Dynabac® (dirithromycin tablets) contains the semi-synthetic macrolide antibiotic dirithromycin for oral administration. It is a pro-drug which is converted non-enzymatically during intestinal absorption into the microbiologically active moiety erythromycylamine.

Chemically, dirithromycin is designated (9 S )-9-Deoxo-11-deoxy-9,11-[imino[(1 R) -2-(2-methoxyethoxy)-ethylidene]oxy] erythromycin and has the molecular formula C ₄₂ H ₇₈ N ₂ O ₁₄ . Its molecular weight is 835.09. The structural formula is:

Chemically, erythromycylamine is designated 9- (S) -9-amino-9-deoxo-erythromycin and has a molecular formula of C ₃₇ H ₇₀ N ₂ O ₁₂ . Its molecular weight is 743.97. The structural formula is:

Dirithromycin is a basic compound. The free base is poorly soluble in water and readily soluble in polar organic solvents. Dirithromycin is hydrolyzed to erythromycylamine in acidic aqueous solutions; hydrolysis is virtually complete within 2 hours.

Dynabac tablets are enteric coated to protect the contents from gastric acid and to permit absorption of the antibiotic in the small intestine. Each enteric-coated tablet contains dirithromycin equivalent to 250 mg and the following inactive ingredients: benzyl alcohol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium carbonate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol, propylene glycol, sodium starch glycolate, talc, titanium dioxide, and triethyl citrate.

:    Absorption --Dirithromycin is rapidly absorbed and converted by nonenzymatic hydrolysis to the microbiologically active compound erythromycylamine. The absolute bioavailability of the oral formulation is approximately 10%. The pharmacokinetic parameters of erythromycylamine in plasma after single-and multiple-dose oral administration of two 250-mg Dynabac tablets once daily for 10 days in 10 fasting healthy subjects (19 to 50 years of age) were as follows:

Distribution --The protein binding of erythromycylamine ranges from 15% to 30%. Erythromycylamine is widely distributed throughout the body with a mean apparent volume of distribution (V _DSS ) of 800 L (504 to 1,041 L).

Rapid distribution of erythromycylamine into tissues and high concentrations within cells result in significantly higher concentrations in tissues than in plasma or serum. There are no data available on cerebrospinal fluid penetration.

Metabolism and Excretion --Erythromycylamine is primarily eliminated in the bile and undergoes little or no hepatic metabolism. Thus, the primary route of elimination is fecal/hepatic with 81% to 97% of the dose eliminated in this manner. Approximately 2% of the administered dose is eliminated through the kidney, mainly within the first 36 hours following drug administration.

The mean plasma half-life of erythromycylamine was estimated to be about 8 h (2 to 36 h), while a mean urinary terminal elimination half-life of about 44 h (16 to 65 h) and a mean apparent total body clearance of approximately 23 L/h (20 to 32 L/h) were observed in patients with normal renal function.

Food Effect on Absorption -- Dynabac tablets should be administered with food or within an hour of having eaten . The effect of food on the bioavailability of dirithromycin was evaluated following oral administration of two 250-mg Dynabac tablets 1 or 4 hours before food and immediately after a standard breakfast. Results obtained indicated a slight increase in the absorption of erythromycylamine when dirithromycin tablets were administered after food, while a significant decrease in C _max (33%) and AUC (31%) occurred when administer 1 hour before food. The effects of high and low fat meals on the bioavailability of dirithromycin were also investigated. The results showed that the amount of dietary fat had little or no effect on the bioavailability of dirithromycin.

Special Populations:

Hepatic Insufficiency --In patients with mild (Child's Grade A) hepatic impairment, mean peak serum concentration, AUC, and volume of distribution increased somewhat with multiple-dose administration; however, based on the magnitude of these changes, no dosage adjustment should be necessary in patients with mildly impaired hepatic function. The pharmacokinetics of dirithromycin in patients with moderate or severe impairment in hepatic function (Child's Grade B or greater) have not been studied.

Renal Insufficiency --The mean peak plasma concentration (C _max ) and AUC tended to increase as creatinine clearance decreased; however, based on data available to date, no dosage adjustment should be necessary in patients with impaired renal function, including dialysis patients.

Geriatric Patients --In a multiple-dose study in which 19 healthy elderly subjects (65 to 83 years of age) were given two 250-mg Dynabac tablets every day for 10 days, C _max and AUC tended to increase with age; however, neither C _max nor AUC was statistically or clinically significantly altered with age. Therefore, based on these pharmacokinetic results, no dosage adjustment should be necessary in elderly patients.

