P&T News: May 1996, Vol. 16, No. 11

Safety Updates: Alendronate, Astemizole, Cisapride, and Tramadol

Pharmacy and Therapeutics Subcommittee of the University Hospital Advisory Committee and the Pharmcy Department
Peer Review Status: Internally Peer Reviewed

Alendronate
Alendronate is an aminobiphosphonate that is indicated for the treatment of osteoporosis in postmenopausal women (10 mg daily) and the treatment of Paget's disease of bone (40 mg daily).

In controlled clinical trials of three years duration in postmenopausal women with osteoporosis, it was recognized that alendronate had the potential to cause local irritation of the upper gastrointestinal mucosa. Esophageal ulcers considered to be drug related were reported in 1.5% of patients taking alendronate in the three-year trials. Since the drug has been marketed, a number of cases of esophagitis and esophageal ulceration in which patients have presented with difficulty or pain on swallowing, and/or retrosternal pain have been reported. When endoscopy was performed, the findings have been consistent with a chemical irritation of the esophagus.

Although infrequent, the reports of esophagitis/ulceration have generally been of a more severe nature than observed in either previous clinical trials, or in ongoing studies of alendronate. In a large majority of the postmarketing reports, it appears patients were not compliant with package insert recommended dosing instructions (e.g., patients were taking alendronate with little or no water, taking it at bedtime and/or lying down within minutes after taking it). Several patients continued taking alendronate after the occurrence of symptoms suggestive of esophageal irritation. In a few cases, patients have been found to have previously undiagnosed esophageal disorders.

In response to these reports, the dosage instructions in hte package insert have been updated. These revised dosing recommendations are outlined below.

Summary of Important Dosing Recommendations for Fosamax&#174 to Reduce the Risk for Esophageal Side Effects

Fosamax&#174 is contraindicated in patients with abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; and in patients who are unable to stand or sit upright for at least 30 minutes (following the administration of the drug).   The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking Fosamax&#174 and/or fail to swallow it with a full glass (6 to 8 oz.) of water, or who continue to take Fosamax&#174 after developing symptoms suggestive of esophageal irritation. Therefore it is very important that the full dosing instructions are provided to, and understood by, the patient.   Because of possible irritant effects of Fosamax&#174 on the upper gastrointestinal mucosa, caution should be used when Fosamax&#174 is given to patients with active upper gastrointestinal problems, such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers.

PLEASE NOTE THE FOLLOWING: Fosamax&#174 should be taken with plain water only, the first thing upon arising for the day, at least 30 minutes before the first food, beverage, or medication of the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients should be instructed to swallow Fosamax&#174 with a full glass (6 to 8 oz.) of water and not lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet. Patients should be specifically instructed not to take Fosamax&#174 at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems. Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn), they should stop taking Fosamax&#174 and consult their physician. In the case of overdosage, milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.

Source: Merok and Company March 1996

Astemizole
The administration of quinine (doses of 430 mg or higher) is now contraindicated with astemizole. This new contraindication is based on pharmacokinetic data and case reports which indicate that quinine may alter the pharmacokinetic parameters of astemizole, which may result in elevated plasma levels of astemizole and desmethylastemizole (an active metabolite).

Tonic water beverages contain varying amounts of quinine. The FDA does not allow more than 2.45 mg/ounce of quinine to be contained in a carbonated beverage. Results of a pharmacokinetic study demonstrated that daily consumption of 80 mg of quinine per day (equivalent to approximately 32 ounces of a tonic water beverage) did not significantly alter the pharmacokinetics of astemizole, nor was it associated with any clinically or statistically significant effect on the QT interval. However, quinine is sometimes prescribed for nocturnal leg cramps in doses of 260 to 300 mg per day.

The revised sections of the astemizole labeling are outlined below.

Contraindications Concomitant administration of astemizole with quinine is contraindicated because human data indicate that administration of quinine (single dose of 430 ma) with astemizole results in elevated plasma levels of astemizole and desmethylastemizole which is accompanied by electrocardiographic QT prolongation. These data also indicate that, although beverages containing quinine (up to 80 mg/day or about 32 ounces of tonic water) may elevate plasma levels of astemizole and desmethylastemizole, this effect is small and is not accompanied by significant prolongation of the QT interval. Warnings Concomitant Administration of astemizole with ketoconazole tablets, itraconazole, erythromycin, or quinine is contraindicated. Precautions: Drug Interactions Concomitant administration of astemizole with quinine is contraindicated. Precautions: Information for Patients Patients should be questioned about use of any other prescription or over-the-counter medication, and should be cautioned regarding the potential for life-threatening arrhythmias with concurrent use of ketoconazole, itraconazole, erythromycin, or quinine. Human data indicate that although beverages containing quinine (up to 80 mg/day or about 32 ounces of tonic water) may elevate plasma levels of astemizole and desmethylastemizole, this effect is small and is not accompanied by significant prolongation of the QT interval. Source: Janssen Pharmaceutica, March 1996

