Penetrex® (enoxacin) is a broad-spectrum azafluoroquinolone antibacterial agent for oral administration. Enoxacin is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid sesquihydrate. The chemical structure of enoxacin is:
Its empirical formula is C 15 H 17 N 4 O 3 F · 1 1 / 2 H 2 O, and its molecular weight is 320.32 (anhydrous). Enoxacin is an ivory-to-slightly yellow powder. In dilute aqueous solution, it is unstable in strong sunlight.
Penetrex is available in 200 mg and 400 mg film-coated tablets. Each "200" and "400" Penetrex tablet contains enoxacin sesquihydrate equivalent to 200 mg and 400 mg of anhydrous enoxacin, respectively. Each Penetrex 200 mg and 400 mg tablet contains the following inactive ingredients: cellulose microcrystalline NF, colloidal silicon dioxide NF, croscarmellose sodium NF, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose NF, hydroxypropyl methylcellulose, magnesium stearate USP, polyethylene glycol, simethicone, sorbic acid, stearate emulsifiers, and titanium dioxide.
Following oral administration to healthy subjects, peak plasma enoxacin concentrations were achieved within 1 to 3 hours. Absolute oral bioavailability of enoxacin is approximately 90%. Maximum plasma concentrations of enoxacin average 0.93 µg/mL and 2.0 µg/mL after single 200 mg and 400 mg doses, respectively. Enoxacin plasma half-life is 3 to 6 hours. Enoxacin is excreted primarily via the kidney. After a single dose, greater than 40% was recovered in urine by 48 hours as unchanged drug. In elderly patients, the mean peak enoxacin plasma concentration was 50% higher than that in young adult volunteers receiving comparable single doses of enoxacin. This appears to correspond to age-associated reduction of renal function in the elderly population. Five metabolites of enoxacin have been identified in human urine and account for 15% to 20% of the administered dose.
Enoxacin diffuses into cervix, fallopian tube, and myometrium at levels approximately 1-2 times those achieved in plasma, and into kidney and prostate at levels approximately 2-4 times those achieved in plasma. Studies have not been conducted to assess the penetration of enoxacin into human cerebrospinal fluid.
Enoxacin is approximately 40% bound to plasma proteins in healthy subjects and is approximately 14% bound to plasma proteins in patients with impaired renal function.
The effect of food on the absorption of enoxacin from the tablet formulation has not been studied.
Some isozymes of the cytochrome P-450 hepatic microsomal enzyme system are inhibited by enoxacin. This inhibition results in significant drug/drug interactions with theophylline and caffeine. Enoxacin interferes with the metabolism of theophylline, resulting in a dose-related decrease in theophylline clearance. Elevated serum theophylline concentrations may increase the risk of theophylline-related adverse reactions. (See PRECAUTIONS : Drug Interactions . )
Clearance of enoxacin is reduced in patients with impaired renal function (creatinine clearance </=30 mL/min/1.73 m 2 ), and dosage adjustment is necessary. (See DOSAGE AND ADMINISTRATION . )
Enoxacin is an inhibitor of the bacterial enzyme DNA gyrase and is a bactericidal agent. Enoxacin may be active against pathogens resistant to drugs that act by different mechanisms.
Enoxacin has been shown to be active against most strains of the following organisms both in vitro and in clinical infections: (See . )
Gram-positive aerobes: Staphylococcus epidermidis, Staphylococcus saprophyticus.
Gram-negative aerobes: Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae, Proteus mirabilis, Pseudomonas aeruginosa.
The following in vitro data are available but their clinical significance is unknown.
In addition, enoxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 2.0 µg/mL or less against most strains of the following organisms; however, the safety and effectiveness of enoxacin in treating clinical infections due to these organisms have not been established in adequate and well-controlled trials.
Gram-negative aerobes: Aeromonas hydrophila, Citrobacter diversus, Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Haemophilus ducreyi, Klebsiella oxytoca, Klebsiella ozaenae, Morganella morganii, Proteus vulgaris, Providencia stuartii, Providencia alcalifaciens, Serratia marcescens, Serratia proteomaculans (formerly S. liquefaciens )
Many strains of Streptococcus species and anaerobes are usually resistant to enoxacin.
