1. NAME OF THE MEDICINAL PRODUCT
Norfloxacin film-coated tablet USP 400mg Taj Pharma.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains:

Norfloxacin USP             400 mg
Excipients                            q.s.
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Film-coated tablet
Round, slightly biconvex, white film-coated tablet with one side scored.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Norfloxacin 400 mg film-coated tablets is a broad-spectrum bactericidal/chemotherapeutic agent, indicated for the treatment of the following infections caused by norfloxacin-susceptible grampositive and gram-negative aerobic bacteria:
· Upper and lower, complicated and uncomplicated, acute and chronic urinary tract infections (including uncomplicated pyelonephritis, excluding acute and chronic complicated pyelonephritis)
· Urinary infections associated with urological surgery or nephrolithiasis

Consideration should be given to an official local guidance, e.g. national recommendations regarding the appropriate use and prescription of antibacterial agents.

4.2  Posology and method of administration
Posology
The dosage depends on the susceptibility of the pathogens and severity of the disease; see recommended dosage in the table below. Oral norfloxacin containing products are not recommended for the treatment of acute or chronic complicated pyelonephritis.
Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.
In case of suspected failure of therapy, microbiological investigation for possible bacterial resistance should be undertaken.

Dosage in adults

Diagnosis Dosage Therapy duration2
Usual dosage for uncomplicated acute cystitis3 400 mg twice daily 3 days
Usual dosage for urinary tract infections 400 mg twice daily 7-10 days1
Complicated urinary tract infections 400 mg twice daily 2 – 3 weeks1
Urinary infections associated with urological surgery or nephrolithiasis The dosage lies between 400 mg BID and 400 mg TID. The daily dose and duration of therapy depends on the severity and relapse rate of the infection.  

1 Symptoms accompanying urinary tract infections such as burning on passing water or fever and pain subside after only one to two days. Nevertheless, the recommended length of treatment should be fully adhered to

2 Prolonged therapy should be guided by evaluation of response of the patient taking into account official therapeutic guidelines and assessment of the risk of development of resistance.

3 This condition is considered to be met in women.

Dosage for patients with renal insufficiency Norfloxacin is suitable for treatment of patients with renal insufficiency. In patients with severe impaired renal function, the advantages and disadvantages of the use of Norfloxacin should be carefully weighed up in each individual case. For patients with a creatinine clearance ≤ 30 ml/min x 1.73 m2 the recommended dosage is one Norfloxacin 400 mg film-coated tablet daily.

At this dosage, fluid and tissue concentrations exceed the MlCs of most norfloxacin-susceptible pathogens responsible for urinary tract infections.

Dosage for elderly patients
Pharmacokinetic studies have shown no evidence of differences in norfloxacin pharmacokinetics in elderly patients, apart from a slight prolongation of half-life. In the absence of renal impairment no adjustment of dosage is necessary for elderly patients.

Paediatric population
Norfloxacin is not recommended for use in children or growing adolescents (see section 4.3).

Method of administration
The film-coated tablets should be swallowed with sufficient fluid (e.g. a glass of water) at least one hour before or two hours after a meal or ingestion of milk (see also section 4.5 under the heading miscellaneous preparations).

The film-coated tablets should preferably be taken in the morning and evening. If only one dose is to be administered daily, this should always be taken at the same time of the day.

4.3 Contraindications
Hypersensitivity to any component of this product tablets or any chemically related quinolone antibacterials or to any of the other excipients listed in section 6.1.

Norfloxacin is contraindicated in patients with a history of tendinitis and/or tendon rupture related to fluoroquinolone administration (see sections 4.4 and 4.8).

Use in children
Norfloxacin is contra-indicated in prepubertal children and growing adolescents. As with other quinolones, Norfloxacin has been shown to cause arthropathy in immature animals. The safety of Norfloxacin in children has not been adequately explored and therefore the use of Norfloxacin in prepubertal children or growing adolescents is contraindicated

Use in pregnancy and lactation and in children and growing adolescents
Norfloxacin must not be used by children and growing adolescents or by pregnant and lactating women. This is because safety has not yet been sufficiently established for these groups of patients (see section 4.6 and 5.3).

