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Trovan - Zithromax

CLINICAL PHARMACOLOGY

TROVAFLOXACIN

Absorption

Trovafloxacin is well-absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 88%.

Pharmacokinetics

The mean pharmacokinetic parameters (±SD) of trovafloxacin after a 100-mg oral dose appear in the table below.

TROVAFLOXACIN PHARMACOKINETIC PARAMETERS - 100-mg SINGLE ORAL DOSE

Cmax (µg/mL) Tmax (hrs) AUC(0-∞)
(µg•h/mL)

(hrs)
1.00.3 0.90.4 11.22.2 9.1
Cmax= Maximum serum concentration; Tmax=Time to Cmax; AUC(0-∞) =Area under concentration vs. time curve to infinite time; T1/2=serum half-life

Oral absorption of trovafloxacin is not altered by concomitant food intake; therefore, it can be administered without regard to food.

The systemic exposure to trovafloxacin (AUC 0-∞) administered as crushed tablets via nasogastric tube into the stomach was identical to that of orally administered intact tablets. Administration of concurrent enteral feeding solutions had no effect on the absorption of trovafloxacin given via nasogastric tube into the stomach. When trovafloxacin was administered as crushed tablets into the duodenum via nasogastric tube, the AUC0-∞ and peak serum concentration (Cmax) were reduced by 30% relative to the orally administered intact tablets. Time to peak serum level (Tmax) was also decreased from 1.7 hrs to 1.1 hrs.

Distribution

The mean plasma protein bound fraction is approximately 76%, and is concentration-independent. Trovafloxacin is widely distributed throughout the body. Rapid distribution of trovafloxacin into tissues results in significantly higher trovafloxacin concentrations in most target tissues than in plasma or serum.

Reproductive Fluid or Tissue Tissue-Fluid/Serum Ratio* (Range)
prostatic tissue 1.0 (0.5-1.6)
cervix (multiple dose) 0.6 (0.5-0.7)
ovary 1.6 (0.3-2.2)
fallopian tube 0.7 (0.2-1.1)
myometrium (multiple dose) 0.6 (0.4-0.8)
uterus 0.6 (0.3-0.8)
vaginal fluid (multiple dose) 4.7 (0.8-20.8)
* Mean values in adults over 2-29 hours following single 200-mg tablet administration (multiple 200-mg doses where noted).

Presence in Human Milk

Trovafloxacin has been detected in the human milk of lactating subjects. (See PRECAUTIONS: Nursing Mothers)

Metabolism

Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). Thirteen percent of the administered dose appears in the urine in the form of the ester glucuronide, and 9% appears in the feces as the N-acetyl metabolite. (2.5% of the dose is found in the serum as the active N-acetyl metabolite.) Other minor metabolites (diacid, sulfamate, hydroxycarboxylic acid) have been identified in both urine and feces in small amounts (<4% of the administered dose).

Excretion

Approximately 50% of an oral dose is excreted unchanged (43% in the feces and 6% in the urine).

After multiple 200-mg doses, to healthy subjects, mean (± SD) cumulative urinary trovafloxacin concentrations were 12.1 ±3.4 µg/mL. With these levels of trovafloxacin in urine, crystals of trovafloxacin have not been observed in the urine of human subjects.

Special Populations

Geriatric

The pharmacokinetics of trovafloxacin are not affected by age (range 19-78 years).

Pediatric

The pharmacokinetics of trovafloxacin have not been fully characterized in pediatric populations less than 18 years of age.

Gender

There are no significant differences in trovafloxacin pharmacokinetics between males and females when differences in body weight are taken into account. After single 200-mg doses, trovafloxacin Cmax and AUC(0-∞) were 60% and 32% higher, respectively, in healthy females compared to healthy males. The clinical importance of the increases in serum levels of trovafloxacin in females has not been established. (See PRECAUTIONS: PATIENT INFORMATION.)

Chronic Hepatic Disease

No dosage adjustment is recommended in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) cirrhosis receiving a 100-mg oral dose. There are no data in patients with severe cirrhosis (Child-Pugh Class C). (See DOSAGE AND ADMINISTRATION.)