The activity of enoxacin against Treponema pallidum has not been evaluated; however, other quinolones are not active against T. pallidum. (See . )
Cross-resistance with other quinolones has been demonstrated.
The addition of human serum has no effect on the in vitro MIC values; however, enoxacin activity is decreased in acidic (pH 5.5) environments.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters give the most precise estimate of susceptibility of bacteria to antimicrobial agents. One such standardized procedure 1 that has been recommended for use with disks to test susceptibility of organisms to enoxacin uses the 10-µg enoxacin disk.
Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for enoxacin.
Reports from the laboratory giving results of the standard single-disk susceptibility test with a 10-µg enoxacin disk should be interpreted according to the following criteria:
A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood concentrations. A report of "Moderately susceptible" suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues or fluids in which high antimicrobial levels are attained. A report of "Resistant" indicates that achievable drug concentrations are unlikely to be inhibitory, and other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control organisms. The 10-µg enoxacin disk should give the following zone diameters:
Other quinolone antibacterial disks should not be substituted when performing susceptibility tests for enoxacin because of spectrum differences. The 10-µg enoxacin disk should be used for all in vitro testing of isolates for enoxacin susceptibility using diffusion techniques.
Dilution Techniques: Use a standardized dilution method 2 (broth, agar, or microdilution) or equivalent with enoxacin powder. The MIC values obtained should be interpreted according to the following criteria:
As with standard diffusion methods, dilution procedures require the use of laboratory control organisms. Standard enoxacin powder should give the following MIC values:
Penetrex® (enoxacin) is indicated for the treatment of adults (>/=18 years of age) with the following infections caused by susceptible strains of the designated microorganisms:
Sexually Transmitted Diseases (See . )
Uncomplicated urethral or cervical gonorrhea due to Neisseria gonorrhoeae.
Uncomplicated urinary tract infections (cystitis) due to Escherichia coli, Staphylococcus epidermidis*, or Staphylococcus saprophyticus*.
Complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, or Enterobacter cloacae*.
*Efficacy for this organism in this organ system at the recommended dose was studied in fewer than ten infections. The dosage regimens for complicated and uncomplicated urinary tract infections are different. (See DOSAGE AND ADMINISTRATION . )
Penicillinase production should have no effect on enoxacin activity.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to enoxacin. Therapy with enoxacin may be initiated while awaiting the results of these studies; therapy should be adjusted if necessary once the results are known. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.
Penetrex is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of enoxacin or any member of the quinolone group of antimicrobial agents.
THE SAFETY AND EFFECTIVENESS OF ENOXACIN IN PEDIATRIC PATIENTS AND ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS : Pediatric Use, Pregnancy, and Nursing Mothers subsections .) Enoxacin has been shown to cause arthropathy in immature rats and dogs when given in oral doses approximately 1.5 and 3.8 times, respectively, the highest human clinical dose based on a mg/m 2 basis after a four-week dosage regimen. Gross and histopathological examination of the weight-bearing joints of the dogs revealed lesions of the cartilage. Other quinolones also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY . )
Convulsions and abnormal electroencephalograms have been reported in some patients receiving enoxacin. Increased intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system stimulation which may lead to: tremors, restlessness/agitation, nervousness/anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving enoxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, enoxacin should be used with caution in patients with known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g. , severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold ( e.g., certain drug therapy, renal dysfunction). (See PRECAUTIONS : General , Information for Patients , Drug Interactions and ADVERSE REACTIONS .)
Enoxacin is a potent inhibitor of the hepatic microsomal enzyme system, resulting in significant drug/drug interactions with theophylline and caffeine. (See PRECAUTIONS : Drug Interactions . )
Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, or itching. Only a few patients had a history of previous hypersensitivity reactions. Serious hypersensitivity reactions have also been reported following treatment with enoxacin. If an allergic reaction to enoxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including enoxacin, 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 broad-spectrum 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
Ruptures of the shoulder, hand and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported with fluoroquinolone antimicrobials. Enoxacin should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. Tendon rupture can occur at anytime during or after therapy with enoxacin.
Enoxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with enoxacin should have a follow-up serologic test for syphilis after 3 months.
General: Alteration of the dosage regimen is necessary for patients with impaired renal function (creatinine clearance </=30 mL/min/1.73 m 2 ). (See DOSAGE AND ADMINISTRATION . )
As with other quinolones, enoxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold ( e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold ( e.g., certain drug therapy, renal dysfunction). (See and PRECAUTIONS : Drug Interactions .)
Moderate-to-severe phototoxicity reactions have been observed in patients exposed to direct sunlight while receiving enoxacin or some other drugs in this class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
Ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with enoxacin, as well as with some other quinolones, but have also been observed in patients receiving placebo in comparative trials. In clinical trials using multiple-dose therapy, ophthalmic tissue levels of enoxacin and other quinolones were significantly higher than respective plasma concentrations. The causal relationship, if any, of quinolones to lenticular abnormalities has not been established.
Decreased spermatogenesis and subsequent decreased fertility were noted in rats and dogs treated with doses of enoxacin that produced plasma levels in the animals three times higher than those produced in humans at the recommended therapeutic dosage. The potential for enoxacin to affect spermatogenesis in male patients is unknown.
Information for Patients:
Patients should be advised:
Bismuth: Bismuth subsalicylate, given concomitantly with enoxacin or 60 minutes following enoxacin administration, decreased enoxacin bioavailability by approximately 25%. Thus, concomitant administration of enoxacin and bismuth subsalicylate should be avoided.
Caffeine: Enoxacin is a potent inhibitor of the cytochrome P-450 isozymes responsible for the metabolism of methylxanthines. In a multiple-dose study, enoxacin caused a dose-related increase in the mean elimination half-life of caffeine, thereby decreasing the clearance of caffeine by up to 80% and leading to a five-fold increase in the AUC and the half-life of caffeine. Trough plasma enoxacin levels were also 20% higher when caffeine and enoxacin were administered concomitantly. Caffeine-related adverse effects have occurred in patients consuming caffeine while on therapy with enoxacin. (See . )
Cyclosporine: Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with other members of the quinolone class.
Digoxin: Enoxacin may raise serum digoxin levels in some individuals. If signs and symptoms suggestive of digoxin toxicity occur when enoxacin and digoxin are given concomitantly, physicians are advised to obtain serum digoxin levels and adjust digoxin doses appropriately.
Non-steroidal anti-inflammatory agents: Seizures have been reported in patients taking enoxacin concomitantly with the nonsteroidal anti-inflammatory drug fenbufen. Animal studies also suggest an increased potential for seizures when these two drugs are given concomitantly. Fenbufen is not approved in the United States at this time.
Sucralfate and antacids: Quinolones form chelates with metal cations. Therefore, administration of quinolones with antacids containing calcium, magnesium, or aluminum; with sucralfate; with divalent or trivalent cations such as iron; or with multivitamins containing zinc may substantially interfere with drug absorption and result in insufficient plasma and tissue quinolone concentrations. Antacids containing aluminum hydroxide and magnesium hydroxide reduce the oral absorption of enoxacin by 75%. The oral bioavailability of enoxacin is reduced by 60% with coadministration of ranitidine. These agents should not be taken for 8 hours before or for 2 hours after enoxacin administration.
Theophylline: Enoxacin is a potent inhibitor of the cytochrome P-450 isozymes responsible for the metabolism of methylxanthines. Enoxacin interferes with the metabolism of theophylline resulting in a 42% to 74% dose-related decrease in theophylline clearance and a subsequent 260% to 350% increase in serum theophylline levels. Theophylline-related adverse effects have occurred in patients when theophylline and enoxacin were coadministered. (See . )
Warfarin: Quinolones, including enoxacin, decrease the clearance of R-warfarin, the less active isomer of racemic warfarin. Enoxacin does not affect the clearance of the active S-isomer, and changes in clotting time have not been observed when enoxacin and warfarin were coadministered. Nevertheless, the prothrombin time or other suitable coagulation test should be monitored when warfarin or its derivatives and enoxacin are given concomitantly.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to determine the carcinogenic potential of enoxacin have not been conducted.
