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1.
June 26, 1998 Janssen Propulsid Important Safety and Efficacy Information.
2. June 1,
1999 Janssen Propulsid Coadministration of Grapefruit
Juice Should be Avoided.
3.
January 25, 2000 FDA Issues Further Warning.
4.
March 24, 2000 Heartburn Drug Removed From Market
5.
March 23, 2000 Limited-Access Program Announced for Propulsid
Brand Names: Acenalin; Acpulsif;
Alimix; Alimix Forte; Alipride; Calmax; Cipride;
Cisapron; Cisawal; Colinorm; Dispep; Enteropride;
Esorid; Gastromet; Guptro; Kaudalit; Kinestase;
Prepulsid; Presid; Propulsid; Propulsin; Pridesia; Pulsid;
Rapulid; Risamol; Syspride; Unamol; Unipride;
Vomiprid; Vomipride
(Foreign brand names outside U.S. in italics)
1.
June 26, 1998 Important
Safety and Efficacy Information
Top
JANSSEN PHARMACEUTICA RESEARCH FOUNDATION
Dear Doctor,
Janssen Pharmaceutica would like to inform you of labeling changes concerning new CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DRUG INTERACTIONS with PROPULSID
(cisapride). In addition, revisions have been made in the PEDIATRIC USE, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION sections.
We wish to draw your attention to the following sections of the revised PROPULSID labeling which contain the essential changes.
Warning: Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking
PROPULSID. Many of these patients also took drugs expected to increase cisapride blood levels by inhibiting the cytochrome P450 3A4 enzymes that metabolize
cisapride. These drugs include clarithromycin, erythromycin, troleandomycin,
nefazodone, fluconazole, itraconazole, ketoconazole, indinavir and ritonavir. Some of these events have been fatal. PROPULSID is contraindicated in patients taking any of these drugs. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DRUG INTERACTIONS).
QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest and sudden death have been reported in patients taking PROPULSID without the above-mentioned contraindicated drugs. Most patients had disorders that may have predisposed them to arrhythmias with
cisapride. PROPULSID is contraindicated for those patients with: history of prolonged electrocardiographic QT intervals; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; uncorrected electrolyte disorders
(hypokalemia, hypomagnesemia); respiratory failure; and concomitant medications known to prolong the QT interval and increase the risk of arrhythmia, such as certain
antiarrhythmics, including those of Class 1A (such as quinidine and procainamide) and Class III (such as
sotalol); tricyclic antidepressants (such as amitriptyline); certain tetracyclic antidepressants (such as
maprotiline); certain antipsychotic medications (such as certain phenothiazines and
sertindole), astemizole, bepridil, sparfloxacin and terodiline. (The preceding lists of drugs are not comprehensive.)
Recommended doses of PROPULSID should not be exceeded.
INDICATIONS & USAGE
PROPULSID (cisapride) is indicated for the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. Because of the risk of serious, and sometimes fatal, ventricular arrhythmias (see Boxed Warning), PROPULSID should generally be reserved for patients who do not respond adequately to lifestyle modifications (See PRECAUTIONS: Information for Patients), antacids and gastric acid reducing agents.
CONTRAINDICATIONS
Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking PROPULSID
(cisapride) with other drugs that inhibit cytochrome P450 3A4. Some of these events have been fatal.
Concomitant oral or intravenous administration of the following drugs with cisapride may lead to elevated cisapride blood levels and is contraindicated (See WARNINGS, PRECAUTIONS and DRUG INTERACTIONS):
Antibiotics: Oral or i.v. erthromycin, clarithromycin (BIAXIN), troleandomycin (TAO)
Antidepressants: Nefazodone (SERZONE)
Antifungals: Oral or i.v. fluconazole (DIFLUCAN), itraconazole (SPORANOX), oral ketoconazole
(NIZORAL)
Protease inhibitors: Indinavir (CRIXIVAN), ritonavir (NORVIR)
PROPULSID is also contraindicated for patients with: history of prolonged electrocardiographic QT intervals; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; uncorrected electrolyte disorders
(hypokalemia, hypomagnesemia); respiratory failure; and concomitant medications known to prolong the QT interval and increase the risk of arrhythmia, such as certain
antiarrhythmics, certain antipsychotics, certain antidepressants , astemizole,
bepridil, sparfloxacin and terodiline. The preceding lists of drugs are not comprehensive.