Renal Insufficiency

The pharmacokinetics of trovafloxacin are not affected by renal impairment.

Trovafloxacin serum concentrations are not significantly altered in subjects with severe renal insufficiency (creatinine clearance < 20 mL/min), including patients on hemodialysis.

Photosensitivity Potential

In a study of the skin response to ultraviolet and visible radiation conducted in 48 healthy volunteers (12 per group), the minimum erythematous dose (MED) was measured for ciprofloxacin, lomefloxacin, trovafloxacin, and placebo before and after drug administration for 5 days. In this study, trovafloxacin (200 mg q.d.) was shown to have a lower potential for producing delayed photosensitivity skin reactions than ciprofloxacin (500 mg b.i.d.) or lomefloxacin (400 mg q.d.), although greater than placebo. (See PRECAUTIONS: PATIENT INFORMATION.)

Drug-drug Interactions

The systemic availability of trovafloxacin following oral tablet administration is significantly reduced by the concomitant administration of antacids containing aluminum and magnesium salts, sucralfate, vitamins or minerals containing iron, and concomitant intravenous morphine administration.

Administration of trovafloxacin (300 mg p.o.) 30 minutes after administration of an antacid containing magnesium hydroxide and aluminum hydroxide resulted in reductions in systemic exposure to trovafloxacin (AUC) of 66% and peak serum concentration (Cmax) of 60%. (See PRECAUTIONS: DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION.)

Concomitant sucralfate administration (1g) with trovafloxacin 200 mg p.o. resulted in a 70% decrease in trovafloxacin systemic exposure (AUC) and a 77% reduction in peak serum concentration (Cmax). (See PRECAUTIONS: DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION.)

Concomitant administration of ferrous sulfate (120 mg elemental iron) with trovafloxacin 200 mg p.o. resulted in a 40% reduction in trovafloxacin systemic exposure (AUC) and a 48% decrease in trovafloxacin Cmax. (See PRECAUTIONS: DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION.)

Concomitant administration of intravenous morphine (0.15 mg/kg) with oral trovafloxacin (200 mg) resulted in a 36% reduction in trovafloxacin AUC and a 46% decrease in trovafloxacin Cmax. Trovafloxacin administration had no effect on the pharmacokinetics of morphine or its pharmacologically active metabolite, morphine- 6-β-glucuronide. (See PRECAUTIONS: DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION.)

Minor pharmacokinetic interactions that are most likely without clinical significance include calcium carbonate, omeprazole, and caffeine.

Concomitant administration of calcium carbonate (1000 mg) with trovafloxacin 200 mg p.o. resulted in a 20% reduction in trovafloxacin AUC and a 17% reduction in peak serum trovafloxacin concentration (Cmax).

A 40-mg dose of omeprazole given 2 hours prior to trovafloxacin (300 mg p.o.) resulted in a 17% reduction in trovafloxacin AUC and a 17% reduction in trovafloxacin peak serum concentration (Cmax).

Administration of trovafloxacin (200 mg) concomitantly with caffeine (200 mg) resulted in a 17% increase in caffeine AUC and a 15% increase in caffeine Cmax. These changes in caffeine exposure are not considered clinically significant.

No significant pharmacokinetic interactions include cimetidine, theophylline, digoxin, warfarin, and cyclosporine.

Cimetidine co-administration (400 mg twice daily for 5 days) with trovafloxacin (200 mg p.o. daily for 3 days) resulted in changes in trovafloxacin AUC and Cmax of less than 5%.

Trovafloxacin (200 mg p.o. daily for 7 days) co-administration with theophylline (300 mg twice daily for 14 days) resulted in no change in theophylline AUC and Cmax.

Trovafloxacin (200 mg p.o. daily for 10 days) co-administration with digoxin (0.25 mg daily for 20 days) did not significantly alter systemic exposure (AUC) to digoxin or the renal clearance of digoxin.

Trovafloxacin (200 mg p.o. daily for 7 days) does not interfere with the pharmacokinetics nor the pharmacodynamics of warfarin (daily for 21 days). Concomitant oral administration of trovafloxacin did not affect the systemic exposure (AUC) or peak plasma concentrations (Cmax) of the S or R isomers of warfarin, nor did it influence prothrombin time.