4.4 Special Warnings and precautions for use
Photosensitivity
Photosensitivity may occur in patients taking norfloxacin tablets or other quinolone-type drugs. Longer periods of exposure to the sun and stronger sunlight should be avoided during treatment. In the same way the use of solarium should be denied during this time. Treatment should be stopped if symptoms of photosensitivity occur.

Tendinitis and/or tendon rupture
As with other quinolones, tendinitis and/or tendon rupture (particularly affecting the Achilles tendon) have been observed rarely during and after norfloxacin use. Such reactions have particularly been noted in elderly patients and patients on glucocorticosteroids. At the first sign of pain or inflammation, norfloxacin therapy should be discontinued immediately and the patient should be given suitable pharmacological treatment.

Use in patients with epilepsy and other CNS disorders
In the case of epileptics and patients with existing CNS disorders (e.g. a low convulsive threshold, a history of convulsions, reduced cerebral blood flow, changes to brain structure or stroke), norfloxacin should only be given if the benefit clearly outweighs the risk, because of the possibility of CNS side effects in these patients. Convulsions have been reported in rare cases in patients receiving norfloxacin. Norfloxacin may lead to exacerbations and aggravation of the symptoms in patients with known or suspected psychiatric disorders, hallucinations and/or confusion. The usually appropriate emergency measures are indicated (e.g. keeping airways free, administer anticonvulsants).

Impaired renal function
In patients with severely impaired renal function, the advantages and disadvantages of use of norfloxacin tablets should be carefully weighed up in each individual case (see section 4.2). As the renal function is reduced by age particularly elderly belong to this group of patients. The urinary concentration of norfloxacin may be reduced if renal function is severely impaired since elimination of norfloxacin occurs predominantly by the renal route.

Crystalluria
In case of prolonged treatment, the occurrence of crystalluria should be monitored. While crystalluria is not expected to occur under normal conditions with dosage regimen 400 mg twice daily, as a precaution, the daily recommended dosage should not be exceeded and the intake of sufficient fluids should be guaranteed to ensure proper state of hydration and adequate urinary output.

Myasthenia gravis
Norfloxacin can exacerbate the symptoms of myasthenia gravis which may result in life threatening weakness of respiratory muscles. Adequate counter measures should be taken at any sing of respiratory distress.
In patients treated with norfloxacin, unmasking or exacerbation of myasthenia gravis has been reported. As this may include potentially life-threatening respiratory failure, patients with myasthenia gravis should be advised to immediately seek medical treatment if exacerbation of symptoms occurs. (see section 4.8).

Vision disorders
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8)

G6PD (Glucose-6-Phosphate-Dehydrogenase) deficiency
Rarely, haemolytic reactions have been reported in patients with latent or actual defects in glucose-6- phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see section 4.8).

Pseudomembranous colitis
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Norfloxacin, 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. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.
If Clostridium difficile associated diarrhea (CDAD) is suspected or confirmed, ongoing antibiotic use not directed against C. difficile should be discontinued and appropriate therapy instituted immediately. Anti-peristaltic drugs are contraindicated in this situation.

Hypersensitivity reactions
Serious and occasionally fatal hypersensitivity (anaphylactic or anaphylactoid) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. In such cases, therapy with Norfloxacin must be discontinued immediately and appropriate emergency action must be started (e.g. antihistamines, glucocorticosteroids, sympathomimetics and ventilation if necessary).

Cardiac disorders
Caution should be taken when using fluoroquinolones, including Norfloxacin , in patients with known risk factors for prolongation of the QT interval such as, for example:
– congenital long QT syndrome
– concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
– uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)
– cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
– Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including Norfloxacin, in these populations.
(See section 4.2 Elderly, section 4.5, section 4.8, section 4.9).