Genetic toxicology tests included in vitro mutagenicity and cytogenetic assays and in vivo cytogenetic and micronucleus tests. Enoxacin did not induce point mutations in bacterial cells or mitotic gene conversion in yeast cells, with or without metabolic activation. Enoxacin did not induce sister chromatid exchanges or structural chromosomal aberrations in mammalian cells in vitro, with or without metabolic activation. In addition, enoxacin did not induce chromosomal aberrations in mice.
There was a minimal, dose-related, statistically significant increase in micronuclei at high doses in mice. The significance of these findings, in the absence of effects in other test systems, is not established.
Enoxacin produced no consistent effects on fertility and reproductive parameters in female rats given oral doses of enoxacin at levels up to 1000 mg/kg. Decreased spermatogenesis and subsequent impaired fertility was noted in male rats given oral doses of 1000 mg/kg. This dose is approximately 13-fold greater than the highest human clinical daily oral dose of 16 mg/kg, assuming a 50 kg person and based on a mg/m 2 basis
Pregnancy Teratogenic effects. Pregnancy Category C. Studies with enoxacin given orally to mice and rats have shown no evidence of teratogenic potential. The intravenous infusion of enoxacin into pregnant rabbits at doses of 10 to 50 mg/kg caused dose-related maternal toxicity (venous irritation, body weight loss, and reduced food intake) and, at 50 mg/kg, fetal toxicity (increased post-implantation loss and stunted fetuses).
At 50 mg/kg, the incidence of fetal malformations was significantly increased in the presence of overt maternal and fetal toxicity. There are no adequate and well-controlled studies in pregnant women. Enoxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See . )
Nursing Mothers: It is not known whether enoxacin is excreted in human milk. Enoxacin is excreted in the milk of lactating rats. Because drugs of this class are excreted in human milk and because of the potential for serious adverse reactions from enoxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in pediatric patients and adolescents below the age of 18 years have not been established. Enoxacin causes arthropathy in juvenile animals. (See and ANIMAL PHARMACOLOGY . )
Geriatric Use: In multiple-dose clinical trials of enoxacin, elderly patients (>/=65 years of age) experienced significantly more overall adverse events than patients under 65 years of age. However, the incidence of drug-related adverse reactions was comparable between age groups.
During clinical trials, approximately 9% of patients treated with a single dose of 400 mg of enoxacin for uncomplicated urethral or endocervical gonorrhea reported adverse events.
The most frequently reported events in single-dose trials, without regard to drug relationship, were nausea and vomiting (2%). Events that occurred in less than 1% of patients are listed below.
CENTRAL NERVOUS SYSTEM: dizziness, somnolence; GASTROINTESTINAL: abdominal pain; GYNECOLOGIC: vaginal moniliasis; SKIN/HYPERSENSITIVITY: rash; LABORATORY ABNORMALITIES: increased AST (SGOT), decreased hemoglobin, decreased hematocrit, eosinophilia, leukocytosis, leukopenia, thrombocytosis, increased urinary protein, increased alkaline phosphatase, increased ALT (SGPT), increased bilirubin, hyperkalemia.
The incidence of adverse events reported by patients in multiple-dose clinical trials, without regard to drug relationship, was 23%. The incidence of drug-related adverse reactions in multiple-dose clinical trials was 16%. Among patients receiving multiple-dose therapy, enoxacin was discontinued because of an adverse event in 3.8% of patients.
The following events were considered likely to be drug-related in patients receiving multiple doses of enoxacin in clinical trials: nausea and/or vomiting 6%, dizziness 2%, headache 1%, abdominal pain 1%, diarrhea 1%, dyspepsia 1%.