Microbiology:

Erythromycylamine, the microbiologically active product of dirithromycin hydrolysis, exerts its activity by binding to the 50S ribosomal subunits of susceptible mircoorganisms resulting in inhibition of protein synthesis.

Dirithromycin/erythromycylamine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the section:

Aerobic gram-positive microorganisms

   Staphylococcus aureus (methicillin-susceptible strains only)

   Streptococcus pneumoniae

   Streptococcus pyogenes

Aerobic gram-negative microorganisms

   Haemophilus influenzae

   Legionella pneumophila

   Moraxella catarrhalis

Other microorganisms

   Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown .

Dirithromycin exhibits in vitro minimum inhibitory concentrations (MIC's) of 0.5 µg/mL or less against most (>/= 90%) strains of streptococci and MIC's of 2 µg/mL or less against most (>/= 90%) strains of the other microorganisms in the following list; however, the safety and effectiveness of dirithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

   Listeria monocytogenes

  Streptococci, groups C, F, and G

   Streptococcus agalactiae

  Viridans group streptococci

Aerobic gram-negative microorganisms

   Bordetella pertussis

Anaerobic microorganisms

   Propionibacterium acnes

NOTE:   Microorganisms that are resistant to other macrolides are cross-resistant to dirithromycin/erythromycylamine. Enterococci and most strains of methicillin-resistant staphylococci are resistant to macrolides.

Susceptibility Tests:    Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method, ¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of dirithromycin powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae and streptococci:

For testing Haemophilus influenzae ^a :

For testing streptococci including Streptococcus pneumoniae ^b :

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard dirithromycin powder should provide the following MIC values:

Diffusion Techniques:   Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure ² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-µg dirithromycin to test the susceptibility of microorganisms to dirithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-µg dirithromycin disk should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae and streptococci:

For testing streptococci including Streptococcus pneumoniae ^e :

Due to lack of standardized methodology and interpretive criteria, it is impossible at present to determine if strains of Haemophilus are susceptible or are resistant to dirithromycin/erythromycylamine using the disk diffusion assay.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for dirithromycin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-µg dirithromycin disk should provide the following zone diameters in these laboratory quality control strains:

Dynabac (dirithromycin tablets) is indicated for the treatment of individuals age 12 years and older with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Dirithromycin should not be used in patients with known, suspected, or potential bacteremias as serum levels are inadequate to provide antibacterial coverage of the blood stream.

Acute Bacterial Exacerbations of Chronic Bronchitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Secondary Bacterial Infection of Acute Bronchitis due to Moraxella catarrhalis or Streptococcus pneumoniae.

Community-Acquired Pneumonia due to Legionella pneumophila, Mycoplasma pneumoniae, or Streptococcus pneumoniae.

Pharyngitis/Tonsilitis due to Streptococcus pyogenes.

NOTE :  The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin. Dynabac generally is effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of Dynabac in the subsequent prevention of rheumatic fever are not available at present.

Uncomplicated Skin and Skin Structure Infections due to Staphylococcus aureus (methicillin-susceptible strains) or Streptococcus pyogenes . (Abscesses usually require surgical drainage.)

CONTRAINDICATIONS

Dynabac is contraindicated in patients with known hypersensitivity to dirithromycin, erythromycin, or any other macrolide antibiotic.

Dirithromycin should not be used in patients with known, suspected, or potential bacteremias as serum levels are inadequate to provide antibacterial coverage of the blood stream.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including dirithromycin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis

PRECAUTIONS

Hepatic Insufficiency --Because dirithromycin/erythromycylamine is principally eliminated via the liver and because no data exist regarding the safety of administering dirithromycin to patients with Child's Grade B or greater hepatic impairment, Dynabac should be administered to such patients only when absolutely necessary. No dosage adjustment should be necessary in patients with mildly impaired hepatic function.

Information to Patients --Dynabac tablets should be taken with food or within one hour of having eaten. They should not be cut, chewed, or crushed.

Drug Interactions:

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.)

insert. --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.

Carcinogenesis, Mutagenesis, Impairment of Fertility --Lifetime studies in animals to evaluate carcinogenic potential have not been performed with dirithromycin.

