Propulsid

DESCRIPTION

Propulsid (cisapride removed from us market) tablets and suspension contain cisapride as the monohydrate, which is an oralgastrointestinalagent chemically designated as (±)-cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy) propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate. Its empirical formula is C₂₃H₂₉ClFN₃O₄·H₂O. The molecular weight is 483.97.

Cisaprideas the monohydrate is a white to slightly beige odorless powder. It is practically insoluble in water, sparingly soluble in methanol, and soluble in acetone. Each 1.04 mg of cisapride as the monohydrate is equivalent to one mg of cisapride.

Propulsid (cisapride removed from us market) is available for oral use in tablets containing cisapride as the monohydrate equivalent to 10 mg or 20 mg of cisapride and as a suspension containing the equivalent of 1 mg/ml of cisapride. The inactive ingredients in the tablets are colloidalsilicondioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, povidone, and starch (corn). The 20 mg tablets also contain FD&C blue no. 2 aluminum lake. The inactive ingredients in the suspension are hydroxypropyl methylcellulose, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 20, propylparaben, sodium chloride, sorbitol, and water. The 1 mg/ml suspension also contains artificial cherry cream flavor and FD&C red no. 40.

INDICATIONS

Cisaprideis indicated for thesymptomatic treatmentof adult patients with nocturnalheartburndue togastroesophageal refluxdisease. Because of the risk of serious, and sometimes fatal,ventriculararrhythmias (seeBOXED WARNING), cisapride should generally be reserved for patients who do not respond adequately to lifestyle modifications (seePRECAUTIONS, Information for the PatientandPATIENT PACKAGE INSERT), antacids andgastricacid reducing agents.

DOSAGE AND ADMINISTRATION

5 ml (1 teaspoon) suspension = 5 mg.

Adults

Initiate therapy with one 10 mg tablet of cisapride or 10 ml of the suspension 4 times daily at least 15 minutes before meals and at bedtime. In some patients the dosage will need to be increased to 20 mg, given as above, to obtain a satisfactory result.

Cisaprideshould be discontinued if relief of nocturnal heartburn does not occur. The minimumeffective doseshould be used. Recommended doses of cisapride should not be exceeded.

It is recommended that the daily dose be halved in patients with hepatic insufficiency.

In elderly patients, steady-state plasma levels are generally higher due to a moderate prolongation of the elimination half-life. Therapeutic doses, however, are similar to those used in younger adults.

HOW SUPPLIED

Propulsid (cisapride (removed from us market)) tablets are provided as scored white tablets debossed "Janssen" and "P/10" containing the equivalent of 10 mg of cisapride. Propulsid (cisapride (removed from us market)) is also provided as blue tablets, debossed "Janssen" and "P/20", containing the equivalent of 20 mg cisapride.

Propulsid (cisapride (removed from us market)) suspension is provided as a bright pink homogeneous suspension containing the equivalent of 1 mg/ml of cisapride.

Unit of use bottles should be dispensed as an intact unit. The PATIENT PACKAGE INSERT should be dispensed with the product.

Storage:Store at 15-25°C (59-77°F). Protect the tablets from moisture. The 20 mg tablets should also be protected from light.

SIDE EFFECTS

In the U.S. clinical trial population of 1728 patients (comprising 506 withgastroesophagealrefluxdisorders, and the remainder with other disorders) the following adverse experiences were reported in more than 1% of patients treated with cisapride and at least as often on cisapride as on placebo. (See TABLE 1.)

TABLE 1
System/Adverse Events	CisaprideN=1042	Placebo N=686
Central & Peripheral Nervous Systems
Headache	19.3%	17.1%
Gastrointestinal
Diarrhea	14.2	10.3
Abdominal pain	10.2	7.7
Nausea	7.6	7.6
Constipation	6.7	3.4
Flatulence	3.5	3.1
Dyspepsia	2.7	1.0
Respiratory System
Rhinitis	7.3	5.7
Sinusitis	3.6	3.5
Coughing	1.5	1.2
Resistance Mechanism
Viral infection	3.6	3.2
Upper respiratory tract infection	3.1	2.8
Body as a Whole
Pain	3.4	2.3
Fever	2.2	1.5
Urinary System
Urinary tract infection	2.4	1.9
Micturitionfrequency	1.2	0.6
Psychiatric
Insomnia	1.9	1.3
Anxiety	1.4	1.0
Nervousness	1.4	0.7
Skin & Appendages
Rash	1.6	1.6
Pruritus	1.2	1.0
Musculoskeletal System
Arthralgia	1.4	1.2
Vision
Abnormal vision	1.4	0.3
Reproductive, Female
Vaginitis	1.2	0.9

The following adverse events also reported in more than 1% of cisapride patients were more frequently reported on placebo: dizziness, vomiting,pharyngitis, chest pain, fatigue,back pain, depression, dehydration, andmyalgia.