Trovafloxacin (200 mg p.o. daily for 7 days) co-administration with cyclosporine (daily doses from 150-450 mg for 7 days) resulted in decreases of 10% or less in systemic exposure to cyclosporine (AUC) and in the peak blood concentrations of cyclosporine.

AZITHROMYCIN

Pharmacokinetics: Following oral administration, azithromycin is rapidly absorbed and widely distributed throughout the body. Rapid distribution of azithromycin into tissues and high concentration within cells result in significantly higher azithromycin concentrations in tissues than in plasma or serum. The 1-g single-dose packet is bioequivalent to four 250 mg capsules.

The mean pharmacokinetic parameters (±SD) of azithromycin after the 1 g single dose packet appear in the table below.

AZITHROMYCIN PHARMACOKINETIC PARAMETERS - 1-g SINGLE-DOSE PACKET IN FASTED STATE

Cmax (µg/mL) Tmax (hrs) AUC(0-72)
(µg•hr/mL)
0.750.42 1.50.7 6.491.54
Cmax = Maximum serum concentration; Tmax=Time to Cmax; AUC (0-72) = Area under concentration vs. time curve to72 hr postdose

When the oral suspension of azithromycin was administered with food, the Cmax increased by 46% and the AUC by 14%.

The AUC of azithromycin was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with ZITHROMAX® capsules (azithromycin); however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.

When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin (500 mg Day 1, 250 mg Days 2-5) in elderly men were similar to those in young adults; however, in elderly women, although higher peakm concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Cervical tissue concentration and tissue to serum concentration ratio are shown in the following table:

TIME AFTER DOSE (h) AZITHROMYCIN CERVICAL TISSUE CONCENTRATION (mg/g)1 CORRESPONDING SERUM LEVEL (mg/mL) TISSUE TO SERUM RATIO1
19* 2.8 0.04 70
1High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial activity of azithromycin is pH related. Azithromycin is concentrated in cell lysosomes which have a low intraorganelle pH, at which the drug's activity is reduced. However, the extensive distribution of drug to tissues may be relevant to clinical activity.
*Sample was obtained 19 hours after a single 500-mg (two 250 mg) capsule dose in adults.

The extensive tissue distribution was confirmed by examination of additional tissues and fluids (e.g., ejaculum, prostate, ovary, uterus, salpinx). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical significance of these tissue concentration data is unknown.

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

There are no pharmacokinetic data available from studies in hepatically- or renally-impaired individuals.

The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses adequate to reach therapeutic steady-state plasma levels is not known. (See PRECAUTIONS.)

Trovafloxacin-Azithromycin

Coadministration of the 1-gram azithromycin Single Dose Packet did not affect the bioavailability of a 100 mg tablet of trovafloxacin in healthy volunteers.

Coadministration with a 100-mg tablet of trovafloxacin produced serum azithromycin concentrations at 1.5 hr post-dose similar to those observed in previous studies with the 1-gram azithromycin Single Dose Packet.

Microbiology

Mechanism of Action: Trovafloxacin

Trovafloxacin is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic and anaerobic microorganisms. The bactericidal action of trovafloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA.

Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. Mechanism of action of fluoroquinolones including trovafloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore, fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between trovafloxacin and the mentioned classes of antibiotics. The overall results obtained from in vitro synergy studies, testing combinations of trovafloxacin with beta-lactams and aminoglycosides, indicate that synergy is strain specific and not commonly encountered. This agrees with results obtained previously with other fluoroquinolones. Resistance to trovafloxacin in vitro develops slowly via multiple-step mutation in a manner similar to other fluoroquinolones. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1x10-7 to 10-10. Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin.

Mechanism of Action: Azithromycin

Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was > 30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Trovafloxacin and azithromycin have both been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS section:

Aerobic gram-negative microorganisms

Neisseria gonorrhoeae

"Other" Microorganisms

Chlamydia trachomatis

Information on the in vitro activity of either trovafloxacin or azithromycin may be found in the respective prescribing information of these products.

