Data Sheet
NOROXIN®
norfloxacin
400 mg tablet
Presentation
Off white oval biconvex tablet scored on one side and marked MSD 705 on the other side. Dimensions are 16 x 8 mm.
Each tablet contains 400 mg of norfloxacin.
Therapeutic Class
NOROXIN is an antibacterial agent.
Indications
NOROXIN is a broad-spectrum bactericidal agent indicated for the treatment of:
- Upper and lower, complicated and uncomplicated, acute urinary tract infections. These infections include cystitis, pyelitis, cystopyelitis, pyelonephritis, chronic prostatitis, epididymitis, and those urinary infections associated with urologic surgery, neurogenic bladder or nephrolithiasis caused by bacteria susceptible to NOROXIN.
- Acute bacterial gastroenteritis caused by susceptible organisms.
- Gonococcal urethritis pharyngitis, proctitis or cervicitis caused by both penicillinase and non-penicillinase producing Neisseria gonorrhoeae
Infections caused by multiply-resistant organisms have been successfully treated with the usual doses of NOROXIN.
Dosage and Administration
NOROXIN should be taken with a glass of water at least one hour before or two hours after a meal or milk ingestion. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminium, sucralfate, or Videx** (didanosine), chewable/buffered tablets or the paediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin.
Susceptibility of the causative organism to NOROXIN should be tested, however, therapy may be initiated before obtaining the results of these tests.
Treatment
| Diagnosis | Dosage | Therapy Duration |
|---|---|---|
| Urinary Tract Infections | 400 mg b.i.d. | 7-10 days |
| Uncomplicated Acute Cystitis | 400 mg b.i.d. | 3-7 days |
| Chronic Prostatitis | 400 mg b.i.d. | 4 weeks |
| Acute Bacterial Gastroenteritis | 400 mg b.i.d. | 5 days |
| Acute Gonococcal Urethritis, Pharyngitis, Proctitis or Cervicitis | 800 mg | single dose |
Renal Impairment
NOROXIN is suitable for the treatment of patients with renal insufficiency. In studies involving patients whose creatinine clearance was less than 30 ml/min/1.73m2, but who did not require haemodialysis, the plasma half-life of norfloxacin was approximately 8 hours. Clinical studies showed there was no difference in the mean half life of norfloxacin in patients with creatinine clearance of less than 10 ml/min/1.73m2, compared to patients with creatinine clearance of 10-30 ml/min/1.73m2. Hence, for these patients the recommended dose is one 400 mg tablet once daily. At this dosage, concentrations in appropriate body tissues or fluids exceed the MIC's for most pathogens sensitive to norfloxacin.
There are insufficient data on which to have a dosage recommendation for the treatment of gonorrhoea in patients with a creatinine clearance of 30 ml/min/1.73m2 or less.
Contraindications
Hypersensitivity to any component of this product or any chemically related quinolone antibacterials.
NOROXIN should not be used in prepubertal children.
Warnings and Precautions
As with other organic acids, NOROXIN should be used with caution in individuals with a history of convulsions or known factors that predispose to seizures. Convulsions have been reported rarely in patients receiving NOROXIN.
Photosensitivity reactions have been observed in patients who are exposed to excessive sunlight while receiving some members of this medicine class. Excessive sunlight should be avoided. Therapy should be discontinued if photosensitivity occurs.
As with other quinolones, tendinitis and/or tendon rupture have been observed rarely in patients taking NOROXIN, especially when corticosteroids are taken concomitantly. If a patient develops symptoms of tendinitis and/or tendon rupture, NOROXIN should be discontinued immediately and the patient advised to seek appropriate medical management.
Rarely, haemolytic reactions have been reported in patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity who take quinolone agents, including NOROXIN (see Adverse Effects).
Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including NOROXIN, in patients with myasthenia gravis (see Adverse Effects).
Some quinolones have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. During post-marketing surveillance, extremely rare cases of torsades de pointes, have been reported in patients taking norfloxacin. These reports generally involve patients who had other concurrent medical conditions and the relationship to norfloxacin has not been established. Among drugs known to cause prolongation of the QT interval, the risk of arrhythmias may be reduced by avoiding use in the presence of hypokalaemia, significant bradycardia, or concurrent treatment with class la or class III antiarrhythmic agents. Quinolones should also be used with caution in patients using cisapride, erythromycin, antipsychotics, tricyclic antidepressants or have any personal or family history of QTc prolongation.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including NOROXIN, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis".
