Dynabac Side Effects, and Drug Interactions - Dirithromycin

Dynabac Side Effects, and Drug Interactions - Dirithromycin

SIDE EFFECTS

Clinical Trials:   In clinical trials, 3299 patients were treated with dirithromycin 500 mg q.d. P.O. for approximately 7 to 14 days. There were no deaths or permanent disabilities thought related directly to drug toxicity. Eighty-seven (2.6%) patients discontinued medication due to adverse reactions. Thirty-five (40%) of the 87 patients who discontinued therapy did so because of nausea or abdominal pain.

In additional clinical trials conducted in North America, 932 patients were treated with dirithromycin 500 mg q.d. for 5 days. There were no deaths or permanent disabilities thought to be related directly to drug toxicity. Thirty-five (3.8%) patients discontinued medication due to adverse reactions. Fifteen (43%) of the 35 patients who discontinued therapy did so because of nausea or abdominal pain.

The following adverse clinical and laboratory reactions were reported during the dirithromycin clinical trials conducted in North America (n=1894 patients treated for 7-14 days and 932 patients treated for 5 days). (See Tables 2 and 3.)

Adverse reactions occurring during all clinical trials with dirithromycin with an incidence of less than 1% but greater than 0.1% included the following (listed alphabetically):

Abnormal stools, allergic reaction, amblyopia, anorexia, anxiety, constipation, dehydration, depression, dry mouth, dysmenorrhea, dysphagia, edema, epistaxis, eye disorder (not further defined), fever, flu syndrome, gastritis, gastroenteritis, hemoptysis, hyperventilation, insomnia, malaise, mouth ulceration, myalgia, myasthenia, neck pain, nervousness, palpitation, paresthesia, peripheral edema, somnolence, sweating, syncope, taste perversion, thirst, tinnitus, tremor, urinary frequency, vaginal moniliasis, vaginitis, vasodilatation.

Adverse laboratory reactions occurring during all clinical trials with dirithromycin with an incidence of less than 1% but greater than 0.1% included the following (listed alphabetically):

Decreased: Albumin, chloride, hematocrit, hemoglobin, lymphocytes, segmented neutrophils, phosphorus, platelet count, serum alkaline phosphatase, serum uric acid, and total protein.

Increased: Alkaline phosphatase, ALT, AST, basophils, calcium, creatinine, GGT, leukocyte count, lymphocytes, hematocrit, hemoglobin, monocytes, phosphorous, total bilirubin, and uric acid.

Macrolide-class adverse reactions Although not observed in patients treated with dirithromycin in clinical trials, the following adverse reactions and altered laboratory test results have been reported in patients treated with macrolide antibiotics:

Bullous fixed eruptions or serious allergic reactions, including anaphylaxis, have been reported. A few cases of transient deafness have been reported with high doses of oral erythromycin. Rarely, cholestatic hepatitis has been reported. In individuals with prolonged QT intervals, erythromycin has been associated, rarely, with the production of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes.

Terfenadine In a prospective study involving six-healthy-male volunteers, dirithromycin did not affect the metabolism of terfenadine. These six volunteers received terfenadine alone (60 mg twice daily) for 8 days, followed by terfenadine in combination with dirithromycin (500 mg once daily) for 10 days. (Both drugs were thus dosed to steady state.) The pharmacokinetics of terfenadine and its acid metabolite and the electrocardiographic QT _c interval were measured during both periods: with terfenadine alone, and with terfenadine plus dirithromycin. In five men, terfenadine levels were undetectable (<5 ng/mL) throughout the study; in one man, the C _max of terfenadine was 8.1 ng/mL with terfenadine alone and 7.2 ng/mL with terfenadine plus dirithromycin. The mean C _max , T _max , and AUC of the acid metabolite of terfenadine were not significantly changed. The mean QT _c interval (msec) was 369 with terfenadine alone and 367 with terfenadine plus dirithromycin.

Also, in vitro experiments demonstrated a lack of interaction between dirithromycin and terfenadine. Thus, the interaction observed between erythromycin and terfenadine is not expected for dirithromycin.

Serious cardiac dysrhythmias, some resulting in death, have occurred in patients receiving terfenadine concomitantly with other macrolide antibiotics. In addition, most macrolides are contraindicated in patients receiving terfenadine therapy who have pre-existing cardiac abnormalities (arrhythmia, bradycardia, QT _c interval prolongation, ischemic heart disease, congestive heart failure, etc.) or electrolyte disturbances. (See terfenadine package insert.)

Theophylline Following co-administration of two 250-mg dirithromycin tablets administered once daily with 200-mg theophylline tablets administered twice daily for 10 days to 14 healthy subjects, the steady-state plasma concentration of theophylline was not significantly altered. In general, most patients treated with dirithromycin who are receiving concomitant theophylline therapy may not require empiric adjustment of theophylline dosage or monitoring of theophylline plasma concentrations. However, theophylline plasma concentrations should be monitored, with dosage adjustment as appropriate, in patients whose pulmonary disease requires maintaining a given theophylline plasma concentration for optimal pulmonary function or in patients with theophylline concentrations at the higher end of the therapeutic range.

Antacids or H ₂ receptor antagonists When dirithromycin is administered immediately following antacids or H ₂ -receptor antagonists, the absorption of dirithromycin is slightly enhanced.

The following drug interactions have been reported with erythromycin products. It is presently not known whether these same drug interactions occur with dirithromycin. Until further data are available regarding the potential interaction of dirithromycin with these compounds, caution should be used during coadministration.

Triazolam Erythromycin has been reported to decrease the clearance of triazolam and, thus, may increase the pharmacologic effect of triazolam.

Digoxin Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels.

Anticoagulants There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly. Increased anticoagulation effects due to a drug interaction with erythromycin may be more pronounced in the elderly.

Ergotamine Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.

Other drugs Drug interactions have been reported with concomitant administration of erythromycin and other medications, including cyclosporine, hexobarbital, carbamazepine, alfentanil, disopyramide, phenytoin, bromocriptine, valproate, astemizole, and lovastatin.