P&T News: March/April 2000

Cisapride: Review of the Investigational Limited Access Program

Kathryn A. Miller, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Joel V. Weinstock, M.D., Division Head, Department of Gastroenterology-Hepatology

Janssen Pharmaceutica, Inc., has announced that it will stop marketing cisapride (Propulsid®) in the U.S. as of July 14, 2000. A prokinetic agent, cisapride is FDA-labeled as a treatment for severe nighttime heartburn in patients with gastroesophageal reflux disease (GERD) who do not adequately respond to other therapies.1 Roughly 30 million patients have taken cisapride since it came on the market, although only about 300,000 people take the drug today.2 Cisapride will continue to be marketed until mid-July in order to give patients and prescribers time to switch to alternative therapies. An investigational limited-access program will be initiated for cisapride tablets and suspension starting May 1, 2000. Under the new program, cisapride will remain available to appropriate patients for whom other therapies are not effective and who meet clearly defined eligibility criteria.

History
Cisapride was approved by the Food and Drug Administration (FDA) in 1993 for patients with heartburn. It is also prescribed for various other disease states such as gastroparesis, dyspepsia, Barrett's esophagus, constipation, Parkinson's disease and excessive regurgitation in infants. Within a year of its approval, the FDA began receiving reports of injuries and deaths in patients receiving cisapride. Serious adverse reactions, including heart rhythm disorders and deaths, were associated mostly with the use of the drug in people taking certain other medications or who had particular underlying medical conditions. The agency revealed that from 1993 to 1998 there were 38 reports of death in patients receiving cisapride in the U.S.; however, the agency was unable to directly link reported deaths to the drug.3 The package labeling was revised to state that "cisapride generally should be reserved for patients who do not adequately respond to lifestyle modifications, antacids, and gastric acid-reducing agents." 4 In June 1999, Janssen Pharmaceutica detailed labeling changes concerning new contraindications and additional drug interaction warnings with cisapride.5 As of December 31, 1999, cisapride has been associated with 341 reports of heart rhythm abnormalities, including 80 deaths.1 A recent analysis of 270 of these adverse event reports (including 70 fatalities) reveals that approximately 85% of these cases occurred in patients with known risk factors.1 In January 2000, the FDA issued stronger warnings to emphasize the original warning and to reiterate that the drug not be given to patients with cardiac arrhythmias or other cardiovascular irregularities.6 On March 23, 2000, Janssen announced that cisapride would no longer be marketed in the U.S.

Labeling Changes
Since its approval in 1993, cisapride's labeling has been revised several times to inform health care professionals and patients about the drug's risks. The most recent changes in January 2000 include some of the following:

1. A 12-lead ECG should be obtained before cisapride is administered.

2. Cisapride is contraindicated in patients with electrolyte disorders (hypokalemia, hypocalcemia and hypomagnesmia) due to:

Also, serum electrolytes should be assessed in diuretic-treated patients before initiating cisapride and periodically thereafter.

3. Cisapride is contraindicated in patients with disorders that may predispose them to arrhythmias:

4. Numerous drug classes and agents increase the risk of developing serious cardiac arrhythmias. Cisapride should not be used by patients taking drugs that may inhibit the metabolism of cisapride or drugs known to prolong the QT interval - See Table 1.

5. The minimum effective dose should be used, and recommended doses should not be exceeded.

6. Cisapride should be discontinued if relief of nocturnal heartburn does not improve within four to six weeks.

Despite these risk management efforts, Janssen Pharmaceutica, in consultation with the FDA, decided that continued general U.S. prescription access to cisapride posed unacceptable risks and would no longer be marketed in the U.S. However, cisapride will remain available to appropriate patients for whom other therapies are not effective and who meet clearly defined eligibility criteria under a new investigational limited-access program. These criteria have been established in close collaboration with the FDA.