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.
Renal Impairment
NOROXIN is suitable for the treatment of patients with renal impairment, however since NOROXIN is primarily excreted by the kidney, urinary levels may be significantly compromised by severe renal dysfunction (see Dosage and Administration).
Pregnancy
The safe use of NOROXIN in pregnant women has not been established and, consequently, the benefits of treatment with NOROXIN should be weighed against potential risks. NOROXIN has been detected in cord blood and amniotic fluid.
Nursing Mothers
When a 200 mg dose was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low and as many drugs are secreted in human milk, caution should be exercised when NOROXIN is administered to a nursing woman.
Children
Safety and efficacy in children have not been established; therefore, NOROXIN should not be used in prepubertal children (see Animal Toxicology).
Driving and Operating Machinery
Norfloxacin may cause dizziness and light-headedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination.
Animal Toxicology
Norfloxacin and related medicines have been shown to cause arthropathy in immature animals of most species tested. The oral administration of single doses of norfloxacin, 6 times the recommended human clinical dose, caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage.
Related medicines (e.g. nalidixic acid and cinoxacin) also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. Dogs six months or older were not susceptible to these changes.
Teratology studies in mice and rats and fertility studies in mice at oral doses of 30 to 50 times the usual dose for humans did not reveal teratogenic or foetal toxic effects. Embryotoxicity was observed in rabbits at doses of 100 mg/kg/day. This was secondary to maternal toxicity and it is a non-specific antimicrobial effect in the rabbit due to an unusual sensitivity to antibiotic-induced changes in the gut microflora.
Although NOROXIN was not teratogenic in cynomolgus monkeys, at several times the therapeutic human dosage an increased percentage of embryonic losses was observed.
No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg.
Adverse Effects
NOROXIN generally is well tolerated. The overall incidence of medicine related adverse effects reported during worldwide clinical trials involving 2346 patients was approximately 3%.
The most common adverse effects (less than 3% but occurring in >0.1% of the patients) have been gastrointestinal, neuropsychiatric and skin reactions, and include nausea, headache, dizziness, rash, heartburn, abdominal pain/cramps and diarrhoea.
In very rare instances (<0.1%), other adverse effects such as anorexia, sleep disturbances, depression, anxiety/nervousness, irritability, euphoria, disorientation, hallucination, tinnitus and epiphora have been reported.
Abnormal laboratory adverse effects were rarely observed during clinical trials; however the following have been reported with an incidence of < 0.3%, leucopaenia, eosinophilia, neutropaenia, thrombocytopenia, elevation of ALT (SGPT), AST (SGOT).
The following additional adverse effects have been reported since the medicine was marketed:
Hypersensitivity Reactions: Hypersensitivity reactions including anaphylaxis, angioedema, dyspnoea, vasculitis, urticaria, arthritis, myalgia and arthralgia and interstitial nephritis.
Skin: Photosensitivity, Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, pruritus.
Gastrointestinal: Pseudomembranous colitis, pancreatitis (rare), hepatitis, jaundice, including cholestatic jaundice and elevated, liver function tests.
Musculoskeletal : Tendinitis, tendon rupture, exacerbation of myasthenia gravis, elevated creatine kinase (CK).
Nervous System/Psychiatric: Polyneuropathy including Guillain-Barré Syndrome, confusion, paraesthesia, hypoesthesia, psychic disturbances including psychotic reactions, convulsions, tremors, myoclonus.
Haematologic: Agranulocytosis, haemolytic anaemia, sometimes associated with glucose 6 phosphate, dehydrogenase deficiency.
Genitourinary: Vaginal candidiasis.
Renal Function: Renal failure.
Special Senses: Dysgeusia, visual disturbances, hearing loss.
Adverse Effects, Causal Relationship Unknown
A definite causal relationship could not be established with regard to the following adverse effects: conjunctivitis, eye pain/irritation, asthenia/fatigue, somnolence, constipation and flatulence. On very rare occasions prolonged QTc interval and ventricular arrhythmia (including torsades de pointes), hypertonia, ataxia, dysarthria, dysphasia, haemophthalmia, nystagmus, periorbital erythema, fever, vomiting, dry mouth, and hypoglycaemia have been reported.
Without establishing a causal relationship, the following have also been reported: increased serum creatinine, proteinuria, increased BUN, and decreased haematocrit.