Aortic aneurysm and dissection
Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Peripheral neuropathy
Peripheral sensory neuropathy and peripheral sensory motor neuropathy have been reported in patients receiving fluoroquinolones which can be rapid in its onset. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.

4.5 Interaction with other medicinal products and other forms of interaction
Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g. caffeine, clozapine, ropinirole, theophylline, tizanidine) may result in increased levels of these drugs, with the potential risk of increased toxicity. Patients taking any concomitant drugs metabolized by CYP1A2 should be carefully monitored

Theophylline
Elevated plasma concentrations of theophylline have been reported during concomitant use of theophylline and quinolones. Adverse reactions caused by theophylline have also been reported sporadically during concomitant use of
norfloxacine and theophylline. The theopylline concentration in plasma should thus be monitored and the dosage of theopylline adjusted if necessary.

Cyclosporine
Elevated serum concentrations of ciclosporine have been reported with concomitant use of norfloxacin. Cicloporine serum levels should be monitored and appropriate ciclosporin dosage adjustments made when these drugs are used concomitantly.

Warfarin
Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When concomitant administration of these products cannot be avoided, measurements of prothrombin time or other suitable coagulation tests should be carried out.

Glibenclamide
The concomitant administration of quinolones including norfloxacin with glibenclamide (a sulphonylurea agent) has, on rare occasions, resulted in severe hypoglycaemia. Therefore monitoring of blood glucose is recommended when these agents are co-administered.

Probenecid
Co-administration of probenecid does not affect serum concentrations of norfloxacin, but urinary excretion of the drug diminishes.

Nitrofurantoin
As with other organic acid antibacterials, antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Concomitant use of norfloxacin and nitrofurantoin should therefore be avoided.

Multivitamins, products containing iron or zinc, antacids or sucralfate
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.

Didanosine
Products containing didanosine should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because the products may interfere with absorption resulting in lower serum and urine levels of norfloxacin.

Caffeine
Some quinolones, including norfloxacin, have also been shown to inhibit the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin.

Non-steroidal anti-inflammatory drug (NSAID)
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 Norfloxacin should be used with caution in individuals receiving NSAIDs concomitantly.

Fenbufen
Animal data have shown that quinolones in combination with fenbufen can lead to convulsions. Therefore, concomitant administration of quinolones and fenbufen should be avoided.

Mycophenolic acid
Lowered bioavailability of mycophenolic acid was observed in healthy volunteers receiving combined treatment with norfloxacin and metronidazole.

Miscellaneous preparations (preparations containing iron or antacids, products containing magnesium, aluminium, calcium or zinc)
Calcium preparations, multivitamin preparations, preparations containing iron or zinc, antacids, and sucralfate should not be ingested simultaneously with Norfloxacin 400 mg film-coated tablets, as this could reduce norfloxacin absorption leading to decreased concentrations in the serum and urine. Norfloxacin 400 mg film-coated tablets should be taken either 2 hours before or at least 4 hours after ingesting such products. This restriction does not apply to H2-receptor antagonisttype antacids.
Oral nutritional solutions and dairy products (mild or liquid milk products such as yoghurt) reduce the absorption of norfloxacin. Norfloxacin should therefore be taken at least 1 hour before or 2 hours after such products.

Drugs known to prolong the QT interval
Norfloxacin400 mg film-coated tablets, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).

4.6 Fertility, Pregnancy and lactation
Pregnancy
Norfloxacin should not be used during pregnancy. Norfloxacin and related substances have been shown to cause damage to the articular cartilage in growing animals. The occurrence of such adverse effects in humans cannot be excluded.

Norfloxacin passes in the umbilical cord blood and amniotic fluid.

Lactation
When a 200-mg dose of Norfloxacin 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 damage of articular cartilage in a growing organism was demonstrated, norfloxacin should only be administered during lactation when strictly indicated.

