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CISAPRIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cisapride and renzapride are oral gastrointestinal prokinetic agents that stimulate gastrointestinal motility and are used in the treatment of gastroesophageal reflux disease. These drugs are substituted benzamides.

Specific Substances

    A) CISAPRIDE
    1) R-51619
    2) cis-4-amino-5-chloro-N-(1-(3-(4-fluorophenoxy)-propyl)-
    3) 3-methoxy-4-piperidyl)-2-methoxybenzamide monohydrate
    4) CAS 81098-60-4
    RENZAPRIDE
    1) (+/-)-endo-4-Amino-N-(1-azabicyclo[3.3.1]non-4-yl)-5-
    2) chloro-o-anisamide
    3) BRL-24924A (hydrochloride)
    4) BRL 24924
    5) Molecular Formula: C16-H22-Cl-N3-O2
    6) CAS 88721-77-1 (racemate)
    7) CAS 112727-80-7

Available Forms Sources

    A) FORMS
    1) Cisapride has been available as 10 and 20 mg tablets and 1 mg/mL oral suspension. In 2000, cisapride was withdrawn from the market in both the United States and the United Kingdom ((Anon, 2000)).
    B) USES
    1) These drugs are substituted benzamides which stimulate gastrointestinal motility and are used mainly for gastric emptying disorders. Renzapride has been shown in clinical trials to be useful in the treatment of diabetic gastroparesis and constipation-predominant irritable bowel syndrome.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Adverse effects may include headaches, gastrointestinal distress, urinary frequency, ECG abnormalities, QT prolongation, and dysrhythmias including Torsades de pointes. Akathisias have been reported, but are rare.
    B) WITH POISONING/EXPOSURE
    1) Overdose experience with cisapride and renzapride are limited. Retching, borborygmi, flatulence, stool frequency, and urinary frequency have been reported by the cisapride manufacturer following an overdose ingestion.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) QT interval prolongation and various dysrhythmias (palpitations, tachycardia, extrasystoles, and torsades de pointes) have been reported following therapeutic administration of cisapride.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Bronchospasm is a rare occurrence associated with cisapride ingestion.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headaches may commonly occur with oral cisapride administration.
    2) Seizures, insomnia, anxiety, extrapyramidal effects, and the appearance of neuroleptic malignant syndrome are rare occurrences associated with therapeutic administration of cisapride.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Gastrointestinal distress, including diarrhea, abdominal pain, dyspepsia, nausea, constipation, and flatulence have been reported.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Urinary frequency and incontinence, and vaginitis have been associated with the therapeutic administration of cisapride.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Rashes and pruritus were uncommon effects following cisapride therapy.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Arthralgias have been reported following therapeutic administration of cisapride.
    0.2.20) REPRODUCTIVE
    A) Cisapride is classified as FDA Pregnancy Category C.
    B) Cisapride is excreted in human breast milk.
    0.2.22) OTHER
    A) DRUG INTERACTION - Drug interactions may occur when administering cisapride or renzapride concurrently with cytochrome CYP3A4 inhibitors. This combination may result in serious and potentially fatal dysrhythmias.

Laboratory Monitoring

    A) Serum levels of cisapride are not clinically useful.
    B) Monitor electrolyte levels if the patient experiences severe and prolonged diarrhea.
    C) Obtain an ECG and institute continuous cardiac monitoring for possible QT prolongation and dysrhythmias.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL
    1) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) TACHYCARDIA
    1) Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops. If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred.
    C) TORSADE DE POINTES
    1) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    a) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    b) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    c) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    D) DYSTONIC REACTIONS
    1) DYSTONIC REACTION: ADULT: BENZTROPINE: 1 to 4 mg once or twice daily IV or IM (max, 6 mg/day); 1 to 2 mg of the injection will usually provide quick relief in emergency situations, OR DIPHENHYDRAMINE: ADULT: 10 to 50 mg IV at a rate not exceeding 25 mg/minute or deep IM (max, 100 mg/dose; 400 mg/day). CHILDREN: Diphenhydramine: 5 mg/kg/day or 150 mg/m(2)/day IV divided into 4 doses at a rate not to exceed 25 mg/min, or deep IM (max,, 300 mg/day). Not recommended in premature infants and neonates.

