The P-I-E-N-O Parkinsn's List Drug Database
cisapride / PropulsidTM
PROKINETIC:
Promotility agent
Description: Cisapride is an oral gastrointestinal prokinetic agent indicated for the treatment of gastroesophageal reflux disease (GERD). Although chemically similar to metoclopramide, cisapride lacks the central nervous system-depressant and antidopaminergic effects that can occur with metoclopramide. In comparative trials of cisapride with metoclopramideD and HA- blockersD DD in patients with GERD, cisapride was shown to be at least as effective as these agents. Also, combination therapy of cisapride with cimetidine or ranitidine produced higher healing rates than did either agent alone in the treatment of esophagitis.DĽ Cisapride was approved for use in July 1993.
Mechanism of Action: Cisapride promotes acetylcholine release from postganglionic nerve endings in the myenteric plexus- longitudinal muscles of the GI tract, thereby indirectly improving gastrointestinal motility. The exact mechanism by which cisapride exerts its prokinetic effects is not known. It has been shown that it acts as both an agonist and antagonist at serotonin receptors throughout the GI tract. Animal studies reveal cisapride is an agonist at type 4 serotonin (5-HTA) receptors and is an antagonist at type 3 serotonin (5-HTA) receptors. It is believed that the prokinetic effects of cisapride are due more to actions at the 5-HTA receptor because agonism at this receptor causes relaxation of smooth muscle in rat esophagus and contraction of smooth muscle in human stomach and guinea-pig colon tissue.D
The resultant clinical effects seen with cisapride therapy include decreased exposure of the esophagus to gastric acid, increased lower esophageal sphincter pressure and esophageal motility, accelerated gastric emptying of both liquids and solids, and decreased colonic transit time. Consequently, these actions contribute to the relief of symptoms and the healing of lesions associated with reflux disease.
Pharmacokinetics: Cisapride is administered orally. Following oral administration, the absolute bioavailability of cisapride is about 40-50%. Peak plasma levels occur 1-2 hours after administration. Protein binding is approximately 98%, primarily to albumin. Metabolism is extensive with no active metabolites. Since cisapride is metabolized by the cytochrome P450 enzyme system (specifically, 3A4), it is susceptible to drug interactions with drugs that are known inhibitors of this system (e.g., erythromycin, ketoconazole). The elimination half-life of cisapride is about 10 hours in healthy volunteers and may be prolonged in patients with hepatic impairment or in the elderly. Cisapride pharmacokinetics are not altered in patients with renal impairment or in patients receiving hemodialysis.
CONTRAINDICATIONS/PRECAUTIONS: Cisapride is classified as pregnancy category C. Adequate studies in pregnant women have not been conducted, so cisapride should be used during pregnancy only when clearly needed. Cisapride is excreted into breast milk at a concentration of about one twentieth that found in maternal plasma. Caution is advised in prescribing cisapride to breast-feeding women.
The use of cisapride in patients in whom increased gastrointestinal motility can be harmful is not recommended. These patients include those with GI bleeding, GI obstruction, or GI perforation.
Cisapride is contraindicated in patients with a known sensitivity or intolerance to the drug. A careful patient history should be taken to determine previous cisapride intolerance or sensitivity.
Although a causal relationship with cisapride has not been established, rare cases of cardiac arrhythmias have been reported. Cisapride should be used with caution in patients with conditions associated with QT prolongation, such as congenital prolonged QT syndrome, uncorrected electrolyte imbalance, or patients taking medications known to prolong QT intervals. Most patients experiencing these adverse reactions were taking other medications, had pre-existing cardiac disease, or had risk factors for arrhythmias (see Adverse Reactions).
DRUG INTERACTIONS: The concurrent use of cisapride with anticholinergics is not recommended. The antimotility effects of drugs with anticholinergic activity will antagonize the beneficial GI effects of cisapride. Drugs with antimotility activity that should be avoided during therapy with cisapride include antispasmodic anticholinergics such as atropine, dicyclomine, and propantheline; certain HA-blockers; opiate agonists; and certain tricyclic antidepressants.
In the gut, octreotide inhibits serotonin while cisapride is a serotonin-receptor agonist. Although no data describing a drug interaction have yet been reported, it is conceivable that an interaction may occur based on the opposing pharmacologic actions of the two compounds. It would be wise to avoid concomitant use of these two drugs until it has been determined if a clinically-relevant interaction exists.
When cisapride is administered concurrently with either cimetidine or ranitidine, the gastrointestinal absorption of cimetidine or ranitidine is increased. Also, cisapride's peak plasma levels and AUC are increased when coadministered with cimetidine, but not with ranitidine.
Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically, isoenzyme 3A4. Postmarketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes, when ketoconazole, a known inhibitor of the cytochrome P450 system, was coadministered with cisapride (written communication, Janssen Pharmaceutica, 2/21/95). Ketoconazole has been shown to cause marked elevations in cisapride plasma concentrations when these drugs were coadministered (written communication, Janssen Pharmaceutica, 2/21/95). Ketoconazole and cisapride should not be coadministered. Although clinical data are not available, itraconazole, miconazole IV, and troleandomycin have been shown to inhibit the hepatic metabolism of cisapride in vitro. On October 14, 1995, the manufacturer issued a warning regarding concomitant use of any of the following drugs in combination with cispride: clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, miconazole, or troleandomycin. These drugs should also be used cautiously, if at all, with cisapride since all have the potential to inhibit the hepatic metabolism of cisapride.
Administration of cisapride to patients receiving anticoagulants, such as warfarin, caused a prolongation of coagulation times. When using these agents concurrently, it is important to monitor coagulation times and adjust doses of the anticoagulant as necessary.
Due to accelerated gastric emptying, cisapride can affect the rate of absorption of drugs that have a narrow therapeutic index or that require careful titration. Drugs that can have an increase in the rate or extent of absorption include acetaminophen, aspirin, diazepam, levodopa, lithium, and tetracycline. Plasma levels of these agents should be monitored, if possible, while receiving cisapride concurrently.
Because cisapride can enhance gastric emptying, blood glucose levels in diabetic patients can be affected, which, in turn, can affect dosing of insulin or oral hypoglycemics.
ADVERSE REACTIONS: The most common adverse reactions associated with cisapride therapy are headache (19.2%), nausea/vomiting (7.6%), abdominal pain (10.2%), rhinitis (7.3%), diarrhea (14.2%), and constipation (6.7%). These reactions also occurred more frequently in patients receiving 20 mg of cisapride than in those receiving 10 mg. Other adverse effects attributed to cisapride therapy are flatulence, dyspepsia, sinusitis, coughing, viral infection, upper respiratory tract infection, pain, fever, urinary tract infection, urinary frequency, insomnia, anxiety, nervousness, rash, pruritus, arthralgia, abnormal vision, vaginitis, dizziness, vomiting, pharyngitis, angina, fatigue, back pain, depression, dehydration, and myalgia.
Although a causal relationship with cisapride has not been established, rare cases of cardiac arrhythmias have been reported. Sinus tachycardia has been reported with cisapride therapy. In these patients, rechallenge with the drug caused relapse of the sinus tachycardia. More serious ventricular arrhythmias have been documented, including QT prolongation and torsade de pointes. Most patients experiencing these adverse reactions were taking other medications (see Drug Interactions), had pre-existing cardiac disease, or had risk factors for arrhythmias.
Adverse events in which cisapride has not been clearly implicated include rare reports of seizures and extrapyramidal effects, elevated liver enzymes, hepatitis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia, and granulocytopenia.
PATIENT INFORMATION:
What do cisapride tablets do?
Cisapride (PropulsidTM ) helps to move gastric contents through the stomach, reducing exposure of the esophagus to gastric acid. Cisapride helps to control and relieve symptoms of gastroesophageal reflux disease such as heartburn. Generic cisapride tablets are not yet available.
What should my doctor, dentist, or pharmacist know before I take cisapride?
They need to know if you have any of these conditions:
How should I take this medicine?
Take cisapride tablets by mouth. Follow the directions on the label. Swallow the tablets with a drink of water. Take cisapride on an empty stomach, at least 15 minutes before eating; and take at bedtime. Do not take your medicine more often than directed.
Special precautions for use in children:
This medicine is not for children.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses. Do not take regularly for more than one week.
What other medicines can interact with cisapride?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Tell your doctor before stopping or starting any of your medicines.
What side effects may I notice from taking cisapride?
Serious side effects with cisapride are rare; they include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with cisapride include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take cisapride?
Visit your doctor for a regular check on your progress. For cisapride to work properly it is important to undertake other non-drug therapy. Eat smaller meals, which puts less pressure in your stomach; elevate the head of your bed 6-8 inches, which allows gravity to work in your favor to decrease the amount of reflux; avoid high-fat foods and chocolate because they can cause heartburn; avoid alcohol and avoid smoking because these can also contribute to the development of heartburn; avoid caffeine in large amounts such as in coffee; and avoid carbonated drinks.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store in a cool, dry place at a controlled room temperature between 15-30C (59-86F). Protect the 20 mg tablets from light. Throw away any unused medicine after the expiration date.
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