Diarrhea, abdominal pain, constipation, flatulence, and rhinitis all occurred more frequently in patients using 20 mg of cisapride than in patients using 10 mg.

Additional adverse experiences reported to occur in 1% or less of patients in the U.S. clinical studies are:dry mouth,somnolence, palpitation,migraine,tremor, and edema.

在其他美国和国际试验和职位marketing experience, there have been rare reports of seizures and extrapyramidal effects. Also reported have beentachycardia, elevated liver enzymes,hepatitis,thrombocytopenia,leukopenia,aplastic anemia,pancytopenia, andgranulocytopenia. The relationship of cisapride to the event was not clear in these cases.

Cardiac arrhythmias, includingventricular tachycardia,ventricular fibrillation, torsades de pointes, and QT prolongation, in some cases resulting in death, have been reported. (SeeCONTRAINDICATIONS,警告,PRECAUTIONS, andDRUG INTERACTIONS.)

Postmarketing Reports

In addition to thecardiovascularadverse 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 product information due to a combination of their seriousness, frequency of reporting, or potential causal connection to cisapride: allergic reactions, including bronchospasm,urticaria, andangioedema; possible exacerbation ofasthma; psychiatric events, including confusion, depression, suicide attempt, and hallucinations; extrapyramidal effects includingakathisia, Parkinson-like symptoms, dyskinetic and dystonic reactions;gynecomastia, female breast enlargement,urinary incontinence, hyperprolactinemia, andgalactorrhea.

The Following Events Were Specifically Reported in the Pediatric Population:Antinuclear antibody (ANA) positive,anemia,hemolytic anemia,methemoglobinemia,hyperglycemia,hypoglycemiawithacidosis, unexplainedapneicepisodes, confusion, impaired concentration, depression, apathy, visual changes accompanied byamnesia, and severephotosensitivityreaction.

There have been rare cases ofsinustachycardia reported. Rechallenge precipitated the tachycardia again in some of those patients.

DRUG INTERACTIONS

Cisaprideis metabolized mainly via the cytochrome P450 3A4 enzyme. In some cases where serious ventricular arrhythmias, QT prolongation, and torsades de pointes have occurred when cisapride was taken in conjunction with one of the cytochrome P450 3A4 inhibitors, elevated blood cisapride levels were noted at the time of the QT prolongation.

Antibiotics:In vitroand/orin vivodata show that clarithromycin, erythromycin, and troleandomycin markedly inhibit themetabolismof cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on theECG.

Anticholinergics:Concurrent administration of certainanticholinergiccompounds, such asbelladonnaalkaloids and dicyclomine, would be expected to compromise the beneficial effects of cisapride.

Anticoagulants (Oral):In patients receiving oral anticoagulants, thecoagulationtimes were increased in some cases. It is advisable to check coagulation time within the first few days after the start and discontinuation of cisapride therapy, with an appropriate adjustment of theanticoagulantdose, if necessary.

Antidepressants:In vitrodata indicate that nefazodone inhibits the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG.

Antifungals:In vitroand/orin vivodata indicate that fluconazole, itraconazole, and oral ketoconazole markedly inhibit the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG. Human pharmacokinetic data indicate that oral ketoconazole markedly inhibits the metabolism of cisapride, resulting in a mean eight-fold increase in AUC of cisapride. A study in 14 normal male and female volunteers suggests that coadministration of cisapride and ketoconazole can result in prolongation of the QT interval on the ECG.

H₂Receptor Antagonists:Cimetidine coadministration leads to an increased peak plasma concentration and AUC of cisapride, there is no effect on cisapride absorption when it is coadministered with ranitidine. The gastrointestinal absorption of cimetidine and ranitidine is accelerated when they are coadministered with cisapride.