Range Of Toxicity

    A) An acute overdose ingestion of cisapride, 540 milligrams, was reported in an adult with mild toxicity.
    B) Dysrhythmias may develop at therapeutic doses in patients with other risk factors (other drugs causing QTC prolongation, drugs that inhibit cytochrome P450 3A4, electrolyte abnormalities, underlying cardiac disorders).

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Adverse effects may include headaches, gastrointestinal distress, urinary frequency, ECG abnormalities, QT prolongation, and dysrhythmias including Torsades de pointes. Akathisias have been reported, but are rare.
    B) WITH POISONING/EXPOSURE
    1) Overdose experience with cisapride and renzapride are limited. Retching, borborygmi, flatulence, stool frequency, and urinary frequency have been reported by the cisapride manufacturer following an overdose ingestion.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER
    1) WITH THERAPEUTIC USE
    a) Fever was reported in 2.2% of 1728 patients involved in cisapride U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).
    3.3.5) PULSE
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia or palpitations were reported in 5 patients following cisapride treatment (Olsson & Edwards, 1992).

Heent

    3.4.3) EYES
    A) ABNORMAL VISION
    1) WITH THERAPEUTIC USE
    a) Abnormal vision occurred in 1.4% of 1728 patients involved in cisapride U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).
    3.4.5) NOSE
    A) RHINITIS/SINUSITIS
    1) WITH THERAPEUTIC USE
    a) During cisapride U.S. clinical trials, 7.3% of 1728 patients developed rhinitis and 3.6% developed sinusitis (Prod Info Propulsid(R), cisapride, 1993).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) QT interval prolongation and various dysrhythmias (palpitations, tachycardia, extrasystoles, and torsades de pointes) have been reported following therapeutic administration of cisapride.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Palpitations, tachycardia, supraventricular extrasystoles, and torsades de pointes have occurred following oral therapeutic administration of cisapride (Olsson & Edwards, 1992; Bran et al, 1995). Symptoms usually resolved following discontinuation of cisapride.
    b) Due to serious dysrhythmias, including ventricular tachycardia and ventricular fibrillation, torsades de pointes, and QT prolongation, or family history of QT prolongation and clinically significant bradycardia, labeling changes and warnings have been issued by Janssen Pharmaceuticals and the FDA concerning the use of cisapride. Drugs that inhibit the cytochrome P450 3A4 enzymes may also increase blood levels of cisapride, resulting in cardiac dysrhythmias. Cisapride is contraindicated during therapy with any of the following: erythromycin, clarithromycin, troleandomycin, nefazodone, fluconazole, itraconazole, ketoconazole, indinavir, ritonavir, and grapefruit juice (Gheurens, 2000; ((Klausner, 1999); Janssen, 1998). It is also contraindicated in patients with electrolyte disorders.
    1) Due to increasing numbers of reported adverse events of heart rhythm abnormalities following cisapride therapy, the manufacturer has withdrawn this product from both the United States and the United Kingdom ((Anon, 2000)).
    c) Patients with a history of prolonged QT intervals, renal failure, ventricular dysrhythmias, ischemic heart disease, CHF, uncorrected electrolyte disorders, respiratory failure, or the above concomitant drugs are advised NOT to take cisapride concurrently (Janssen, 1998).
    d) CASE SERIES - Hill et al (1998), in a prospective, blinded study, evaluated the incidence of cisapride-associated ventricular repolarization abnormalities in 35 children. The authors suggested that cisapride may cause prolongation of ventricular repolarization in children. No increased heterogeneity of repolarization or delayed depolarization was seen. The prodysrhythmias seen appeared to be exacerbated by concurrent drugs that inhibited cytochrome P450 3A4 hepatic metabolism, by overdosages, or mechanisms that resulted in decreased serum clearance.
    e) CASE SERIES - Walker et al (1999), in a cohort analysis of 36,743 patients prescribed cisapride, found an incidence of arrhythmic events was 1.6 times greater in periods of recent use. They found no identifiable increase in risk when cisapride was taken at about the same time as QT-prolonging drugs or CYP3A4 inhibitors.
    2) WITH POISONING/EXPOSURE
    a) OVERDOSE (Premature Newborns) - Bradycardic dysrhythmias requiring resuscitation were reported in two premature newborns given a 10-fold overdose (2 mg/kg instead of 0.2 mg/kg) of cisapride and in a newborn given cisapride concurrently with erythromycin. The overdoses were nonfatal (Ward et al, 1999).
    B) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) The FDA's MedWatch reporting program received reports, from September 1993 to April 1996, of 34 patients who developed torsades de pointes while on cisapride therapy. Four patients were reported to have died. Imidazole antifungal agents or macrolide antibiotics may have been concurrently ingested in some cases, causing an increase in serum cisapride levels due to inhibition of cisapride metabolism (Wysowski & Bacsanyi, 1996; (Piquette, 1999).
    C) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT/INFANT - A 2-month-old infant, with gastroesophageal reflux disease, was treated with cisapride, 0.3 mg/kg every 6 hours, and subsequently developed bradycardia. An ECG revealed a 2:1 atrioventricular conduction (atrial rate of 196 beats/min and a ventricular rate of 98 beats/min) and a prolonged corrected QT interval of 510 milliseconds. Sinus rhythm returned to normal and the QT interval decreased to 410 milliseconds on discontinuation of the drug (Lewin et al, 1996). Gunasekaran & DuBrow (1998) also reviewed this case and suggested that the role of ranitidine, also used to treat this infant, could have been a possible causative effect of the prolonged QT interval.
