The History and Withdrawal of Cisapride
Cisapride, once a widely used prokinetic agent sold under the brand name Propulsid®, was initially approved by the U.S. Food and Drug Administration (FDA) in 1993 to treat nocturnal heartburn caused by gastroesophageal reflux disease (GERD). Its mechanism of action involved increasing gastrointestinal motility, helping to move food more efficiently through the digestive tract. Beyond GERD, it was also used to manage conditions like gastroparesis and chronic intestinal pseudo-obstruction. For several years, it was considered a successful treatment, with millions of patients receiving it.
However, a concerning pattern of adverse events began to emerge. The FDA and Janssen Pharmaceutica started receiving reports of serious heart rhythm abnormalities, including ventricular fibrillation, Torsades de Pointes, and QT interval prolongation. A significant number of these events were fatal. After issuing a "black box" warning in 1998, the manufacturer, in consultation with the FDA, made the decision to voluntarily withdraw cisapride from the U.S. market in July 2000.
The Critical Dangers and Limited Access
The primary reason for cisapride's withdrawal was its effect on the electrical activity of the heart. The drug can block cardiac potassium channels, specifically the human ether-a-go-go-related gene (hERG channels), which prolongs the QT interval on an electrocardiogram (ECG). A prolonged QT interval can lead to dangerous, life-threatening ventricular arrhythmias, especially a condition called Torsades de Pointes.
Who is at risk?
Patients with the following conditions were found to be at particularly high risk for these cardiac events when taking cisapride:
- Pre-existing heart disease, including ventricular arrhythmias or ischemic heart disease
- Congenital long QT syndrome
- Uncorrected electrolyte imbalances, such as hypokalemia or hypomagnesemia
- Significant bradycardia
- Severe dehydration, malnutrition, or eating disorders
- Concomitant use of drugs that inhibit the CYP3A4 liver enzyme or are known to prolong the QT interval
The Compassionate Use Program
Today, cisapride is no longer commercially available for widespread use. In the United States, it is only obtainable through a strictly controlled, limited-access or compassionate-use program managed by the manufacturer, Janssen Pharmaceutica. Patients must meet specific, rigorous clinical eligibility criteria and require close medical supervision and monitoring.
How to take cisapride under limited access
For the select patients in the compassionate use program, strict adherence to the prescribing protocol is mandatory:
- Administration: Cisapride is taken orally, typically as a tablet or liquid suspension.
- Timing: It is usually taken before meals and at bedtime.
- Dosage: The prescribed amount should never be exceeded.
- Monitoring: A baseline 12-lead ECG is required before starting treatment, and the drug should not be administered if the QTc interval is prolonged (>450 milliseconds). Regular monitoring of serum electrolytes (potassium, calcium, magnesium) is also required.
- Drug Interactions: It is strictly contraindicated with numerous other medications. A comprehensive list of disallowed drugs is reviewed as part of the program.
- Food Interactions: Grapefruit juice is known to increase cisapride's blood levels, significantly raising the risk of cardiac events, and must be avoided.
Cisapride vs. Modern Alternatives
| Feature | Cisapride (Propulsid®) | Modern Alternatives (e.g., PPIs, other prokinetics) |
|---|---|---|
| Availability | Only via a highly restricted compassionate-use program | Widely available via standard prescription |
| Cardiac Risk | Known to cause fatal heart arrhythmias (QT prolongation, Torsades de Pointes) | Not associated with the same severe cardiac risks |
| Mechanism of Action | Increases GI motility by stimulating acetylcholine release | Varies; e.g., Proton Pump Inhibitors (PPIs) block acid production; others stimulate motility differently |
| Monitoring Required | Extensive cardiac and electrolyte monitoring is mandatory | Routine monitoring, but not typically intensive cardiac monitoring for these risks |
| Primary Use (Historical) | Nocturnal heartburn, gastroparesis | GERD, peptic ulcers, and various motility disorders |
| Drug Interactions | Numerous, including macrolide antibiotics, antifungals, and antidepressants | Fewer life-threatening interactions of this type, but still requires consideration with other medications |
Veterinary Use of Cisapride
It is important to note that cisapride continues to be used in veterinary medicine, particularly for dogs and cats with gastrointestinal motility issues, such as megacolon in cats. The serious cardiac side effects observed in humans have not been seen in pets. This medication is obtained through compounding pharmacies, as it is not FDA-approved for animals. Pet owners must follow their veterinarian's instructions carefully and understand the difference between human and veterinary use.
Conclusion
While cisapride was once a common treatment for gastrointestinal disorders, its association with serious, and sometimes fatal, cardiac arrhythmias led to its withdrawal from the general market in 2000. Consequently, the question of how to take cisapride is relevant only to a very small, medically supervised group of patients on a compassionate-use protocol. For all other patients, safer and more modern alternatives are available. The history of this drug serves as a stark reminder of the critical importance of patient safety, drug interaction awareness, and close medical supervision when using potent medications.
Disclaimer: The information provided is for educational purposes only and is not medical advice. Consult a healthcare professional for diagnosis and treatment.