The most frequently reported events in all multiple-dose clinical trials, without regard to drug relationship, were as follows: nausea and/or vomiting 8%, dizziness and/or vertigo 3%, headache 2%, diarrhea 2%, abdominal pain 2%, insomnia 1%, dyspepsia 1%, rash 1%, nervousness and/or anxiety 1%, unusual taste 1%, pruritus 1%.
Additional events that occurred in less than 1% of patients but >0.1% of patients are listed below.
BODY AS A WHOLE: asthenia, fatigue, fever, malaise, back pain, chest pain, edema, chills; GASTROINTESTINAL: flatulence, constipation, dry mouth/throat, stomatitis, anorexia, gastritis, bloody stools; CENTRAL NERVOUS SYSTEM: somnolence, tremor, convulsions, paresthesia, confusion, agitation, depression, syncope, myoclonus, depersonalization, hypertonia; SKIN/HYPERSENSITIVITY: photosensitivity reaction, urticaria, hyperhidrosis, mycotic infection, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome; SPECIAL SENSES: tinnitus, conjunctivitis, visual disturbances including amblyopia; MUSCULOSKELETAL: myalgia, arthralgia; CARDIOVASCULAR: palpitations, tachycardia, vasodilation; RESPIRATORY: dyspnea, cough, epistaxis; HEMIC AND LYMPHATIC: purpura; UROGENITAL: vaginal moniliasis, vaginitis, urinary incontinence, renal failure.
The following adverse events occurred in less than 0.1% of patients in multiple-dose clinical trials but were considered significant: pseudomembranous colitis, hyperkinesia, amnesia, ataxia, hypotonia, psychosis, emotional lability, hallucination, schizophrenic reaction.
LABORATORY CHANGES: The following laboratory abnormalities appeared in >/=1.0% of patients receiving multiple doses of enoxacin: elevated AST (SGOT), elevated ALT (SGPT). It is not known whether these abnormalities were caused by the drug or the underlying conditions.
Worldwide Post-Marketing Experience
The most frequent spontaneously-reported adverse events in the worldwide post-marketing experience with multiple- and single-dose enoxacin use have been rashes, seizures/convulsions, and photosensitivity reactions; however, there is no evidence that the incidences of these events were larger than those observed in the clinical trials population.
Quinolone-class adverse reactions: Although not reported in completed clinical studies with enoxacin, a variety of adverse events have been reported with other quinolones.
Clinical adverse events include: erythema nodosum, hepatic necrosis, possible exacerbation of myasthenia gravis, nystagmus, intestinal perforation, hyperpigmentation, interstitial nephritis, polyuria, urinary retention, renal calculi, cardiopulmonary arrest, cerebral thrombosis, and laryngeal or pulmonary edema.
Laboratory adverse events include: agranulocytosis, elevation of serum triglycerides and/or serum cholesterol, prolongation of the prothrombin time, candiduria, and crystalluria.
In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage and the patient carefully observed and given supportive treatment. Enoxacin is poorly removed (<5% over 4 hours) by hemodialysis.
Penetrex® (enoxacin) should be taken at least one hour before or at least two hours after a meal.
See for information on appropriate pathogens and patient populations.
Uncomplicated urethral or cervical gonorrhea: 400 mg single dose
Uncomplicated urinary tract infections: 200 mg q12h for 7 days
Complicated urinary tract infections: 400 mg q12h for 14 days
Dosage Adjustment for Renal Impairment: Dosage should be adjusted in patients with a creatinine clearance value of 30 mL/min/1.73 m 2 or less. After a normal initial dose, the dosing interval should be adjusted as follows:
When only the serum creatinine is known, the following formula may be used to estimate creatinine clearance.
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
Dosage adjustment is not necessary in elderly patients with normal renal function, but dose should be adjusted according to the previous guidelines in elderly patients with compromised renal function.
Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F) [see USP].
This product should be dispensed in a container with a child-resistant cap.
Keep out of the reach of children.
Enoxacin and other members of the quinolone class have been shown to cause arthropathy in immature animals of most species tested. (See . )
Rev. 7/98 IN-5391D!
Aventis Pharmaceuticals Products Inc.
Parsippany, NJ 07054