    b) CASE REPORT/ADULT - A 64-year-old male developed syncope, QT interval prolongation, and non-sustained ventricular tachycardia seven days after beginning high-dose cisapride therapy, 40 mg every 6 hours. Over the next 6 days, the cisapride dosage was gradually reduced to 5 mg four times daily, causing the patient's QT interval to return to normal (Bran et al, 1995).
    c) The FDA's MedWatch reporting program received reports, from September 1993 to April 1996, of 23 patients who developed prolonged QT intervals while on cisapride therapy. Imidazole antifungal agents or macrolide antibiotics may have been concurrently ingested in some cases, causing an increase of serum cisapride levels due to inhibition of cisapride metabolism (Wysowski & Bacsanyi, 1996).
    d) CASE REPORT - A 53-year-old female was reported to have QT prolongation (0.456 sec on day of admission with previous baseline of 0.380 sec) with syncopal episodes following concurrent use of cisapride with clarithromycin, promethazine, fluoxetine, clonidine, and omeprazole. Drug interactions were suggested to be the causative factor (Gray, 1998).
    e) CASE SERIES - Prospective exam of cisapride's effect on QT interval was evaluated in 100 children. A modest increase in QT interval (mean change in QTc of 15.5 msec, or 4%) was associated with cisapride therapy, with an incidence of QTc >440 msec being low. Other factors that would result in increased cisapride serum levels appeared to have compounded long QTc intervals in most children (Khongphatthanayothin et al, 1998).
    f) CASE SERIES - Khoshoo et al (2000) reported a 2% (2 out of 100) incidence of QT prolongation of corrected QT interval beyond the normal range (456 and 486 milliseconds) in infants aged 3 to 6 months given cisapride 1 mg/kg per 24 hours for up to 4 months. No evidence of dysrhythmias or conduction defects on ECG was seen.
    g) CASE SERIES - Scott et al (2000) studied the effect of cisapride on QT interval in 9 patients with end-stage renal disease (ESRD). They found that cisapride therapy resulted in significantly prolonged QTc intervals in these patients on hemodialysis, suggesting a predisposition to developing cardiac dysrhythmias in ESRD patients taking cisapride.
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) Cisapride, given to rats at doses of 50 to 400 mcg/kg IV, caused immediate dose-related hypotension. Antimuscarinic agents, given to the rats 10 minutes prior to the dose of cisapride, caused partial inhibition of the hypotensive response to cisapride (Onat et al, 1994).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Bronchospasm is a rare occurrence associated with cisapride ingestion.
    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm developed in three patients (two with stable asthma) following ingestion of cisapride, 10 to 30 mg two to three times daily (Pillans, 1995).
    b) CASE REPORT - An 18-year-old female, with severe steroid-dependent asthma, developed chest tightness and wheeze 3 hours after beginning cisapride therapy, 10 mg three times daily, to treat gastroesophageal reflux disease. The patient's peak flow rate (PFR) at baseline was 490 L/min and, after the symptoms of chest tightness and wheeze began, her PFR dropped to 360 L/min. The PFR returned to baseline after withdrawal of cisapride therapy (Nolan et al, 1990).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headaches may commonly occur with oral cisapride administration.
    2) Seizures, insomnia, anxiety, extrapyramidal effects, and the appearance of neuroleptic malignant syndrome are rare occurrences associated with therapeutic administration of cisapride.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches were reported in 19.3% of 1728 patients involved in cisapride U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) There have been rare reports of seizures occurring during cisapride U.S. and international clinical trials. A relationship between the occurrence of seizures and cisapride use was not clearly established (Prod Info Propulsid(R), cisapride, 1993).
    C) CENTRAL STIMULANT ADVERSE REACTION
    1) WITH THERAPEUTIC USE
    a) During cisapride U.S. clinical trials, insomnia developed in 1.9% of 1728 patients, and anxiety and nervousness occurred in 1.4% (Prod Info Propulsid(R), cisapride, 1993).
    D) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) Extrapyramidal effects, including dystonic-like reactions, are less common occurrences with cisapride use (Prod Info Propulsid(R), cisapride, 1993; Bucci et al, 1995).
    b) CASE REPORT - Wax & Reiser (1995) reported a case of severe akathisias associated with initiation of cisapride therapy in a 48-year-old female. Agitation, uncontrollable shaking, and running in circles began after the third dose. Symptoms resolved following a dose of lorazepam.
    E) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 77-year-old active male presented to the ED with a diagnosis of neuroleptic malignant syndrome following one month therapy with cisapride and metoclopramide for gastroparesis. Concurrently with NMS, the patient experienced alternating hyperventilation with apnea. Eight days after discontinuing the two drugs, his symptoms improved. Death occurred 45 days later as a result of asphyxiation from vomiting. Necropsy revealed an almost normal CNS (Shintani et al, 1995). The contribution of metoclopramide was probably more a factor to the NMS than that of cisapride.