Protease Inhibitors:In vitrodata indicate that indinavir and ritonavir markedly inhibit the metabolism of cisapride which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG.

Other:Coadministration ofgrapefruitjuice with cisapride increases the bioavailability of cisapride and concomitant use should be avoided.

Cisaprideshould not be used concomitantly with other drugs known to prolong the QT interval: certain antiarrhythmics, including those of Class IA (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 sertindole); astemizole, bepridil, sparfloxacin, and terodiline. The preceding lists of drugs are not comprehensive.

The acceleration of gastric emptying by cisapride could affect the rate of absorption of other drugs. Patients receiving narrow therapeutic ratio drugs or other drugs that require careful titration should be followed closely; if plasma levels are being monitored, they should be reassessed.

OVERDOSE

With overdose, rare cases of QT prolongation and ventricular arrhythmia have been reported.

A one-month-old male infant received 2 mg/kg of cisapride 4 times per day for 5 days. The patient developed third degreeheart blockand subsequently died of right ventricular perforation caused bypacemakerwire insertion.

In instances of overdose, patients should be evaluated for possible QT prolongation and ventricular arrhythmias, including torsades de pointes. Treatment should include gastric lavage and/oractivated charcoal, close observation and general supportive measures.

Reports of overdosage with cisapride also include an adult who took 540 mg and for 2 hours experienced retching,borborygmi, flatulence,stoolfrequency, and urinary frequency.

Single oral doses of cisapride at 4000 mg/kg, 160 mg/kg, 1280 mg/kg, and 640 mg/kg were lethal in adult rats,neonatalrats, mice, and dogs, respectively. Symptoms of acute toxicity wereptosis, tremors, convulsions,dyspnea, loss of righting reflex, catalepsy, catatonia, hypotonia, and diarrhea.

CONTRAINDICATIONS

Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking 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警告,PRECAUTIONS, andDRUG INTERACTIONS).

Antibiotics: Oral or IV erythromycin, clarithromycin (Biaxin), troleandomycin (TAO).

Antidepressants: Nefazodone (Serzone).

Antifungals: Oral or IV fluconazole (Diflucan), itraconazole (Sporanox), oral ketoconazole (Nizoral).

ProteaseInhibitors: Indinavir (Crixivan), ritonavir (Norvir).

Cisaprideis Also Contraindicated for Patients With:History of prolonged electrocardiographic QT intervals or known family history of congenital long QT syndrome; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestiveheart failure; clinically significant bradycardia; 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.

Cisaprideshould not be used in patients with uncorrected hypokalemia or hypomagnesemia or who might experience rapid reduction of plasmapotassiumsuch as those administered potassium-wastingdiuretics and/orinsulin在急性设置。

Cisaprideshould not be used in patients in whom an increase in gastrointestinal motility could be harmful,e.g.,in the presence of gastrointestinalhemorrhage, mechanical obstruction, or perforation. Cisapride is contraindicated in patients with known sensitivity or intolerance to the drug.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Cisaprideis metabolized mainly via the cytochrome P450 3A4 enzyme. Cisapride is extensively metabolized; unchanged drug accounts for less than 10% of urinary and fecal recovery following oral administration. Norcisapride, formed by N-dealkylation, is the principal metabolite in plasma, feces, and urine. Cisapride is rapidly absorbed after oral administration; peak plasma concentrations are reached 1 to 1.5 hours after dosing. The absolute bioavailability of cisapride is 35-40%. When gastric acidity was reduced by high dosehistamineH₂receptor blocker andsodium bicarbonatein fasting subjects, there was a decrease in the rate, and to a lesser degree the extent, of cisapride tablet absorption. (This has not been established for the suspension.) Cisapride binds to an extent of 97.5-98% to plasma proteins, mainly toalbumin. The volume of distribution of cisapride is about 180 L, indicating extensive tissue distribution.

The plasma clearance of cisapride is about 100 ml/min. The mean terminal half-life reported for cisapride ranges from 6 to 12 hours; longer half-lives, up to 20 hours, have been reported following intravenous (IV) administration.

没有不寻常的药物由于时间积累-dependent or non-linear changes in pharmacokinetics. After cessation of the repeated dosing, the elimination half-lives (8 to 10 hr) were in the same order as after single dosing. The degree of accumulation of cisapride and/or its metabolites may be somewhat higher in patients with hepatic or renal impairment and in elderly patients compared to young healthy volunteers, but the differences are not consistent. Dose adjustments are recommended in patients with hepatic impairment. (SeeDOSAGE AND ADMINISTRATION.)

