CENTRAL NERVOUS SYSTEM: headache, 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.

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.

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).

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.

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.

Enoxacin has been shown to cause arthropathy in immature rats and dogs. 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.

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).

Enoxacin is a potent inhibitor of the hepatic microsomal enzyme system, resulting in significant drug/drug interactions with theophylline and caffeine.  

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.  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. 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."

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.

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).

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.

to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded;

that enoxacin may be associated with hypersensitivity reaction, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction;

Pregnancy:  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.

Nursing Mothers: Drugs of this class are excreted in human milk.

Pediatric Use:  Enoxacin causes arthropathy in juvenile animals.

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.

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.

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 drugs.

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.

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.

ANIMAL PHARMACOLOGY

Enoxacin and other members of the quinolone class have been shown to cause arthropathy in immature animals of most species tested.