Prokine

Prokine® (Prokine) 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, Prokine® should generally be reserved for patients who do not respond adequately to lifestyle modifications, antacids and gastric acid reducing agents.

Prokine increases the rate at which your esophagus, stomach, and intestines move during digestion. It also increases the rate at which your stomach empties into your intestines and increases the strength of your lower esophageal sphincter (the muscle between your stomach and your esophagus).

Prokine is used to treat gastric reflux (the regurgitation of stomach acid into the esophagus), which is usually experienced as heartburn.

Prokine may also be used for purposes not listed in this medication guide.

5 ml (1 teaspoon) suspension = 5 mg.

Adults

Initiate therapy with one 10 mg tablet of Prokine 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.

Prokine should be discontinued if relief of nocturnal heartburn does not occur. The minimum effective dose should be used. Recommended doses of Prokine 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

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

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

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.

See also:
What is the most important information I should know about Prokine?

The concomitant oral or parenteral use of the following potent cytochrome P450 3A4 inhibiting drugs may lead to elevated Prokine blood levels and is contraindicated.

Antifungals: oral or i.v. fluconazole, itraconazole, ketoconazole.

Antibiotics: oral or i.v. erythromycin, clarithromycin.

Protease Inhibitors: ritonavir, indinavir (in vitro studies suggest that saquinavir is only a weak inhibitor).

Antidepressants: nefazodone.

Prokine 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 or in patients who might experience rapid reduction of plasma potassium such as those administered potassium-wasting diuretics and/or insulin in acute settings); 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 and terfenadine.

The preceding lists of drugs are not comprehensive.

Prokine is contraindicated in prematurely born infants (born at gestational age of less than 36 weeks), from 0 through 3 months after the delivery date.

Prokine is contraindicated in patients with known sensitivity or intolerance to the drug.

Prokine is contraindicated whenever gastrointestinal stimulation might be dangerous, i.e., gastrointestinal hemorrhage, mechanical obstruction or perforation.

Manufacturers’ Warnings In Clinical States: Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking Prokine with other drugs that inhibit cytochrome P450 3A4. Prokine is contraindicated in patients taking any of these drugs. Some of these contraindicated drugs are listed in the Contraindications section. Some of these patients did not have cardiac disease. However, most had been receiving multiple other medications and had pre-existing cardiac disease or risk factors for arrhythmias. QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest and sudden death have been reported in patients taking Prokine without the above-mentioned contraindicated drugs. Most patients had disorders that may have predisposed them to arrhythmias with Prokine. Some of these events have been fatal.

Prokine is contraindicated in patients with the following risk factors for cardiac arrhythmia: uncorrected electrolyte disturbances (hypokalemia, hypomagnesemia such as seen in patients taking potassium-wasting diuretics, severe dehydration, vomiting, malnutrition, or in patients who might experience a rapid reduction of plasma potassium, such as insulin administered in acute settings), renal failure (particularly when on chronic dialysis), chronic obstructive pulmonary disease, respiratory failure, conditions associated with QT prolongation (such as congenital long QT syndrome, idiopathic QT prolongation, QT prolongation associated with diabetes mellitus, combination with medications known to prolong the QT interval), prolonged QT interval at baseline and history of significant cardiac disease (including serious ventricular arrhythmia, torsades de pointes, second or third degree AV block, congestive heart failure, ischemic heart disease and sinus node dysfunction).

Additionally, concomitant medications known to prolong the QT interval risk of arrhythmia, such as certain antiarrhythmics, including those of Class 1A (such as but not limited to quinidine and procainamide) and Class III (such as but not limited to amiodarone and sotalol); tricyclic antidepressants (such as but not limited to amitriptyline); certain tetracyclic antidepressants (such as but not limited to maprotiline); certain antipsychotic medications (such as but not limited to certain phenothiazines); astemizole and terfenadine should also be avoided.

The preceding lists of drugs are not comprehensive.

Potential benefits should be weighed against risks prior to the administration of Prokine to patients who have, or may develop prolongation of cardiac conduction intervals, particularly QTc. In addition, patients with or suspected of having the above risk factors should be evaluated prior to the administration of Prokine. An ECG should be considered as part of this evaluation to exclude a prolonged QT interval.

Prokine is used in adults in the treatment of night-time heartburn that occurs when stomach contents reflux in to the food pipe (gastro esophageal reflux disease [GERD]).

See also:
What other drugs will affect Prokine?

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

Antibiotics: In vitro and/or in vivo data show that clarithromycin, erythromycin, and troleandomycin markedly inhibit the metabolism of Prokine, which can result in an increase in plasma Prokine levels and prolongation of the QT interval on the ECG.

Anticholinergics: Concurrent administration of certain anticholinergic compounds, such as belladonna alkaloids and dicyclomine, would be expected to compromise the beneficial effects of Prokine.

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

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

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

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

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

Other: Coadministration of grapefruit juice with Prokine increases the bioavailability of Prokine and concomitant use should be avoided.

Prokine should 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 Prokine 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.

See also:
What are the possible side effects of Prokine?

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

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

Diarrhea, abdominal pain, constipation, flatulence and rhinitis all occurred more frequently in patients using 20 mg of Prokine® 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.

In other U.S. and international trials and in postmarketing experience, there have been rare reports of seizures and extrapyramidal effects. Also reported have been tachycardia, elevated liver enzymes, hepatitis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia and granulocytopenia. The relationship of Prokine® to the event was not clear in these cases.

Cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation, in some cases resulting in death, have been reported.

Ongoing Postmarketing Surveillance: Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking Prokine®. From July 1993 through May 1999, more than 270 such cases have been spontaneously reported, including 70 fatalities. In approximately 85% of these cases the events occurred when Prokine®was used in patients with known risk factors. These risk factors included the administration of other drugs which caused QT prolongation, inhibited the cytochrome P450 3A4 enzymes that metabolize Prokine, or depleted serum electrolytes; or the presence of disorders that may have predisposed patients to arrhythmias. In approximately 0.7% of these cases, the events occurred in the absence of identified risk factors; in the remaining cases, risk factor status was unknown. Because the cases were reported voluntarily from a population of unknown size, estimates of adverse event frequency cannot be made. Prokine®-induced serious ventricular arrhythmias and death may not correlate with the degree of drug-induced prolongation of the QT interval detected by 12-lead ECG.

In addition to the cardiovascular adverse events, the following events have been identified during post-approval use of Prokine® 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 Prokine®: allergic reactions, including bronchospasm, urticaria, and angioedema; possible exacerbation of asthma; psychiatric events, including confusion, depression, suicide attempt, and hallucinations; extrapyramidal effects including akathisia, Parkinson-like symptoms, dyskinetic and dystonic reactions; 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 reaction.

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

In many countries (including Canada) Prokine has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to Prokine, which predisposes to arrhythmias. The FDA issued a warning letter regarding this risk to health care professionals and patients.