Cisapride
A number of drug interactions have been identified between cisapride and other drugs that inhibit cytochrome P450 3A4, resulting in serious cardiac arrhythmias. Interacting drugs include ketoconazole, itraconazole, fluconazole, miconazole, troleandomycin, erythromycin, and clarithromycin. The changes in the package insert are provided below and include a "boxed warning" at the beginning of the labeling.

Warnings: Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking PROPULSID&#174 with other drugs that inhibit cytochrome P450 3A4, such as ketoconazole, itraconazole, miconazole, troleandomycin, erythromycin, fluconazole, and clarithromycin. some of these events have been fatal. PROPULSID&#174 is contraindicated in patients taking any of these drugs.

Contraindications Concomitant administration of ketoconazole, itraconazole, miconazole, fluconazole, erythromycin, clarithromycin, or troleandomycin with PROPULSID&#174 is contraindicated. (See WARNINGS and PRECAUTIONS: Drug Interactions). Warnings PROPULSID&#174 undergoes metabolism mainly by the hepatic cytochrome P450 3A4 isoenzyme. Drugs which inhibit this enzyme such as ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, fluconazole, or troleandomycin can lead to elevated cisapride blood levels. Rare cases of serious cardiac arrhythmias, including ventricular arrhythmias and torsades de pointes associated with QT prolongation have been reported in patients taking cisapride with ketoconazole, itraconazole, miconazole, erythromycin, clarithromycin, or fluconazole. Some of these patients did not have known cardiac histories; however, most had been receiving multiple other medications and had pre-existing cardiac disease or risk factors for arrhythmias. Some of these cases have been fatal. Precautions General: Potential benefits should be weighed against risks prior to administration of cisapride to patients with conditions associated with QT prolongation, such as congenital prolonged QT syndrome, uncorrected electrolyte disturbances or in patients who are taking other medications known to prolong QT interval. Adverse Reactions Rare cases of cardiac arrhythmias, including ventricular arrhythmias, torsades de pointes, and QT prolongation, in some cases resulting in death, have been reported. Most of these patients had been receiving multiple other medications and had pre-existing cardiac disease or risk factors for arrhythmias. A causal relationship to PROPULSID&#174 has not been established. Source: Janssen Pharmaceutica, October 1995

Tramadol
Tramadol is a centrally acting analgesic indicated for the management of moderate to moderately severe pain. While initially promoted as a safer, non-addictive alternative to narcotic analgesics or nonsteroidal anti-inflammatory drugs, post-marketing surveillance has indicated that tramadol has the potential for abuse, seizures, and anaphylactoid reactions. The post-marketing surveillance information is outlined below. Tramadol is not stocked at UIHC.

Drug Abuse One hundred fifteen spontaneous domestic reports of adverse events described as drug abuse, dependence, withdrawal, or intentional overdose have been received. This does not include cases of accidental overdose. Patients with a past or present history of addiction or dependence on opioids account for the majority of these reports. ULTRAM should not be used in such patients. Seizures Eighty-three domestic reports of an adverse event described as seizures or convulsions have been received. Seizures have been reported after the first dose, at the recommended dosage range as well as at higher doses. In the majority of cases, a predisposing factor was identified. The risk of seizures is increased in patients taking concomitant medications that may reduce the seizure threshold (such as tricyclic antidepressants, and other tricyclic compounds, and selective serotonin reuptake inhibitors) and with certain medical conditions. Anaphylactoid Reactions Eleven domestic reports of anaphylactoid reactions have been received. Some of these reactions were reported to occur following the first dose and also in patients with a history of codeine allergy. Therefore, ULTRAM is contraindicated in patients hypersensitive to tramadol, any other component of this product, or opioids. Dosage and Administration It is important that patients clearly understand and adhere to the dosage and administration instructions for ULTRAM. Recommended single and daily dosages should not be exceeded in an attempt to enhance pain relief. The recommended single and total daily dosages, one to two 50 mg tablets q46hours, as needed, to a maximum of 400 mg/day, remain the same. Source: Ortho-McNeil Pharmaceutical, March 1996

Summary
The aforementioned examples illustrate the importance of reporting suspected adverse drug reactions and drug interactions.

These reports are used by the Food and Drug Administration and manufacturers to update prescribing information and healthcare professionals on evolving safety-related medication issues.

Next Page | Title Page