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Gastrointestinal distress, including diarrhea, abdominal pain, dyspepsia, nausea, constipation, and flatulence have been reported.
    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported in 14.2% of 1728 patients who ingested cisapride during U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).
    b) In a therapeutic study of oral cisapride, 4% of 851 patients developed diarrhea (Bennett, 1989).
    c) Diarrhea and abdominal cramps developed in a patient who ingested 540 mg of cisapride in a suicide attempt. The patient's recovery was complete (Bennett, 1989).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Approximately 173 patients developed abdominal pain and 47 patients developed dyspepsia during the U.S. clinical trials for cisapride (Prod Info Propulsid(R), cisapride, 1993).
    2) WITH POISONING/EXPOSURE
    a) Abdominal cramps and diarrhea occurred in a patient following a 540 mg overdose of cisapride (Bennett, 1989).
    C) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 131 patients involved with the cisapride U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Approximately 116 of 1728 patients, involved in the cisapride U.S. clinical trials, developed constipation as a result of cisapride ingestion (Prod Info Propulsid(R), cisapride, 1993).
    E) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Flatulence was reported in 3.5% of 1728 patients following therapeutic administration of cisapride during U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).
    2) WITH POISONING/EXPOSURE
    a) An adult overdosed on 540 mg of cisapride and, 2 hours later, experienced retching, borborygmi, flatulence, stool frequency, and urinary frequency (Prod Info Propulsid(R), cisapride, 1993).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzymes and hepatitis are rare occurrences that have been reported during the U.S. and international clinical trials for cisapride. A relationship between the occurrence of hepatotoxicity and cisapride use was not clearly established (Prod Info Propulsid(R), cisapride, 1993).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Urinary frequency and incontinence, and vaginitis have been associated with the therapeutic administration of cisapride.
    3.10.2) CLINICAL EFFECTS
    A) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) Urinary frequency has been reported following therapeutic oral administration of cisapride (Prod Info Propulsid(R), cisapride, 1993; Boyd & Rohan, 1994; Pillans & Wood, 1994).
    2) WITH POISONING/EXPOSURE
    a) An adult experienced stool and urinary frequency 2 hours after an overdose ingestion of 540 mg (Prod Info Propulsid(R), cisapride, 1993).
    B) URINARY INCONTINENCE
    1) WITH THERAPEUTIC USE
    a) Urinary incontinence was reported in 5 of 12 patients who described urinary tract disorders, following cisapride use, to the Adverse Drug Reactions Advisory Committee between 1991 and 1993. The onset of the incontinence usually began within 36 hours of starting cisapride therapy. All patients recovered after the cisapride was discontinued (Boyd & Rohan, 1994).
    C) VAGINITIS
    1) WITH THERAPEUTIC USE
    a) Vaginitis developed in 1.2% of 1728 patients following cisapride therapy during U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Bone marrow suppression, including thrombocytopenia, leukopenia, aplastic anemia, pancytopenia and granulocytopenia were rare occurrences that have been reported during the cisapride U.S. and international clinical trials. A relationship between the occurrence of bone marrow suppression and cisapride use was not clearly established (Prod Info Propulsid(R), cisapride, 1993).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rashes and pruritus were uncommon effects following cisapride therapy.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rashes occurred with 1.6% of 1728 patients and pruritus occurred with 1.2% of patients following cisapride therapy during U.S. clinical trials (Prod Info Propulsid(R), cisapride, 1993).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Arthralgias have been reported following therapeutic administration of cisapride.
    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Approximately 24 of 1728 patients, who ingested cisapride during U.S. clinical trials, developed arthralgias (Prod Info Propulsid(R), cisapride, 1993).

