receptor antagonist & cholinergic stimulant
`• Stimulates motility of upper GI
` tract
`• Increases gastric contractions
`• Increases gastric emptying and
` intestinal transit time
`• Enhances LES pressure
`• Blocks stimulation of CTZ
`
`EPS
`Depression
`Anxiety
`Drowsiness
`Galactorrhea
`Amenorrhea
`Gynecomastia
`
`• Cholinergic agent
`• Stimulants GI smooth muscle contraction
`• Does not improve peristalsis
`• Does not enhance GI transit
`
`• Mimics the effects of motilin on GI smooth muscle
`• Stimulates gastric emtying
`• May enhance esophageal contractions
`• May increase LES pressure
`
`Abdominal
`cramps
`Diarrhea
`Urinary fre-
`quency
`Nausea
`Vomiting
`Headache Hypertension
`Blurred vision
`
`Nausea
`GI upset
`
`• Crosses the BBB, increasing risk of CNS side effects.
`• Higher risk of side effects in elderly due to reduced drug clearance.
`• Primarily renally eliminated; adjust dose in renal insufficiency (if CrCl < 50 ml/min,
`recommend
` half of usual dose).
`• May exacerbate Parkinson's disease
`symptoms and diminish effectiveness of dopamine agonists such as levodopa.
`
`• Motor stimulant rather than prokinetic agent.
`• Use is limited by side effects.
`• May be added to metoclopramide (when side effects limit metoclopramide dose).
`
`
`
`
`
`• Clinically ineffective for GERD.
`• Used for treatment of diabetic gastroparesis.
`• Monitor for drug interactions.
`• May increase risk of antibiotic resistance development.
`• Only macrolide currently used for its
`prokinetic properties.
`
`BBB Blood brain barrier; CrCl Creatinine clearances; CNS Central nervous system; CTZ Chemo-receptor trigger zone; EPS Extrapyramidal symptoms;
`GERD Gastroesophageal reflux disease; GI Gastrointestinal;
`LES Lower esophageal sphincter
`
`Effectiveness of Alternative Agents
`
`Of the alternative prokinetic agents, metoclopramide is used most often due to its proven efficacy. However, metoclopramide must be used with caution in patients with decreased renal function, including the elderly, because of increased central nervous
`system side effects. The use of bethanechol is limited by cholinergic side effects. Erythromycin has been used for diabetic gastroparesis, but it is not clinically effective in the management of GERD. While the intravenous preparation of domperidone was
`withdrawn from the market due to reports of adverse cardiovascular effects, oral domperidone (not available in the United States) may be a future option based on efficacy data and safety profile.
`Conclusion
`
`When choosing an agent to replace cisapride, therapy must be patient specific. Health care professionals must weigh risks (e.g., side effects, drug interactions) versus benefits when initiating alternative therapy.
`
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