PROPULSID should not be used in patients with uncorrected hypokalemia or hypomagnesemia or who might experience rapid reduction of plasma potassium such as those administered potassium-wasting diuretics and/or insulin in acute settings.
WARNINGS
ECG should be considered prior to initiation of cisapride. Cisapride should not be used in patients with a prolonged QT interval at baseline, those with a history of torsades de pointes, or those with long QT syndrome. Cisapride should also be avoided in patients with sinus node dysfunction, and in those with second or third degree atrioventricular block.
Cisapride should not be used concomitantly with other drugs known to prolong the QT interval; certain
antiarrhythmics, including those of Class 1A (such as quinidine and procainamide) and Class III (such as
sotalol): tricyclic antidepressants (such as amitriptyline); certain tetracyclic antidepressants (such as
maprotiline); certain antipsychotic medications (such as certain phenothiazines and
sertindole); astemizole, bepridil, sparfloxacin and terodiline. (See CONTRAINDICATIONS, PRECAUTIONS and DRUG INTERACTIONS.) The preceding lists of drugs are not comprehensive.
PRECAUTIONS
General: Potential benefits should be weighed against risks prior administration of cisapride to patients who have or may develop prolongation of cardiac conduction intervals, particularly
QTc. These include patients with conditions that could predispose them to the development of serious arrhythmias, such as multiple organ failure,
COPD, apnea and advanced cancer. (See CONTRAINDICATIONS.)
PROPULSID (cisapride) should not be used in patients with uncorrected hypokalemia or
hypomagnesemia, such as those with severe dehydration, vomiting or malnutrition, or those taking potassium-wasting diuretics. PROPULSID should not be used in patients who might experience rapid reduction of plasma potassium, such as those administered potassium-wasting diuretics and/or insulin in acute settings.
Pediatric Use: Safety and effectivenesss in pediatric patients have not been established. Although causality has not been established, serious adverse events, including death, have been reported in infants and children treated with
cisapride. Several pediatric deaths were due to cardiovascular events (third degree heart block and ventricular
tachycardia).
Pediatric deaths have been associated with seizures and there has been at least one case of "sudden unexplained death" in a 3-month-old infant. Other unlabeled potentially serious events which have been reported in pediatric patients include: antinuclear antibody (ANA) positive, anemia, hemolytic anemia,
methemoglobinemia, hyperglycemia, hypoglycemia with acidosis, unexplained apneic episodes, confusion, impaired concentration, depression, apathy, visual changes accompanied by amnesia, and severe photosensitivity reaction.
A one-month-old male infant received 2 mg/kg of cisapride four times per day for 5 days. The patient developed third degree heart block and subsequently died of right ventricular perforation caused by pacemaker wire insertion.
ADVERSE REACTIONS
Postmarketing Reports: In addition to the cardiovascular adverse events, the following events have been identified during post-approval use of cisapride in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion in this insert due to a combination of their seriousness, frequency of reporting, or potential causal connection to
cisapride: allergic reactions, including bronchospasm, urticaria, and angioedema; possible exacerbation of asthma; psychiatric events, including confusion, depression, suicide attempt, and hallucinations;
gynecomastia, female breast enlargement, urinary incontinence, hyperprolactinemia and
galactorrhea.
The following events were specifically reported in the pediatric population: antinuclear antibody (ANA) positive, anemia, hemolytic anemia,
methemoglobinemia, hyperglycemia, hypoglycemia with acidosis, unexplained apneic episodes, confusion, impaired concentration, depression, apathy, visual changes accompanied by amnesia, and severe photosensitivity reactions.
DOSAGE AND ADMINISTRATION
PROPULSID should be discontinued if relief of nocturnal heartburn does not occur. The minimum effective dose should be used. Recommended doses of PROPULSID should not be exceeded.
It is recommended that the daily dose be halved in patients with hepatic insufficiency.