Interactions
Coadministration of probenecid does not affect serum concentrations of norfloxacin, but urinary excretion of the drug diminishes.
As with other organic acid antibacterials, antagonism has been demonstrated in vitro between NOROXIN and nitrofurantoin.
Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolised by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored.
Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been rare reports of theophylline-related adverse effects in patients on concomitant therapy with norfloxacin and theophylline.
Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required.
Elevated serum levels of cyclosporin have been reported with concomitant use with norfloxacin. Therefore, cyclosporin serum levels should be monitored and appropriate cyclosporin dosage adjustments made when these medicines are used concomitantly.
Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants including warfarin or its derivatives and fluindione or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
The concomitant administration of quinolones including norfloxacin with glibenclamide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycaemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.
Multivitamins, products containing iron or zinc, antacids or sucralfate should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin.
Videx (Didanosine) chewable/buffered tablets or the paediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin.
Some quinolones, including norfloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin..
The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly.
Animal data have shown that quinolones in combination with fenbufen can lead to convulsions. Therefore, concomitant administration of quinolones and fenbufen should be avoided.
Overdosage
No specific information is available on the treatment of overdosage with NOROXIN. Adequate hydration must be maintained.
Actions
Microbiology
NOROXIN has a broad spectrum of antibacterial activity against gram-positive and gram-negative aerobic pathogens. The fluorine atom at the 6 position provides increased potency against gram-negative organisms and the piperazine moiety at the 7 position is responsible for antipseudomonal activity.
NOROXIN inhibits bacterial deoxyribonucleric acid synthesis and is bactericidal. At the molecular level, three specific events were attributed to NOROXIN in Escherichia coli cells:
- inhibition of the ATP-dependent DNA supercoiling reaction catalysed by DNA gyrase;
- Inhibition of the relaxation of supercoiled DNA;
- promotion of double-stranded DNA breakage.
Resistance to norfloxacin due to spontaneous mutation is a rare occurrence (range, 10-9 - 10-12). Resistance of the organism has developed during therapy with norfloxacin in less than 1% of patients being treated. Organisms in which development of resistance is greatest are the following:
Pseudomonas aeruginosa
Klebsiella pneumoniae
Acinetobacter spp.
Enterococci
Methicillin-resistant Staphylococcus areus
Because of its specific structure, NOROXIN is generally active against organisms that are resistant to other organic acids such as nalidixic, oxolinic, and pipemidic acids, cinoxacin, and flumequine. Organisms resistant to norfloxacin in vitro are also resistant to these organic acids. Preliminary studies suggest that norfloxacin-resistant organisms are also generally resistant to pefloxacin, ofloxacin, ciprofloxacin and enoxacin. There is no cross-resistance between norfloxacin and structurally unrelated antibacterial agents such as penicillins, cephalosporins, tetracyclines, macrolides, aminocyclitols and sulphonamides, 2,4 diaminopyrimidines, or combinations thereof (e.g. cotrimoxazole).
Analysis of the overall clinical experience with NOROXIN revealed a high correlation between the results of susceptibility tests conducted in vitro and the bacteriological and clinical efficacy of the agent in humans.
NOROXIN is active in vitro against the following bacteria:
Bacteria found in urinary tract infections:
Enterobacteriaceae
Citrobacter spp.
Citrobacter koseri (formerly known as Citrobacter diversus)
Citrobacter freundii
Edwardsiella tarda
Enterobacter spp.
Enterobacter aerogenes
Enterobacter agglomerans
Enterobacter cloacae
Escherichia coli
Hafnia alvei
Klebsiella spp.
Klebsiella oxytoca
Klebsiella pneumoniae
Morganella morganii
Proteus spp. (indole positive)
Proteus mirabilis
Proteus vulgaris
Providencia spp.
Providencia rettgeri
Providencia stuartii
Serratia spp.
Serratia marcescens
Pseudomonadaceae
Pseudomonas aeruginosa
Pseudomonas cepacia
Pseudomonas fluorescens
Pseudomonas stutzeri
Other
Flavobacterium spp.
Gram-positive cocci
Enterococcus faecalis
Group G streptococci
Staphylococcus spp.