No mutagenic potential was demonstrated when dirithromycin was used in standard tests of genotoxicity, which included the following bacterial mutation tests in vitro and in vivo mammalian systems:

Bacterial Reverse-Mutation Test (Ames test)

DNA repair (UDS) in rat hepatocytes

Chinese hamster lung fibroblast (V79) test

Micronucleus test in mice

Sister-chromatid exchange--human lymphocytes

Sister-chromatid exchange--Chinese hamsters

Mouse Lymphoma Assay

In rats, fertility and reproductive performance were not affected when dirithromycin was administered at doses up to 21 times the maximum recommended human dose on a mg/m ² basis

Pregnancy: Effects. Pregnancy Category C --Teratology studies conducted in rats at doses up to 21 times the maximum recommended human dose on a mg/m ² basis and in rabbits at doses up to 4 times the maximum recommended human dose on a mg/m ² basis have revealed no evidence of impaired fertility or harm to the fetus due to dirithromycin administration. An additional teratology study in CD-1 mice demonstrated that fetal weight was significantly depressed at the 1000 mg/kg dose (8 times the maximum recommended human dose on a mg/m ² basis), and there was an increased occurrence of incomplete ossification among these fetuses--a manifestation of retarded development. This decrease in ossification was also seen in rats given 1000 mg/kg/day for 2 weeks prior to mating, throughout the mating period, and throughout gestation.

There are no adequate and well-controlled studies in pregnant women. Dirithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery --Dirithromycin has not been studied for use during labor and delivery. Treatment with dirithromycin should be given during labor and delivery only if clearly needed.

Nursing Mothers --It is not known whether either dirithromycin or erythromycylamine is excreted in human milk. It is known that dirithromycin is excreted in the milk of lactating rodents and that other drugs of this class are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dirithromycin is administered to a nursing woman.

Pediatric Use --Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use --In a clinical pharmacology study, 19 healthy geriatric volunteers (65 to 83 years of age) with normal renal and hepatic function had no statistically significant differences in AUC or C _max when compared with 10 healthy adult volunteers (19 to 50 years of age). In clinical trials in geriatric patients who received the usual recommended adult dose (500 mg q.d. P.O.), clinical efficacy and safety were comparable with results in non-geriatric adult patients.

ADVERSE REACTIONS

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.

OVERDOSAGE

The toxic symptoms following an overdose of a macrolide antibiotic may include nausea, vomiting, epigastric distress, and diarrhea. Forced diuresis, peritoneal dialysis, hemodialysis, or hemoperfusion have not been established as beneficial for an overdose of dirithromycin. Hemodialysis has been shown to be ineffective in hastening the elimination of erythromycylamine from plasma in patients with chronic renal failure.

DOSAGE AND ADMINISTRATION

Dynabac (dirithromycin tablets) should be administered with food or within 1 hour of having eaten. (See CLINICAL PHARMACOLOGY , Food Effect on Absorption .) Dynabac tablets should not be cut, crushed, or chewed.

HOW SUPPLIED

Dynabac® (dirithromycin tablets) are available in:

The 250 mg tablets are white, enteric-coated, elliptical-shaped, imprinted with "DYNABAC" and "UC5364." They are available as follows:

Bottles of 60  NDC 0451-0490-60 (UC5364).

Box of 3 (D5-Pak™, pack of 10) NDC 0451-0490-10 (UC5304).

Store at controlled room temperature, 15° to 30°C (59° to 86°F).

ANIMAL PHARMACOLOGY AND TOXICOLOGY

Cardiac and skeletal muscle lesions occurred in rats in studies up to three months by the intravenous route and in six-month studies in the rat and the dog by the oral route. While no target organ toxicity was identified in three-month oral studies, both cardiac and skeletal muscles were identified as target tissues after one-month intravenous studies in rats. Histologic changes from oral dosing occurred only after more than four months of treatment in rats and after six months in dogs. These findings were associated with high tissue-to-plasma concentration ratios of antimicrobial activity. The extensive drug uptake by tissues was reversible upon termination of treatment. Lesions in cardiac and skeletal muscle also were reversed upon termination of treatment. Dirithromycin and/or its microbiologically active metabolite appeared to accumulate in tissues with time. Despite the drug uptake in rat tissues at high multiples (approximately 14 times the anticipated clinical dose in mg/m ² ), there were no lesions in this species until oral treatment was extended beyond four months.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically--Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.
2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests--Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.

CAUTION --Federal (USA) law prohibits dispensing without prescription.

Literature revised October 11, 1999

PV 2597 UCP                                      [101199]

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