We at Janssen want you to be aware of this important information to ensure the proper use of PROPULSID in your patients. Please refer to the enclosed revised package insert for full prescribing information. The Medical Community can further our understanding of adverse events by reporting all cases to Janssen at 1-800-Janssen (526-7736) or to the FDA MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, or by mail to
MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857. For additional medical information, please call 1-800-Janssen from 8 AM to 8 PM Eastern Time, Monday through Friday.
Sincerely,
Mark A. Klausner, M.D.
Vice President, Medical Affairs
Dear Doctor,
Janssen Pharmaceutics would like to inform you of labeling changes
concerning new CONTRAINDICATIONS and DRUG INTERACTIONS with PROPULISID (cisapride)
We wish to draw your attention to the following sections of the revised
PROPULSID labeling which contains the essential changes. Underlined words denote
newly added information. Similar revisions have been incorporated into the
PROPULSID Medication Guide.
BOXED WARNING AND CONTRAINDICATIONS
Two new medical conditions have added to the Contraindications and Boxed
Warning sections of PROPULSID labeling. These include known family history of
congenital long QT syndrome and clinically significant bradycardia.
The purpose of these additions is to further clarify the contraindicated
medical conditions for PROPULSID. These conditions are independent risk factors
for QT prolongation.
DRUG INTERACTIONS
According to the Drug Interaction section of PROPULSID labeling:
Coadministration of grapefruit juice with cisapride increases the
bioavailabilty of cisapride and concomitant use should be avoided.
This addition is based on the results of a drug interaction study conducted
in normal volunteers, which demonstrated that the coadministration of grapefruit
juice and cisapride resulted in an increased bioavailability of cisapride.
As always, Janssen is committed to the safe and appropriate use of its
products. Therefore, we at Janssen want you to be aware of this important
information to ensure the proper use of PROPULSID in your patients. Please refer
to the enclosed revised packaged insert for full prescribing information,
including boxed warning and enclosed medication guide. The medical community can
further our understanding of adverse events by reporting all cases to Janssen at
1-800-JANSSEN (526-7736) or to the FDA MedWatch program by phone at
1-800-FDA-1088, by fax at 1-800-FDA-0178, or by mail to MedWatch, HF-2, FDA,
5600 Fishers Lane, Rockville, MD, 20857. For additional medical information,
please call 1-800-JANSSEN (526-7736) from 8AM to 8PM Eastern Time, Monday
through Friday.
Sincerely,
Mark A. Klausner, MD
Vice President
Drug Safety and Epidemiology
3.
January
25, 2000 FDA Issues Further Warning Top
NEW YORK (Reuters) - The U.S. Food and Drug Administration
said on Monday it had issued a warning to doctors about possible dangers of
Johnson & Johnson's treatment for heartburn, Propulsid, following reports of
scores of fatalities among users of the medication.
The U.S. Food and Drug Administration said it acted after
analyzing 270 reports of adverse events, including 70 fatalities, among people
who have taken the drug since it was launched in 1993. The agency said about 85
percent of the cases involved patients with identifiable risks.
J&J does not disclose sales of individual drugs. But
some analysts have estimated that Propulsid's global 1999 sales approached $1
billion, making it the New Jersey drugmaker's third biggest-selling
pharmaceutical.
``Today's actions are prompted by continuing reports of
heart rhythm disorders and deaths associated mostly with the use of the drug in
people who are either taking certain other medications or who have certain
underlying conditions that are known risk factors,'' the FDA said.
The FDA said that because of the reports, the medicine's
insert label will be changed to require that doctors perform an
electrocardiogram and various blood tests prior to prescribing it.
The label change will state that Propulsid should not be
used by patients already taking certain types of medicines for allergies,
angina, nausea and irregular heart rhythm as well as those taking certain types
of antibiotics, anti-depressants, antifungals, anti-psychotics and protease
inhibitors against the HIV virus.
J&J said the antidepressants which should not be taken
with Propulsid include the entire class of older therapies known as tricyclics,
while the forbidden antibiotics include three members of the macrolide family --
including erythromycin.
Moreover, the FDA said it also advised that patients not
take Propulsid if they have a history of irregular heartbeat, abnormal
electrocardiograms, heart disease, kidney disease, lung disease, low blood
levels of potassium, calcium or magnesium, eating disorders, dehydration or
persistent vomiting.