Staphylococcus Coag. Negative
Staphylococcus aureus (including penicillinase-producing and most
methicillin-resistant strains)
Staphylococcus epidermidis
Staphylococcus saprophyticus
Streptococcus agalactiae
Viridans group streptococci
Bacteria associated with acute gastroenteritis:
Aeromonas hydrophila
Campylobacter foetus subsp. Jejuni
Enterotoxigenic Escherichia coli
Plesiomonas shigelloides
Salmonella spp.
Salmonella typhi
Shigella spp.
Shigella boydii
Shigella dysenteriae
Shigella flexneri
Shigella sonnei
Vibrio cholerae
Vibrio parahemolyticus
Yersinia anterocolitica
In addition, NOROXIN is active against Bacillus cereus, Neisseria gonorrhoeae, Ureaplasma urealyticum, Haemophilus influenzae and Haemophilus ducreyi.
NOROXIN is not active against anaerobes, including Actinomyces spp., Fusobacterium spp. Bacteroides spp. and Clostridium spp. other than C. perfringens.
Susceptibility Testing
The FDA standardised disc (formerly, Kirby-Bauer) technique of antibiotic susceptibility testing is recommended using a 10 mcg disc of 6 mm diameter.
| Category | Zone Diameter (mm) |
MIC (mcg/mL) |
|---|---|---|
| Susceptible | > 17 | < 4 |
| Intermediate | 13-16 | 8 |
| Resistant | < 12 | > 16 |
These susceptibility criteria apply only to organisms isolated from urine (urinary tract), and faeces (gastrointestinal tract).
Neisseria gonorrhoeae and organisms isolated from tissue are considered susceptible to NOROXIN if the zone diameter is > 21 mm or MIC < 1 mcg/mL.
Pharmacokinetics
NOROXIN is rapidly absorbed following oral administration. In healthy volunteers at least 30-40% of an oral dose of NOROXIN is absorbed. This results in a serum concentration of 1.5 mcg/ml being attained approximately one hour after administration of a 400 mg dose. Mean serum half-life is 3-4 hours and is independent of dose.
The following are the mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400 mg doses, unless otherwise indicated:
Renal parenchyma 7.3 mcg/g
Prostate 2.5 mcg/g
Seminal fluid 2.7 mcg/ml|
Testicle 1.6 mcg/g
Uterus/cervix 3.0 mcg/g
Vagina 4.3 mcg/g
Fallopian Tube 1.9 mcg/g
Gallbladder tissue 1.8 mcg/g*
Bile 6.9 mcg/mL (after two 200 mg doses)
*measured 4-6 hours after one 400 mg dose
Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400 mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 mcg of norfloxacin/gm faeces were obtained at 12, 24, and 48 hours, respectively.
Renal excretion occurs by both glomerular filtration and net tubular secretion, as evidenced by the high rate of renal clearance (approx. 275 ml/min). After a single 400 mg dose, urinary concentrations reach a value of 200 or more mcg/ml in healthy volunteers and remain above 30 mcg/mL for at least 12 hours. In the first 24 hours, 33-48% of the medicine is recovered in the urine.
In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Norfloxacin absorption appears unaffected. However, the effective half life of norfloxacin in these elderly subjects is 4 hours.
Following a single 400 mg dose of norfloxacin, the disposition of the drug in patients with creatinine clearance greater than 30 ml/min/1.73m2 is similar to that of healthy volunteers. In patients with creatinine clearance less than 30 ml/min/1.73m2, the renal elimination of norfloxacin decreases significantly. The effective serum half-life is approximately 8 hours. Norfloxacin absorption appears unaffected by decreasing renal function.
Norfloxacin exists in the urine as norfloxacin and six active metabolites of lesser antimicrobial potency. The parent compound accounts for over 70% of total excretion. The bactericidal potency of NOROXIN is not affected by the pH of urine.
The protein binding is less than 15%.
Peak serum levels of NOROXIN are slightly lower when administered with food than when given fasting.
Pharmaceutical Precautions
Keep in a cool place protected from sunlight and excessive heat.
Medicine Classification
Prescription Medicine.
Package Quantities
100 tablets.
Also available for use in acute cystitis in blister packs of 6 tablets.
Further Information
Norfloxacin is chemically described as 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN303. The structural formula is:
No colouring agents or gluten are included in this product.
Name and Address
Merck Sharp & Dohme (New Zealand) Limited
P O Box 99 851
Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673
Date of Preparation
31 May 2007
DP-NRX-0507(310507)
®Registered Trademark of Merck & Co Inc., Whitehouse Station, NJ, USA
** Trade name