Reproductive

    3.20.1) SUMMARY
    A) Cisapride is classified as FDA Pregnancy Category C.
    B) Cisapride is excreted in human breast milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    CisaprideC
    Reference: Prod Info Propulsid(R), 1993.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Cisapride is excreted in human breast milk at concentrations approximately one-twentieth of the concentrations observed in plasma (Prod Info Propulsid(R), cisapride, 1993).
    2) Approximately 0.1% of an administered dose of cisapride is excreted in breast milk (Lauritsen et al, 1990).
    3) A study was conducted to determine the amount of cisapride excreted in human breast milk. Ten puerperal women were given oral cisapride, 20 mg every 8 hours for four days. The breast milk was then collected and tested for the appearance of cisapride.
    a) It was determined that the amount that would have been ingested by an infant was 1 mcg/kg/day, approximately 0.1% of the dose of the mother. This amount is 600 to 800 times lower than the usual therapeutic dose for an infant (Hofmeyr & Sonnendecker, 1986).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum levels of cisapride are not clinically useful.
    B) Monitor electrolyte levels if the patient experiences severe and prolonged diarrhea.
    C) Obtain an ECG and institute continuous cardiac monitoring for possible QT prolongation and dysrhythmias.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum levels of cisapride are not clinically useful.
    2) Monitor electrolyte levels if the patient experiences severe and prolonged diarrhea.
    B) COAGULATION STUDIES
    1) Coagulation times should be monitored one week after the start and discontinuation of cisapride therapy when cisapride is concurrently administered with anticoagulants (Prod Info Propulsid(R), cisapride, 1993).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring for possible QT prolongation and dysrhythmias.

Methods

    A) CHROMATOGRAPHY
    1) Cisapride neonatal plasma concentrations were measured using a high- performance liquid chromatographic (HPLC) method (Preechagoon & Charles, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Serum levels of cisapride are not clinically useful.
    B) Monitor electrolyte levels if the patient experiences severe and prolonged diarrhea.
    C) Obtain an ECG and institute continuous cardiac monitoring for possible QT prolongation and dysrhythmias.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) TACHYARRHYTHMIA
    1) Sinus tachyarrhythmias do not need to be routinely treated (slowed) unless the patient demonstrates signs and/or symptoms of hemodynamic instability. In those cases, tachyarrhythmias may respond to IV esmolol.
    2) TACHYCARDIA SUMMARY
    a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    c) ESMOLOL/ADULT LOADING DOSE
    1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).
    d) ESMOLOL/ADULT MAINTENANCE DOSE
    1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
    2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
    3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    e) CAUTION
    1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).
    B) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    8) ANIMAL STUDY/MEXILETINE: Following cisapride overdosing in canines resulting in long QT syndrome, mexiletine (3 mg/kg IV) was administered, which increased the heart rate, shortened the repolarization phase and prolonged the effective refractory period. Mexiletine may be a potential treatment for cisapride-induced long QT syndrome. Caution should be observed in the presence of preexisting impaired cardiac function, since mexiletine could suppress the ventricular contraction together with a decrease of cardiac output, leading to potential cardiovascular collapse (Satoh et al, 2000).
    C) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).