Propulsid (cisapride), which was approved by the FDA in
tablet form in 1993 and in suspension form in 1995, is sold by J&J's Janssen
Pharmaceutica unit.
The medicine is used to treat severe night-time heartburn
for patients with gastroesophageal reflux disease (GERD) who do not adequately
respond to other therapies.
In patients with GERD, acid and stomach contents back up
into the esophagus, causing heartburn and other symptoms. Persistent heartburn
can lead to esophageal cancer.
Jannsen spokesman Greg Panico declined to speculate how
seriously Propulsid's sales would be hurt by the FDA warning letter, the label
changes and the newly mandated medical tests. ''its on the market and helping
people,'' Panico said, adding that it would remain on the market.
``Our drug is safe, when used appropriately. But after any
label change there is some dropoff in a drug's sales,'' he said. Panico added
that the 270 adverse event reports stretched out over a 7-year period, during
which time he said 30 million prescriptions for the drug had been written in the
United States.
One Wall Street analyst, who asked not to be identified,
said he believed the FDA warning and required medical tests would ''decimate''
sales of Propulsid.
``With the FDA warning, Propulsid is no longer a drug of
choice for GERD. Its sales could be driven down to the $200 million or $300
million (annual) range, at which point Johnson & Johnson might decide to
pull the drug from the market,'' the analyst said.
Johnson & Johnson late last year began marketing an
ulcer drug, Aciphex (rabeprazole), that is also approved for GERD. Some patients
now taking Propulsid might switch over to Aciphex, although Aciphex has a
different mechanism of action, analysts said.
Aciphex is a so-called proton pump inhibitor, a class of
ulcer drugs that help limit production of gastric acids. Another proton pump
inhibitor also approved for GERD, Prevacid (lansoprazole), is sold by a joint
venture between Illinois-based drugmaker Abbott Laboratories and Takeda Chemical
Industries Ltd of Japan .
Shares of J&J fell 6-1/8 to 83-11/16, or 7.3 percent,
amid a sharp decline in the U.S. pharmaceutical sector and broad decline in U.S.
markets.
4.
Heartburn Drug Removed From Market Top
The Associated Press
3-24-00
By PAUL RECER
WASHINGTON (AP) - The popular heartburn drug Propulsid, which has been associated with 80 deaths, will no longer be marketed after July, except in special circumstances, its maker and federal regulators said.
Known chemically as cisapride, the drug has been prescribed for patients who suffer severe heartburn, or gastroesophageal reflux disease, and have not responded to other drugs.
Manufacturer Janssen Pharmaceutica of Titusville, N.J., said Thursday it no longer would market the drug as of July 14. The company, a subsidiary of Johnson & Johnson, acted in consultation with the Food and Drug Administration.
Janssen said it will make Propulsid available on a limited basis for certain patients who can enroll in a special program beginning May 1. Other therapies must not be effective for these patients, who must meet criteria being established in collaboration with the FDA.
The drug will continue to be distributed until July 14 and will remain in pharmacies until mid-August, Janssen said in an announcement posted on its Web site.
Patients who are now taking Propulsid are advised to speak with their doctor.
Propulsid, one of J&J's top selling drugs, was approved by the FDA in 1993. But there has been a series of increasingly strong actions to warn against serious side effects from the drug.
As of Dec. 31, 80 deaths and 341 heart rhythm abnormalities have been associated with Propulsid, FDA officials said Thursday.
Janssen maintained in its announcement, ``Propulsid remains safe and effective for the vast majority of patients when used according to the approved prescribing information.''
In 1998, the FDA announced that there had been some deaths among patients taking the drug and issued a warning that Propulsid was linked to cardiac problems in some patients. The drug's label was revised then to reflect this concern.
In January, the FDA issued an even more severe warning. Patients were urged to be tested to make sure the drug had not affected their hearts. New labels also warned that Propulsid should not be used by patients with disorders of the heart, kidney or lung, or by patients who were taking some medications to treat heart problems, allergies, depression or AIDS.