The pharmacokinetics of cisapride in pediatric patients are not well characterized. Therefore, it is unknown if the dose-response relationship in the adult population can be extrapolated to the pediatric population. (SeePRECAUTIONS, Pediatric Use.)

Pharmacodynamics

The onset of pharmacological action of cisapride is approximately 30 to 60 minutes after oral administration.

Cisapridepromotes gastric motility. The mechanism of action of cisapride is thought to be primarily enhancement of release ofacetylcholineat the myentericplexus. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. It is less potent than metoclopramide indopaminereceptor-blocking effects in rats. It does not increase or decrease basal or pentagastrin-induced gastric acid secretion.

In vitrostudies have shown that cisapride is aserotonin-4 (5-HT₄) receptoragonist.

Electrophysiological studies inin vivoanesthetized guinea pig and rabbit models andin vitroisolated rabbit Purkinje fibers and ventricular papillary muscle and isolated rabbit ventricularmyocytemodels, have shown that cisapride prolonged cardiac repolarization without slowing conduction by selectively blocking the rapid component of the delayed rectifying K⁺current (l_kr) which leads to a lengthening of the action potential (QT Syndrome).

Esophagus:Twenty milligrams oral cisapride given once to healthy volunteers increased LESP, starting 45 minutes after dosing, with a peak response at 75 minutes. The full duration of the effect was not monitored, and doses smaller than 20 mg were ineffective. Ten milligrams oral cisapride, administered 3 times daily for several days to patients withGERD, resulted in a significant increase in LESP, and an increased esophageal acid clearance.

Stomach:Cisapride(single 10 mg doses or 10 mg given orally 3 times daily up to 6 weeks) significantly accelerated gastric emptying of both liquids and solids. Acceleration of gastric emptying, measured over a 4 hour period following a radio-labeled test meal given at lunch time, was greatest when 10 mg cisapride was given both in the morning and again before the test meal, intermediate when 20 mg was given as a single administration in the morning and least when only 10 mg was given on the morning of the test meal. The increases in gastric emptying were proportional to the plasma levels of cisapride measured in these subjects over the same 4 hours that the gastric emptying test was conducted.

CLINICAL STUDIES

Clinical trials have shown that cisapride can reduce the severity of symptoms of nocturnal heartburn associated with gastroesophageal reflux disease. Two placebo-controlled studies, one using a dose of 10 mg qid, the other both 10 and 20 mg qid, showed effects on nighttime heartburn, although the 10 mg dose in the second study was only marginally effective. There were no consistent effects on daytime heartburn, symptoms ofregurgitation, or histopathology of theesophagus. Use of antacids was only infrequently affected and slightly decreased. In a third controlled trial of similar design to the others, neither 10 mg nor 20 mg taken 4 times daily was superior to placebo. In these clinical trials cisapride did not wshow a significant effect on LESP.

In a clinical trial comparing 10 mg cisapride to placebo, pHprobeevaluation, in a relatively small number of patients, did not reveal a significant difference in pH.

PATIENT INFORMATION

PATIENT PACKAGE INSERT

READ COMPLETELY BEFORE USE. If you have a medical condition or take a drug listed here, including erythromycin (such as E.E.S., E-Mycin, Ilotycin, Pediazole), clarithromycin (Biaxin) or fluconazole (Diflucan), Do Not Take Cisapride.

Brand Name:PROPULSID (cisapride (removed from us market)) (pro-pul-sid)

Generic Name:Cisapride

Available As:10 mg & 20 mg tablets (P/10, P/20)

1 mg/ml suspension (liquid form).

What is the Most Important Information I Should Know About Cisapride?

Cisapridemay cause serious irregular heartbeats that may be fatal. Taking cisapride together with certain other medicines increases the likelihood that you will have irregular heartbeats. Cisapride shouldneverbe taken with these other medicines. A list of these medicines is supplied below (see Who Should Not Take Cisapride?). If you faint or feel faint, become dizzy or have irregular heartbeats while using cisapride,stoptaking your medication and seek medical attentionimmediately.

What is Cisapride?