Table 1. Drugs That May Interact with Cisapride

 

Antibiotics

ClarithromycinY
ErythromycinY
MetronidazoleY
GrepafloxacinY **
TroleandomycinY D

Antifungals

FluconazoleY
ItraconazoleY
KetoconazoleY
Miconazole¨

Antidepressants

Amitriptyline**
Maprotiline**
NefazodoneY
Desipramine**
FluoxetineY
FluvoxamineY
Imipramine**
SertralineY

Calcium channel blockers

Bepridil**
DiltiazemY
MibefradilY D

 

Antiarrhythmics

Bepridil**
Procainamide**
Quinidine**
Sotalol**
AmiodaroneY **
Disopyramide**
Flecainide**
Mexiletine**
Propafenone**

Antineoplastic agents

Cyclophosphamide**¨
Docetaxel**Y
Etoposide¨
Ifosfamide**Y
Flutamide¨
Paclitaxel**Y
Tamoxifen¨
Tretinoin**
Vinblastine¨
Vincristine¨
Vinorelbine¨

 

Antipsychotic drugs

Thioridazine**
Pimozide**

Antihistamines

AstemizoleY D
TerfenadineY D

Hypolipidemic agents

Lovastatin¨
Pravastatin¨

Immunosuppressive agents

Cyclosporine¨
Tacrolimus¨

HIV protease inhibitors

IndinavirY
RitonavirY
NelfinavirY
SaquinavirY

Miscellaneous

QuinineY
ZafirlukastY
Zileuton¨

Manufacturer recommendations for contraindications are in bold and italics
** Use with caution due to potential additive effects on QT interval
Y P450 3A4 Isoenzyme: Inhibitors
¨ P450 3A4 Isoenzyme: Substrates
D No longer on the market in the United States

Criteria for the Investigational Limited-Access Program

Information on the investigational limited-access program will be sent to physicians in April, and patient enrollment will begin May 1, 2000. However, to assure that the medication is available to patients during the transition, distribution will continue until July 14, 2000, and cisapride will remain in pharmacies until mid-August. The following are the three treatment protocols for the investigational limited access program:

Adults: gastroesophageal reflux disease (GERD), gastroparesis, pseudo-obstruction, and severe chronic constipation
Pediatrics: refractory GERD (associated with failure to thrive, asthma, bradycardia, apnea, or other serious conditions) or pseudo-obstruction
Neonates: feeding intolerance

In order for patients to be enrolled in the program, they must have failed all standard therapeutic modalities and have undergone an appropriate diagnostic evaluation, including radiologic examinations or endoscopy. In addition, physicians must perform baseline screening tests, including laboratory tests and 12-lead ECG to screen for contraindicated risk factors. A physician evaluation, laboratory tests, and 12-lead ECG must be repeated at regular intervals according to the protocol.

The prescribing physician participating in the investigational limited access program must be board eligible or certified in one or more of the following areas: Internal medicine (including gastroenterology and cardiology), Family practice, Pediatrics (including neonatology) or Surgery. The patient must also be under the care of a gastroenterologist by consultation if the prescribing physician is not a gastroenterologist. Because the above protocols reflect investigational uses of cisapride, institutional review board (IRB) approval, completion of a Form FDA 1572, and signed informed consent are also required.

Table 2. Lifestyle Modifications

  • Stop smoking or reduce the number of cigarettes you smoke.
  • Elevate the head of your bed when you sleep.
  • Avoid eating large meals or eating just before bedtime.
  • Do not lie down right after eating.
  • If you are overweight or your doctor recommends it, try to lose weight.
  • Avoid fatty foods and foods containing chocolate, caffeine or citrus.
  • Avoid alcoholic drinks.

Summary
Cisapride will no longer be marketed in the U.S. starting July 14, 2000. Despite risk management efforts to detail the reports of heart rhythm abnormalities and deaths, Janssen Pharmaceutica and the FDA decided that continued general U.S. prescription access to cisapride posed unacceptable risks.

