Lefen (ANTIBACTERIALS)

Treatment

Lefen (ANTIBACTERIALS) (lomefloxacin HCl) film-coated tablets are indicated for the treatment of adults with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below: (See DOSAGE AND ADMINISTRATION for specific dosing recommendations.)

Lower Respiratory Tract

Acute Bacterial Exacerbation of Chronic Bronchitis caused by Haemophilus influenzae or Moraxella catarrhalis.¹

NOTE: Lefen (ANTIBACTERIALS) IS NOT INDICATED FOR THE EMPIRIC TREATMENT OF ACUTE BACTERIAL EXACERBATION OF CHRONIC BRONCHITIS WHEN IT IS PROBABLE THAT S PNEUMONIAE IS A CAUSATIVE PATHOGEN. S PNEUMONIAE EXHIBITS IN VITRO RESISTANCE TO LOMEFLOXACIN, AND THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN THE TREATMENT OF PATIENTS WITH ACUTE BACTERIAL EXACERBATION OF CHRONIC BRONCHITIS CAUSED BY S PNEUMONIAE HAVE NOT BEEN DEMONSTRATED. IF LOMEFLOXACIN IS TO BE PRESCRIBED FOR GRAM–STAIN– GUIDED EMPIRIC THERAPY OF ACUTE BACTERIAL EXACERBATION OF CHRONIC BRONCHITIS, IT SHOULD BE USED ONLY IF SPUTUM GRAM STAIN DEMONSTRATES AN ADEQUATE QUALITY OF SPECIMEN ( > 25 PMNs/LPF) AND THERE IS BOTH A PREDOMINANCE OF GRAM-NEGATIVE MICROORGANISMS AND NOT A PREDOMINANCE OF GRAM-POSITIVE MICROORGANISMS.

Urinary Tract

Uncomplicated Urinary Tract Infections (cystitis) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Staphylococcus saprophyticus. (See DOSAGE AND ADMINISTRATION and Clinical Studies—Uncomplicated Cystitis.)

Complicated Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Citrobacter diversus,¹ or Enterobacter cloacae.¹

NOTE: In clinical trials with patients experiencing complicated urinary tract infections (UTIs) due to P aeruginosa, 12 of 16 patients had the microorganism eradicated from the urine after therapy with lomefloxacin. None of the patients had concomitant bacteremia. Â Serum levels of lomefloxacin do not reliably exceed the MIC of Pseudomonas isolates. THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN TREATING PATIENTS WITH PSEUDOMONAS BACTEREMIA HAVE NOT BEEN ESTABLISHED.

Appropriate culture and susceptibility tests should be performed before antimicrobial treatment in order to isolate and identify microorganisms causing infection and to determine their susceptibility to lomefloxacin. In patients with UTIs, therapy with Lefen (ANTIBACTERIALS) film-coated tablets may be initiated before results of these tests are known; once these results become available, appropriate therapy should be continued. In patients with an acute bacterial exacerbation of chronic bronchitis, therapy should not be started empirically with lomefloxacin when there is a probability the causative pathogen is S pneumoniae.

Beta-lactamase production should have no effect on lomefloxacin activity.

Prevention / prophylaxis

Lefen (ANTIBACTERIALS) is indicated preoperatively for the prevention of infection in the following situations:

• Transrectal prostate biopsy: to reduce the incidence of urinary tract infection, in the early and late postoperative periods (3–5 days and 3–4 weeks postsurgery).
• Transurethral surgical procedures: to reduce the incidence of urinary tract infection in the early postoperative period (3–5 days postsurgery).

Efficacy in decreasing the incidence of infections other than urinary tract infection has not been established. Lefen (ANTIBACTERIALS), like all drugs for prophylaxis of transurethral surgical procedures, usually should not be used in minor urologic procedures for which prophylaxis is not indicated (eg, simple cystoscopy or retrograde pyelography). (See DOSAGE AND ADMINISTRATION.)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Lefen (ANTIBACTERIALS) and other antibacterial drugs, Lefen (ANTIBACTERIALS) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

REFERENCES

¹Although treatment of infections due to this microorganism in this organ system demonstrated a clinically acceptable overall outcome, efficacy was studied in fewer than 10 infections.