Susceptibility Tests

Trovafloxacin

Dilution Techniques:Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trovafloxacin mesylate powder. The MIC values should be interpreted according to the following criteria:

For testing Neisseria gonorrhoeaea:

MIC (µg/mL) Interpretation
≤ 0.125 Susceptible (S)
0.25 Intermediate (I)
≥ 0.5 Resistant (R)
a These interpretive standards are applicable to agar dilution tests with GC agar base and 1% defined growth supplement1.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the 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 trovafloxacin mesylate powder should provide the following MIC values:

Microorganism MIC Range (µg/mL)
Neisseria gonorrhoeaeb ATCC 49226 0.004-0.016
b This quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using GC agar base with 1% defined growth supplement1.

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 procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with trovafloxacin mesylate equivalent to 10 µg trovafloxacin to test the susceptibility of microorganisms to trovafloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a trovafloxacin mesylate disk (equivalent to 10 µg trovafloxacin) should be interpreted according to the following criteria:

The following zone diameter interpretive criteria should be used for testing Neisseria gonorrhoeaec:

Zone Diameter (mm) Interpretation
≥ p37 Susceptible (S)
34-36 Intermediate (I)
≤ 33 Resistant (R)
c These interpretive standards are applicable to disk diffusion tests with GC agar base and 1% defined growth supplement2 incubated in 5% CO2.

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 trovafloxacin.

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 trovafloxacin mesylate equivalent to 10-µg trovafloxacin disk should provide the following zone diameters in this laboratory quality control strain:

Microorganism Zone Diameter Range (mm)
Neisseria gonorrhoeaed ATCC 49226 42-55
d This quality control range is only applicable to tests performed by disk diffusion using GC agar base and 1% defined growth supplement2.

No testing method or interpretive criteria have been established for trovafloxacin against Chlamydia trachomatis.

Azithromycin

No interpretive criteria have been established for testing azithromycin against Neisseria gonorrhoeae. This species is usually not tested against azithromycin.

No testing method or interpretive criteria have been established for azithromycin against Chlamydia trachomatis.

Animal Pharmacology

Trovafloxacin

Quinolones have been shown to cause arthropathy in immature animals.

Arthropathy and chondrodysplasia were observed in immature animals given trovafloxacin. (See WARNINGS.)

At doses from 10 to 15 times the human dose based on mg/kg or approximately 3 to 5 times based on mg/m2, trovafloxacin has been shown to cause arthropathy in immature rats and dogs. In addition, these drugs are associated with an increased incidence of chondrodysplasia in rats compared to controls. There is no evidence of arthropathies in fully mature rats and dogs at doses from 40 or 10 times the human dose based on mg/kg or approximately 5 times based on mg/m2 for a 6-month exposure period.

Unlike some other members of the quinolone class, crystalluria and ocular toxicity were not observed in chronic safety studies with rats or dogs with either trovafloxacin or its prodrug, alatrofloxacin.

Quinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of non-steroidal antiinflammatory drugs (NSAIDS). Neither trovafloxacin administered orally at 500 mg/kg, nor alatrofloxacin administered intravenously at 75 mg/kg, showed an increase in measures of seizure activity in mice at doses when used in combination with the active metabolite of the NSAID, fenbufen.

As with other members of the quinolone class, trovafloxacin at doses 5 to 10 times the human dose based on mg/kg or 1 to 5 times the human dose based on mg/m2 produces testicular degeneration in rats and dogs dosed for 6 months.

At a dose of trovafloxacin 10 times the highest human dose based on mg/kg or approximately 5 times based on mg/m2, elevated liver enzyme levels which correlated with centrilobar hepatocellular vacuolar degeneration and necrosis were observed in dogs in a 6-month study. A subsequent study demonstrated reversibility of these effects when trovafloxacin was discontinued.

Azithromycin

Phospholipidosis (intracellular phospholipid binding) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs administered doses which, based on pharmacokinetics, are as low as two times greater than the recommended adult human dose and in rats at doses comparable to the recommended adult human dose. This effect has been reversible after cessation of azithromycin treatment. The significance of these findings for humans is unknown.

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.

Last reviewed on RxList: 10/3/2008
This monograph has been modified to include the generic and brand name in many instances.

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