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Janssen to Withdraw Cisapride from General Access

Cheryl A. Thompson

Continued inappropriate use of cisapride, or Propulsid, has prompted Janssen Pharmaceutica to stop distributing the prokinetic agent in the United States as of July 14, giving health care providers 16 weeks to convert patients to alternative treatments. A limited-access program, with eligibility criteria to be developed by the company and the Food and Drug Administration (FDA), will enable certain patients to continue using the drug.

Over the past few years, the labeling for cisapride has more strongly warned health care providers of the drug's potential to cause serious cardiovascular problems in patients taking certain other medications or having specific underlying health conditions. A strengthened warning about cisapride use was issued two months ago. 

FDA urges patients with cisapride prescriptions to promptly contact their health care providers to discuss alternative treatments. 

Central to this discussion is the reason why the patient has a prescription for the drug. Although cisapride was approved by the FDA for the treatment of adults complaining of nighttime heartburn related to gastroesophageal reflux disease (GERD), the drug is probably used for conditions not mentioned in the package insert. FDA notified Janssen in 1998 that some of the company's promotional brochures implied the drug assisted with esophageal clearance, increased lower esophageal sphincter tone, and promoted gastric emptying. 

Pharmacy professor Rosemary R. Berardi, Pharm.D., FASHP, of the University of Michigan, Ann Arbor, identified four groups of cisapride-taking adults who should be considered: 

  • Adults with GERD who need a "prokinetic" or "promotility" agent,"   
  • Adults with gastroparesis,   
  • Adults who have nighttime heartburn caused by GERD, and   
  • Adults with severe refractory constipation or severe constipation caused by irritable bowel syndrome (IBS).

Berardi, a member of the FDA Gastrointestinal Drugs Advisory Committee, said that the drug, despite its faults, had a legitimate place in the therapy of GERD when maximum dosages of proton-pump inhibitors (PPIs) provided inadequate relief or when patients had an underlying motility problem, such as gastroparesis. 

For patients with GERD who need a prokinetic or promotility agent, Berardi suggested health care providers first "try to maximize the PPI therapy." Increase the dosage to the maximum daily amount stated in the package insert, and divide that maximum dose into smaller portions to be taken at various times during the day. If that approach does not work well, Berardi suggested having patients try a short course of metoclopramide, a drug with a chemical structure similar to cisapride's. 

Metoclopramide, however, comes with its own problems. Any patient, particularly an elderly patient or someone whose renal function is not optimal, who takes metoclopramide "should be closely monitored for side effects of that drug," Berardi said. "It can really impair the [patient's] quality of life." Metoclopramide has a track record for causing depression, drowsiness, and extrapyramidal symptoms, such as muscle tremors. 

If the trial course of metoclopramide does not work or if patients cannot tolerate the drug, Berardi suggested that health care providers contact Janssen about obtaining cisapride through the limited-access program. 

A trial of metoclopramide therapy should also be attempted with patients who have gastroparesis, Berardi said. Besides the drug's adverse effects, however, these patients and their health care providers should watch for signs of tachyphylaxis. In cases of tachyphylaxis, patients must take increasingly higher dosages of the drug to obtain the same benefits as before but, in doing so, increase the risk for adverse effects. 

If metoclopramide therapy does not work out well for patients with gastroparesis, Berardi said, health care providers should consider the limited-access program for cisapride or therapy with erythromycin, which stimulates gastrointestinal motility. This latter option comes with the hazards from long-term antimicrobial use, she added. 

There seems to be two first-choice options for patients with nighttime heartburn caused by GERD. Berardi suggested use of a PPI. Pharmacy professor Donald R. Miller, Pharm.D., FASHP, of North Dakota State University, Fargo, suggested metoclopramide, cautioning that the extrapyramidal symptoms "would be problematic for older people." 

Patients who use cisapride to treat severe refractory or IBS-related constipation should try using agents specific for constipation, Berardi said. 

Miller suggested the following initial dosages for metoclopramide therapy: 10 mg four times a day; or, for older patients, 5 mg four times a day. Berardi added that the dosage should be 5 mg three or four times a day for patients whose renal function is not optimal. 

Physicians will receive information about the limited-access program in April, Janssen said. Enrollment will start May 1. Supplies of cisapride tablets and suspension will remain in pharmacies until mid-August, the company said. 

Berardi urged pharmacists to take on an advocacy role and, with patients' consent, encourage physicians to request access to cisapride when alternative treatments do not produce desired results. "There are clearly situations where benefit outweighs risk with this drug," she said.

[ASHP posted an update about cisapride in April, 2000.]