Lefen (ANTIBACTERIALS) (lomefloxacin HCl) may be taken without regard to meals. Sucralfate and antacids containing magnesium or aluminum, or Videx® (didanosine), chewable/buffered tablets or the pediatric powder for oral solution should not be taken within 4 hours before or 2 hours after taking lomefloxacin. Risk of reaction to solar UVA light may be reduced by taking Lefen (ANTIBACTERIALS) at least 12 hours before exposure to the sun (eg, in the evening). (See CLINICAL PHARMACOLOGY.)

See INDICATIONS AND USAGE for information on appropriate pathogens and patient populations.

Treatment

Patients with normal renal function

The recommended daily dose of Lefen (ANTIBACTERIALS) is described in the following chart:

Elderly patients

No dosage adjustment is needed for elderly patients with normal renal function (ClCr ≥ 40 mL/min/1.73 m²).

Patients with impaired renal function

Lomefloxacin is primarily eliminated by renal excretion. (See CLINICAL PHARMACOLOGY.) Modification of dosage is recommended in patients with renal dysfunction. In patients with a creatinine clearance > 10 mL/min/1.73 m² but < 40 mL/min/1.73 m², the recommended dosage is an initial loading dose of 400 mg followed by daily maintenance doses of 200 mg (½ tablet) once daily for the duration of treatment. It is suggested that serial determinations of lomefloxacin levels be performed to determine any necessary alteration in the appropriate next dosing interval.

If only the serum creatinine is known, the following formula may be used to estimate creatinine clearance.

Dialysis patients

Hemodialysis removes only a negligible amount of lomefloxacin (3% in 4 hours). Hemodialysis patients should receive an initial loading dose of 400 mg followed by daily maintenance doses of 200 mg (½ tablet) once daily for the duration of treatment.

Patients with cirrhosis

Cirrhosis does not reduce the nonrenal clearance of lomefloxacin. The need for a dosage reduction in this population should be based on the degree of renal function of the patient and on the plasma concentrations. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION - Patients with impaired renal function.)

Prevention / prophylaxis

The recommended dose of Lefen (ANTIBACTERIALS) is described in the following chart:

Lefen (ANTIBACTERIALS) (lomefloxacin HCl) is contraindicated in persons with a history of hypersensitivity to lomefloxacin or any member of the quinolone group of antimicrobial agents.

WARNINGS

MODERATE TO SEVERE PHOTOTOXIC REACTIONS HAVE OCCURRED IN PATIENTS EXPOSED TO DIRECT OR INDIRECT SUNLIGHT OR TO ARTIFICIAL ULTRAVIOLET LIGHT (eg, sunlamps) DURING OR FOLLOWING TREATMENT WITH LOMEFLOXACIN. THESE REACTIONS HAVE ALSO OCCURRED IN PATIENTS EXPOSED TO SHADED OR DIFFUSE LIGHT, INCLUDING EXPOSURE THROUGH GLASS. PATIENTS SHOULD BE ADVISED TO DISCONTINUE LOMEFLOXACIN THERAPY AT THE FIRST SIGNS OR SYMPTOMS OF A PHOTOTOXICITY REACTION SUCH AS A SENSATION OF SKIN BURNING, REDNESS, SWELLING, BLISTERS, RASH, ITCHING, OR DERMATITIS.

These phototoxic reactions have occurred with and without the use of sunscreens or sunblocks. Single doses of lomefloxacin have been associated with these types of reactions. In a few cases, recovery was prolonged for several weeks. As with some other types of phototoxicity, there is the potential for exacerbation of the reaction on re-exposure to sunlight or artificial ultraviolet light prior to complete recovery from the reaction. In rare cases, reactions have recurred up to several weeks after stopping lomefloxacin therapy.

