No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg.
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 symptomatic and supportive treatment. Adequate hydration must be maintained.
Nolicin (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents.
In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship.
The most common adverse experiences ( > 1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%).
Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting.
Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%).
Multiple-Dose StudiesIn clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship.
The most common adverse experiences ( > 1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%).
Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting.
Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria.
Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria.
Post-MarketingThe most frequently reported adverse reaction in post-marketing experience is rash.
CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with Nolicin (see WARNINGS). Visual disturbances have been reported with drugs in this class.
The following additional adverse reactions have been reported since the drug was marketed:
Hypersensitivity ReactionsHypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS).
SkinToxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS), leukocytoclastic vasculitis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
GastrointestinalPseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS).
HepaticHepatic failure, including fatal cases.
CardiovascularOn rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes.
RenalInterstitial nephritis, renal failure.
Nervous System/PsychiatricPeripheral neuropathy that may be irreversible, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion.
MusculoskeletalTendinitis, tendon rupture; exacerbation of myasthenia gravis (see WARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK), muscle spasms.
HematologicNeutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6phosphate dehydrogenase deficiency; thrombocytopenia.
Special SensesHearing loss, tinnitus, diplopia, dysgeusia.
Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis.
Fluoroquinolones, including Nolicin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly s een adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting Nolicin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions (see WARNINGS, Tendinitis and Tendon Rupture, Peripheral Neuropathy and Central Nervous System Effects).
Discontinue Nolicin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including Nolicin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
Tendinitis And Tendon RuptureFluoroquinolones, including Nolicin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur within hours or days of starting Nolicin, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.
The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors.
Discontinue Nolicin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including Nolicin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture (see ADVERSE REACTIONS). Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
Peripheral NeuropathyFluoroquinolones, including Nolicin, have been associated with an increased risk of peripheral neuropathy. 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 fluoroquinolones, including Nolicin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible in some patients (see WARNINGS). Discontinue Nolicin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including Nolicin, in patients who have previously experienced peripheral neuropathy (see ADVERSE REACTIONS).
Central Nervous System EffectsFluoroquinolones, including Nolicin, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses. Quinolones may also cause CNS stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted.
The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS).
Exacerbation Of Myasthenia GravisFluoroquinolones, including Nolicin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid Nolicin in patients with known history of myasthenia gravis. (See PATIENT INFORMATION and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.)
Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times2 the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see Animal Pharmacology).
Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including
Nolicin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PATIENT INFORMATION and ADVERSE REACTIONS).
Hypersensitivity ReactionsSerious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including Nolicin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated.
Clostridium Difficile Associated DiarrheaClostridium Difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Nolicin and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Syphilis TreatmentNorfloxacin 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 norfloxacin should have a follow-up serologic test for syphilis after three months.
PRECAUTIONS GeneralNeedle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output.
Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION).
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure.
Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing).
Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS).
Prescribing Nolicin 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.
Information For PatientsAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Serious Adverse ReactionsAdvise patients to stop taking Nolicin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.
Inform patients of the following serious adverse reactions that have been associated with Nolicin or other fluoroquinolone use:
Patients should be advised:
Patients should be counseled that antibacterial drugs including Nolicin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Nolicin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Nolicin or other antibacterial drugs in the future.
Laboratory TestsAs with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.
Carcinogenesis, Mutagenesis, Impairment of FertilityNo increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times2 the usual human dose (on a mg/kg basis).
Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times2 the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79).
Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times2 the usual human dose (on a mg/kg basis).
Pregnancy Teratogenic EffectsPregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing MothersIt is not known whether norfloxacin is excreted in human milk.
When a 200-mg dose of Nolicin was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseThe safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and Animal Pharmacology.)
Geriatric UseGeriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Nolicin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing Nolicin to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue Nolicin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see BOXED WARNING; WARNINGS; and ADVERSE REACTIONS, Post-Marketing).
Of the 340 subjects in one large clinical study of Nolicin for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS).
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 DOSAGE AND ADMINISTRATION).
A pharmacokinetic study of Nolicin in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY).
In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using Nolicin concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia).
REFERENCES
1 Efficacy for this organism in this organ system was studied in fewer than 10 infections.
2 Based on a patient weight of 50 kg.