Janssen said that despite the warnings, ``some inappropriate use has continued'' in the United States. The best solution, the company said, was limiting access to the drug ``while ensuring that appropriate patients who have exhausted other treatment options can still benefit from it.''
The FDA had ordered an advisory board meeting in April to discuss the problems with Propulsid. That meeting has now been canceled.
Dr. Florence Houn of the FDA said that Propulsid had a unique action that was important to some patients. She said the pill triggered motility, a wave like action in the gut, that moved gastric acid away from the esophagus, thus preventing nighttime heartburn for some patients.
J&J said Propulsid sales were about $950 million worldwide last year but that it expects sales this year to drop to $250 million.
It was the second time this week that safety concerns prompted the FDA and a drug maker to act on a medication.
On Tuesday, a diabetes drug that has been linked to at least 61 deaths was withdrawn from the market after a review of safety data showed it was more toxic to the liver than comparable drugs. The FDA said that it requested that Rezulin, a drug for treatment of Type 2, or adult-onset, diabetes, no longer be sold. The agency said that Parke-DavisWarner-Lambert, the drug manufacturer, agreed to the action.
EDITOR'S NOTE - For more information on the limited access program, call 1-800-JANSSEN 9 a.m.-5 p.m. Eastern time Monday through Friday.
5.
March 23, 2000 Limited-Access Program Announced for Propulsid
Top
- Product No Longer to be Promoted in United States -
TITUSVILLE, N.J., March 23 /PRNewswire/ -- A limited-access program will be initiated for Propulsid(R) (cisapride) tablets and suspension, and the product will no longer be marketed in the United States, it was announced today by Janssen Pharmaceutica of Titusville, NJ. Propulsid is a prescription treatment approved by the Food and Drug Administration (FDA) for symptomatic treatment of adults with nighttime heartburn due to gastroesophageal reflux disease (GERD).
Under the new program, Propulsid will remain available to appropriate patients for whom other therapies are not effective and who meet clearly defined eligibility criteria. These criteria are being established in close collaboration with the FDA.
Information on the limited-access program will be sent to physicians across the country in April, and enrollment will begin May 1. However, to assure that the medication is available to appropriate patients during the transition, distribution will continue until July 14, and the product will remain in pharmacies until mid August. Patients who have current prescriptions for Propulsid are advised to speak with their doctors.
Since the U.S. approval of Propulsid in 1993, there have been a number of serious cardiovascular side effects in individuals who also were taking certain contraindicated medications or who had specific underlying health conditions. In an effort to ensure that the drug was being prescribed safely and appropriately, labeling changes were initiated over the past several years, making the prescribing information as detailed and specific as possible.
Despite these warnings, some inappropriate use has continued in the United States. Janssen and the FDA now believe the best way to address this situation is to limit access to the medication, while ensuring that appropriate patients who have exhausted other treatment options can still benefit from it. Propulsid remains safe and effective for the vast majority of patients when used according to the approved prescribing information.
Details regarding how the limited-access program will work -- including eligibility criteria and the application process -- are currently being developed by Janssen in consultation with the FDA. In the meantime, consumers and health-care professionals with questions may call 800-JANSSEN from 9 a.m. to 5 p.m. Monday to Friday, Eastern Standard Time.
Janssen Pharmaceutica is a wholly owned subsidiary of Johnson & Johnson and is a leader in the research and treatment of gastrointestinal disorders. In addition, it markets prescription medications for the treatment of chronic pain, disorders of the central nervous system and fungal infections. Headquartered in Beerse, Belgium, with affiliates in 32 countries, Janssen's U.S. operations are centered in Titusville, NJ.
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations, forecasts and assumptions that are subject to risks and uncertainties which could cause actual outcomes and results to differ materially from these statements. Risks and uncertainties include general industry and market conditions; general domestic and international economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign healthcare reforms; trends toward managed care and healthcare cost containment, and governmental laws and regulations affecting domestic and foreign operations. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99(b) of the company's Annual Report on Form 10-K for the fiscal year ended January 3, 1999. Copies of this Form 10-K are available on request from the company. The company disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
SOURCE Janssen Pharmaceutica
CO: Janssen Pharmaceutica; Johnson & Johnson
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