EXPOSURE TO DIRECT OR INDIRECT SUNLIGHT (EVEN WHEN USING SUNSCREENS OR SUNBLOCKS) SHOULD BE AVOIDED WHILE TAKING LOMEFLOXACIN AND FOR SEVERAL DAYS FOLLOWING THERAPY. LOMEFLOXACIN THERAPY SHOULD BE DISCONTINUED IMMEDIATELY AT THE FIRST SIGNS OR SYMPTOMS OF PHOTOTOXICITY. RISK OF PHOTOTOXICITY MAY BE REDUCED BY TAKING LOMEFLOXACIN IN THE EVENING (See DOSAGE AND ADMINISTRATION.)

THE SAFETY AND EFFICACY OF LOMEFLOXACIN 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.) The oral administration of multiple doses of lomefloxacin to juvenile dogs at 0.3 times and to rats at 5.4 times the recommended adult human dose based on mg/m² (0.6 and 34 times the recommended adult human dose based on mg/kg, respectively) caused arthropathy and lameness. Histopathologic examination of the weight-bearing joints of these animals revealed permanent lesions of the cartilage. Other quinolones also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in juvenile animals of various species. (See Animal Pharmacology.)

Convulsions have been reported in patients receiving lomefloxacin. Whether the convulsions were directly related to lomefloxacin administration has not yet been established. However, convulsions, increased intracranial pressure, and toxic psychoses have been reported in patients receiving other quinolones. Nevertheless, lomefloxacin has been associated with a possible increased risk of seizures compared to other quinolones. Some of these may occur with a relative absence of predisposing factors. Quinolones may also cause central nervous system (CNS) stimulation, which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If any of these reactions occurs in patients receiving lomefloxacin, the drug should be discontinued and appropriate measures instituted. However, until more information becomes available, lomefloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, or other factors that predispose to seizures. (See ADVERSE REACTIONS.) Psychiatric disturbances, agitation, anxiety, and sleep disorders may be more common with lomefloxacin than other products in the quinolone class.

The safety and efficacy of lomefloxacin in the treatment of acute bacterial exacerbation of chronic bronchitis due to S pneumonia have not been demonstrated. This product should not be used empirically in the treatment of acute bacterial exacerbation of chronic bronchitis when it is probable that S pneumoniae is a causative pathogen.

In clinical trials of complicated UTIs due to P aeruginosa, 12 of 16 patients had the microorganism eradicated from the urine after therapy with lomefloxacin. No patients had concomitant bacteremia. Serum levels of lomefloxacin do not reliably exceed the MIC of Pseudomonas isolates. THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN TREATING PATIENTS WITH PSEUDOMONAS BACTEREMIA HAVE NOT BEEN ESTABLISHED.

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 of these patients had a history of previous hypersensitivity reactions. Serious hypersensitivity reactions have also been reported following treatment with lomefloxacin. If an allergic reaction to lomefloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency 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 lomefloxacin, and may range from mild to life-threatening in severity. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antimicrobial 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 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.

QT interval prolongation/torsades de pointes

Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving quinolones, including lomefloxacin. These rare cases were associated with one or more of the following factors: age over 60, female gender, underlying cardiac disease, and/or use of multiple medications. Lomefloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.

Peripheral neuropathy

Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including lomefloxacin. Lomefloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Tendon effects

Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including lomefloxacin. Postmarketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Lomefloxacin 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 tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including lomefloxacin.

PRECAUTIONS

General

Alteration of the dosage regimen is recommended for patients with impairment of renal function (ClCr < 40 mL/min/1.73 m²). (See DOSAGE AND ADMINISTRATION.)

Prescribing Lefen (ANTIBACTERIALS) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 52 weeks while concurrently being administered lomefloxacin. The lomefloxacin doses used in this study caused a phototoxic response. In mice treated with both UVA and lomefloxacin concomitantly, the time to development of skin tumors was 16 weeks. In mice treated concomitantly in this model with both UVA and other quinolones, the times to development of skin tumors ranged from 28 to 52 weeks.