Abstracts

Case Reports

    A) ADVERSE EFFECTS
    1) DYSTONIC REACTION - A 43-year-old female was started on oral cisapride therapy, 10 mg four times daily, to treat gastroesophageal reflux disease, and 3 days later, developed a dystonic-like reaction. The patient rhythmically moved her head from side to side while staring into space, was generally unresponsive to external stimuli, had increased muscle tone, exhibited occasional tongue protrusion, and walked with a slow shuffling gait (Bucci et al, 1995).
    a) The patient recovered completely following administration of diphenhydramine and discontinuation of cisapride.
    2) QT PROLONGATION - Bran et al (1995) present a case of a 64-year-old male who developed syncope and diaphoresis on the 7'th day of cisapride therapy, 40 mg every 6 hr for gastritis. He had no history of cardiac arrhythmias, and ECG was normal prior to initiation of cisapride therapy.
    a) Telemetry revealed a QT prolongation of 0.55 ms with occasional ectopic ventricular activity. Serum potassium and magnesium were low (3.4 mmol/L and 0.65 mmol/L, respectively). QT interval remained prolonged, even after correction of electrolytes. Then, on dose reduction of cisapride to 5 mg 4 times daily, the QT interval returned to normal.

Range Of Toxicity

Summary

    A) An acute overdose ingestion of cisapride, 540 milligrams, was reported in an adult with mild toxicity.
    B) Dysrhythmias may develop at therapeutic doses in patients with other risk factors (other drugs causing QTC prolongation, drugs that inhibit cytochrome P450 3A4, electrolyte abnormalities, underlying cardiac disorders).

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) CISAPRIDE - Usual adult dose is 10 milligrams four times daily 15 minutes before meals and at bedtime. Dosage may be increased to 20 milligrams 4 times daily (Prod Info Propulsid(R), cisapride, 1993). The drug was removed from the United States and United Kingdom markets in 2000 ((Anon, 2000)).
    2) RENZAPRIDE - Preliminary clinical trials have found 1 to 2 milligrams to be effective (Mackie et al, 1991; Robertson et al, 1989; Staniforth & Rose, 1989).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) CISAPRIDE - The efficacy and safety in children has not been established (Prod Info Propulsid(R), cisapride, 1993) and the drug is no longer available in the United States nor the United Kingdom ((Anon, 2000)).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) CISAPRIDE - The Food and Drug Administration's MedWatch reporting program, between September 1993 to April 1996, reported four fatalities that occurred following ingestions of cisapride and the subsequent development of dysrhythmias (Wysowski & Bacsanyi, 1996).

Maximum Tolerated Exposure

    A) ADULT
    1) CISAPRIDE -
    a) An adult ingested 540 milligrams of cisapride. Within 2 hours he/she experienced retching, borborygmi, flatulence, stool frequency, and urinary frequency (Prod Info Propulsid(R), cisapride, 1993).
    b) A 64-year-old male developed QT interval prolongation and syncope following administration of high-dose cisapride, 40 milligrams every 6 hours. The syncope and QT interval prolongation resolved when the cisapride dosage was reduced to 5 milligrams four times daily (Bran et al, 1995).
    B) INFANT
    1) CISAPRIDE -
    a) A 2-month-old infant developed 2:1 atrioventricular conduction (atrial rate of 196 beats/minute and ventricular rate of 98 beats/minute) and a prolonged corrected QT interval of 510 milliseconds following initiation of cisapride therapy, 0.3 milligrams/kilogram every 6 hours. The corrected QT interval and the sinus rhythm returned to normal after the discontinuation of cisapride (Lewin et al, 1996).
    C) ACUTE
    1) CISAPRIDE -
    a) TDLo - (UNREPORTED) HUMAN, Female: 200 mcg/kg (RTECS , 2000)

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CISAPRIDE
    1) LD50- (ORAL)MOUSE:
    a) 8715 mg/kg (RTECS, 2000)
    b) 1280 mg/kg (Prod Info Propulsid(R), 1993)
    2) LD50- (ORAL)RAT:
    a) 4166 mcg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cisapride increases the release of acetylcholine at the myenteric plexus level of the gastrointestinal tract, increases the lower esophageal resting tone, and increases the amplitude of lower esophageal contractions. Gastrointestinal motility is then stimulated, gastric emptying is accelerated, and colonic peristalsis is increased (Reynolds, 1996).
    B) Renzapride is a type 3 serotonin antagonist and a type 4 serotonin agonist. Following a therapeutic dose, renzapride blocks serotonin 3 receptors and stimulates serotonin 4 receptors; it does not exhibit dopamine D(2) receptor antagonism. It also has been shown to stimulate gastric acid secretion during low-dose pentagastrin infusion, and block secretion during high-dose pentagastrin stimulation. Due to this interchange of mechanisms, this drug lowers esophageal sphincter pressure and increases gastric emptying.

References

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