Cisaprideis a medication intended only to treat the symptoms of nighttime heartburn in adults. Nocturnal, or nighttime, heartburn is a common symptom of a medical condition called gastroesophageal reflux disease (GERD). It occurs when stomach contents wash back, or "reflux," into the esophagus (amusculartube that carries food from the mouth to the stomach). Reflux is very common at nighttime because stomach contents can easily wash backwards when you are lying down. Usually, physicians recommend that patients with nighttime heartburn make simple lifestyle changes and use antacids or acid-reducing agents to relieve their symptoms. (See What Else Can I do for Nighttime Heartburn? for more details.) These other medications should be tried first because of the risk of serious, and sometimes fatal, irregular heartbeats associated with the use of cisapride.

Who Should Not Take Cisapride?

Some patients who have taken certain medications together with cisapride have experienced serious problems such as fainting, dizziness, and irregular heartbeats. These interactions can be fatal. Medications thatshould notbe taken with cisapride include:

Antibiotics: Erythromycin (such as E.E.S., E-Mycin, Ilotycin, Pediazole), clarithromycin (Biaxin), troleandomycin (TAO).

Antidepressants: Nefazodone (Serzone).

Antifungals: Fluconazole (Diflucan), itraconazole (Sporanox), oral ketoconazole (Nizoral).

Protease Inhibitors: Indinavir (Crixivan), ritonavir (Norvir).

同样,你不应该把cisapride某些heart medications and certain allergy medications. There are also other medications that are handled by your body in the same way as the drugs listed above and may cause the same serious problems (fainting, dizziness, and possibly fatal irregular heartbeats) when taken with cisapride.

• Tell your doctor about all other drugs you are taking, especially diuretics ("water pills") and heart medications.While taking cisapride, do not start a new medicine without first consulting your doctor or pharmacist.
• Cisaprideshould not be used in patients with certain medical conditions. In particular, tell your doctor if you have any type of heart condition or kidney or lung disease before taking cisapride. Be sure your doctor knows about your personal and familymedical history.
• If you have not tried other medications to relieve your nighttime heartburn, tell your doctor before using cisapride.
• The safety and effectiveness of cisapride in children younger than 16 years have not been demonstrated for any use.Serious adverse events, including death, have been reported in infants and children while being treated with cisapride, although there is no conclusive evidence that cisapride caused them.

How Should I Take Cisapride?

• Take cisapride exactly as your doctor prescribes it. Cisapride does not work for everyone. If you do not get relief of your nighttime heartburn, talk to your doctor about whether to stop using cisapride.
• Never take more than the recommended dose of cisapride. Always take your medication for as long as the doctor has prescribed it, even if you are beginning to feel better right away.
• If you forget to take a dose, do not take the missed dose. Take the next dose at the regularly scheduled time.Never take more than your normal dose at any one time to make up for the missed dose.

What Should I Avoid While Taking Cisapride?

• Nevertake cisapride with the medications listed in Who Should Not Take Cisapride?
• Do not take cisapride with grapefruit juice.
• Tell your doctor if you are pregnant or nursing. Your doctor will recommend whether you should take cisapride while pregnant or nursing, based on the benefits and risks.

What are the Possible Side Effects of Cisapride?

• 如果你或感到头晕,头晕或我rregular heartbeats while using cisapride, stop taking it and contact your doctor immediately. Call your doctor if you experience any unusual symptoms after or while taking cisapride.
• All prescription medications have some potential side effects for some users. The most common side effects associated with cisapride are headache, diarrhea, stomach pain, nausea, constipation, and arunny nose. Other side effects have been reported less frequently. Be sure to ask your doctor or pharmacist about the side effects of any medication you are taking, including cisapride.

What Else Can I do for Nighttime Heartburn?

• 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 areoverweightor your doctor recommends it, try to lose weight
• Avoid fatty foods and foods containing chocolate,caffeineor citrus
• Avoid alcoholic beverages

All of these lifestyle changes will help to restore your body to a more normal way of functioning.

General Information

This information provides a summary about cisapride. Medicines are sometimes prescribed for purposes other than those listed in the PATIENT PACKAGE INSERT. If you have additional questions or concerns, need to report problems associated with the use of cisapride, or want more information about cisapride, contact your doctor or pharmacist. You can also call the Janssen One-to-One Customer Action Center toll-free at 1-800-526-7736 for more information. This medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.