Ninety-two percent (92%) of the mice treated concomitantly with both UVA and lomefloxacin developed well-differentiated squamous cell carcinomas of the skin. These squamous cell carcinomas were nonmetastatic and were endophytic in character. Twothirds of these squamous cell carcinomas contained large central keratinous inclusion masses and were thought to arise from the vestigial hair follicles in these hairless animals.

In this model, mice treated with lomefloxacin alone did not develop skin or systemic tumors.

There are no data from similar models using pigmented mice and/or fully haired mice

The clinical significance of these findings to humans is unknown.

Mutagenesis

One in vitro mutagenicity test (CHO/HGPRT assay) was weakly positive at lomefloxacin concentrations ≥ 226 μ g/mL and negative at concentrations < 226 μ g/mL. Two other in vitro mutagenicity tests (chromosomal aberrations in Chinese hamster ovary cells, chromosomal aberrations in human lymphocytes) and two in vivo mouse micronucleus mutagenicity tests were all negative.

Impairment of fertility

Lomefloxacin did not affect the fertility of male and female rats at oral doses up to 8 times the recommended human dose based on mg/m² (34 times the recommended human dose based on mg/kg).

Pregnancy

Teratogenic effects - Pregnancy Category C

Reproductive function studies have been performed in rats at doses up to 8 times the recommended human dose based on mg/m² (34 times the recommended human dose based on mg/kg), and no impaired fertility or harm to the fetus was reported due to lomefloxacin. Increased incidence of fetal loss in monkeys has been observed at approximately 3 to 6 times the recommended human dose based on mg/m² (6 to 12 times the recommended human dose based on mg/kg). No teratogenicity has been observed in rats and monkeys at up to 16 times the recommended human dose exposure. In the rabbit, maternal toxicity and associated fetotoxicity, decreased placental weight, and variations of the coccygeal vertebrae occurred at doses 2 times the recommended human exposure based on mg/m². There are, however, no adequate and well-controlled studies in pregnant women. Lomefloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

It is not known whether lomefloxacin is excreted in human milk. However, it is known that other drugs of this class are excreted in human milk and that lomefloxacin is excreted in the milk of lactating rats. Because of the potential for serious adverse reactions from lomefloxacin 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

The safety and effectiveness of lomefloxacin in pediatric patients and adolescents less than 18 years of age have not been established. Lomefloxacin causes arthropathy in juvenile animals of several species. (See WARNINGS and Animal Pharmacology.)

Geriatric use

Of the total number of subjects in clinical studies of lomefloxacin, 25% were ≥ 65 years and 9% were ≥ 75 years. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY — Pharmacokinetics in the geriatric population.)

In clinical trials, most of the adverse events reported were mild to moderate in severity and transient in nature. During these clinical investigations, 5,623 patients received Lefen (ANTIBACTERIALS). In 2.2% of the patients, lomefloxacin was discontinued because of adverse events, primarily involving the gastrointestinal system (0.7%), skin (0.7%), or CNS (0.5%).

Adverse clinical events

The events with the highest incidence ( ≥ 1%) in patients, regardless of relationship to drug, were headache (3.6%), nausea (3.5%), photosensitivity (2.3%) , dizziness (2.1%), diarrhea (1.4%), and abdominal pain (1.2%).

Additional clinical events reported in < 1% of patients treated with Lefen (ANTIBACTERIALS), regardless of relationship to drug, are listed below:

Autonomic: increased sweating, dry mouth, flushing, syncope.

Body as a whole: fatigue, back pain, malaise, asthenia, chest pain, face edema, hot flashes, influenza-like symptoms, edema, chills, allergic reaction, anaphylactoid reaction, decreased heat tolerance.

Cardiovascular: tachycardia, hypertension, hypotension, myocardial infarction, angina pectoris, cardiac failure, bradycardia, arrhythmia, phlebitis, pulmonary embolism, extrasystoles, cerebrovascular disorder, cyanosis, cardiomyopathy.

Central and peripheral nervous system: tremor, vertigo, paresthesias, twitching, hypertonia, convulsions, hyperkinesia, coma.