Physicians and pharmacists should be aware that distribution of cisapride will no longer continue after July 14, 2000, and that cisapride will no longer be available for general prescribing in mid-August. It is recommended that physicians evaluate their patients currently being treated with cisapride. Suggestions for lifestyle modifications and alternative therapies should be considered. In addition, physicians should review criteria for the investigational limited-access program to determine if their patients may be appropriate candidates.

Janssen, in consultation with the FDA, is currently finalizing all program materials. Physicians interested in enrolling patients or obtaining further information regarding the investigational limited access program should call toll-free 1-877-795-4247 beginning May 1, 2000.

REFERENCES

1. Janssen Pharmaceutica Inc. Cisapride Package Insert. Titusville, NJ. January 2000.
2. The New York Times. March 24, 2000.
3. FDA Talk Paper. FDA Strengthens Warning Label for Propulsid. June 29, 1998.
4. Janssen Pharmaceutica Inc. Cisapride Package Insert. Titusville, NJ. September 1998.
5. Janssen Pharmaceutica Inc. Important Safety Information. Titusville, NJ. June 1, 1999.
6. Janssen Pharmaceutica Inc. Important Drug Warning. Titusville, NJ. January 24, 2000.

SELF-PRESCRIBING CONTROLLED SUBSTANCES BY PHYSICIANS

Effective January 2000, the self-prescribing or self-dispensing of controlled substances (in any schedule) by physicians became grounds for disciplinary action by the Iowa Board of Medical Examiners. In addition, Iowa Code was modified to regulate the prescribing or dispensing of controlled substances to members of the physician's immediate family for an extended period of time. The Iowa Code now reads as follows:

653-12.4(272C) Additional grounds for discipline.

The Board (of Medicine) has authority to impose discipline for any violation of Iowa Code Chapter 147, 148, or 272C or the rules promulgated thereunder. The board may impose any of the disciplinary sanctions set forth in rule 12.33(272C), including civil penalties in an amount not to exceed $10,000, when the board determines that the licensee is guilty of any of the following acts or offenses:

12.4(19) Indiscriminately or promiscuously prescribing, administering or dispensing any drug for other than lawful purpose.

a. Self-prescribing or self-dispensing controlled substances.
b. Prescribing or dispensing controlled substances to members of the licensee's immediate family for an extended period of time.
(1) Prescribing or dispensing controlled substances to members of the licensee's immediate family is allowable for an acute condition or on an emergency basis when the physician conducts an examination, establishes a medical record, and maintains proper documentation.
(2) Immediate family includes spouse or life-partner, natural or adopted children, grandparent, parent, sibling, or grandchild of the physician; and natural or adopted children, grandparent, parent, sibling, or grandchild of the physician's spouse or life-partner.

The interpretation of this law is that a physician cannot prescribe a controlled substance for him-/herself, or prescribe continuing therapy using a controlled substance for immediate family members. Another authorized prescriber with a valid DEA registration number should write the prescription for the physician or members of his/her family, and this should be properly documented in the appropriate medical record.

PERCOCET® - AVAILABLE IN NEW STRENGTHS

Percocet® (oxycodone and acetaminophen) is now available in three new strengths. In addition to the original strength (oxycodone 5 mg/ acetaminophen 325 mg), Percocet® is also available as: oxycodone 2.5 mg/ acetaminophen 325mg, oxycodone 7.5 mg/ acetaminophen 500mg, and oxycodone 10 mg/ acetaminophen 650 mg. All of these strengths are DEA Controlled Substance Class II drugs.

Use of only the name Percocet® is no longer acceptable. When prescribing Percocet® the strength of both the oxycodone and acetaminophen components must appear on the written prescriptions to avoid potential errors (e.g., Percocet® 5 mg/325 mg 1 to 2 tablets every 6 hours PRN pain). Pharmacies cannot fill a prescription for a DEA Controlled Substance Class II drug (C-II) without the appropriate strength on the prescription.

UIHC only carries the Percocet® 5mg/325 mg strength.

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