Gastrointestinal: dyspepsia, vomiting, flatulence, constipation, gastrointestinal bleeding, dysphagia, stomatitis, tongue discoloration, gastrointestinal inflammation.

Hearing: earache, tinnitus.

Hematologic: purpura, lymphadenopathy, thrombocythemia, anemia, thrombocytopenia, increased fibrinolysis.

Hepatic: abnormal liver function.

Metabolic: thirst, hyperglycemia, hypoglycemia, gout.

Musculoskeletal: arthralgia, myalgia, leg cramps.

Ophthalmologic: abnormal vision, conjunctivitis, photophobia, eye pain, abnormal lacrimation.

Psychiatric: insomnia, nervousness, somnolence, anorexia, depression, confusion, agitation, increased appetite, depersonalization, paranoid reaction, anxiety, paroniria, abnormal thinking, concentration impairment.

Reproductive system: Female: vaginal moniliasis, vaginitis, leukorrhea, menstrual disorder, perineal pain, intermenstrual bleeding. Male: epididymitis, orchitis.

Resistance mechanism: viral infection, moniliasis, fungal infection.

Respiratory: respiratory infection, rhinitis, pharyngitis, dyspnea, cough, epistaxis, bronchospasm, respiratory disorder, increased sputum, stridor, respiratory depression.

Skin/Allergic: pruritus, rash, urticaria, skin exfoliation, bullous eruption, eczema, skin disorder, acne, skin discoloration, skin ulceration, angioedema. (See also Body as a whole.)

Special senses: taste perversion.

Urinary: hematuria, micturition disorder, dysuria, strangury, anuria.

Adverse laboratory events

Changes in laboratory parameters, listed as adverse events, without regard to drug relationship include:

Hematologic: monocytosis (0.2%), eosinophilia (0.1%), leukopenia (0.1%), leukocytosis (0.1%).

Renal: elevated BUN (0.1%), decreased potassium (0.1%), increased creatinine (0.1%).

Hepatic: elevations of ALT (SGPT) (0.4%), AST (SGOT) (0.3%), bilirubin (0.1%), alkaline phosphatase (0.1%).

Additional laboratory changes occurring in < 0.1% in the clinical studies included: elevation of serum gamma glutamyl transferase, decrease in total protein or albumin, prolongation of prothrombin time, anemia, decrease in hemoglobin, thrombocythemia, thrombocytopenia, abnormalities of urine specific gravity or serum electrolytes, increased albumin, elevated ESR, albuminuria, macrocytosis.

Post-Marketing Adverse Events

Post-marketing adverse events

Adverse events reported from worldwide marketing experience with lomefloxacin are: anaphylaxis, cardiopulmonary arrest, laryngeal or pulmonary edema, ataxia, cerebral thrombosis, hallucinations, painful oral mucosa, pseudomembranous colitis, hemolytic anemia, hepatitis, tendinitis, diplopia, photophobia, phobia, exfoliative dermatitis, hyperpigmentation, Stevens-Johnson syndrome, toxic epidermal necrolysis, dysgeusia, interstitial nephritis, polyuria, renal failure, urinary retention, and vasculitis.

Quinolone-class adverse events

Additional quinolone-class adverse events include: peripheral neuropathy, torsades de pointes, erythema nodosum, hepatic necrosis, possible exacerbation of myasthenia gravis, dysphasia, nystagmus, intestinal perforation, manic reaction, renal calculi, acidosis and hiccough.

Laboratory adverse events include: agranulocytosis, elevation of serum triglycerides, elevation of serum cholesterol, elevation of blood glucose, elevation of serum potassium, albuminuria, candiduria, and crystalluria.

Information on overdosage in humans is limited. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient should be carefully observed and given supportive treatment. Adequate hydration must be maintained. Hemodialysis or peritoneal dialysis is unlikely to aid in the removal of lomefloxacin as < 3% is removed by these modalities.

Clinical signs of acute toxicity in rodents progressed from salivation to tremors, decreased activity, dyspnea, and clonic convulsions prior to death. These signs were noted in rats and mice as lomefloxacin doses were increased.