4.7 Effects on ability to drive and use machines
Even when used correctly, Norfloxacin 400 mg film-coated tablets may alter patients’ reactivity to the point that their ability to drive or operate machinery is impaired, especially at the start of treatment, on increasing the dose or switching medication, and in conjunction with alcohol. Fluoroquinolones including norfloxacin may result in an impairment of the patient’s ability to drive or operate machinery due to transient loss of vision (see section 4.8). Patients should be advised to see how they react to norfloxacin before driving or operating machinery.

4.8 Undesirable Effects
The following adverse reactions have been observed in clinical studies or obtained from postmarketing reports: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from the available data)

Infections and infestations
Uncommon: vaginal candidiasis

Blood and lymphatic system disorders
Common: eosinophilia, leucopenia, neutropenia
Uncommon: thrombocytopenia, reduced hematocrit and prolonged prothrombin time, hemolytic anemia sometimes associated with Glucose-6-phosphateDehydrogenase deficiency.
Very rare: agranulocytosis

Immune system disorders
Rare: angioedema, hypersensitivity reaction, vasculitis, anaphylactic reaction, dyspnea, urticaria, petechiae, hemorrhagic bullae, papules with vasculitis.

Metabolism and nutrition disorders
Uncommon: anorexia

Psychiatric disorders
Uncommon:
depression, sleep disturbances, nervousness, anxiety
Rare: disorientation, irritability, euphoria, hallucination, psychic disturbances, confusion, psychotic reactions

Nervous system disorders
Common: headache, dizziness, lightheadedness and drowsiness
Uncommon: paraesthesia, sensory disturbances, dysgeusia, bitter taste, convulsions tremor, polyneuropathy including Guillain-Barré syndrome, myoclonus including exacerbation of myasthenia gravis, tiredness, mood swings, paresthesia, insomnia, depression, anxiety, nervousness, irritability, hallucinations, polyneuropathy including Guillain-Barré syndrome, (epilepsylike) convulsions, possible exacerbation of myasthenia gravis (see section 4.4).

Eye disorders
Uncommon visual disturbances, increased lacrimation
Not known: transient loss of vision

Ear and labyrinth disorders
Uncommon: tinnitus
Very rare: hearing loss

Cardiac disorders
Uncommon: palpitation
Very rare: QT-prolongation has been reported.
Not known: ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see section 4.4 and 4.9).

Gastrointestinal disorders
Common: nausea, abdominal pain/cramps, nausea
Uncommon: diarrhea, heartburn, vomiting, anorexia, pancreatitis, dry mouth, flatulence, dyspepsia, dysphagia, constipation
Rare: pseudomembranous colitis

Hepatobiliary disorders
Common: elevation of ALAT (SGPT), ASAT (SGOT)
Rare: jaundice, hepatitis, cholestatic hepatitis

Skin and subcutaneous tissue disorders
Common: rash
Uncommon: pruritus, urticarial, severe skin reactions, exfoliative dermatitis, Lyell’ syndrome and erythema multiforme (Stevens-Johnson syndrome), photosensitivity, pruritus. Musculoskeletal, connective tissue and bone disorders
Rare: photosensitivity
Very rare: rhabdomyolysis
Not known: leucocytoclastic vasculitis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal, connective tissue and bone disorders
Rare: arthralgia, myalgia, arthritis, tendinitis, tendon rupture

Renal and urinary disorders
Common:
elevated serum creatinine
Uncommon: elevation of serum urea, crystalluria.
Rare: interstitial nephritis, renal failure

Investigations
Common: elevated alkaline phosphatase and LDH
Very rare: elevated creatinine kinase (CK)

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose
At present no experience is available with norfloxacin overdosing. In the event of recent 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. In recent acute overdosage patients should be advised to drink calcium-containing fluids so that norfloxacin forms a complex with calcium which undergoes only minimal absorption from the gastrointestinal tract. Adequate hydration must be maintained. Crystalluria was observed in few patients who had been treated with high doses of norfloxacin. These patients should drink enough liquid to ensure a proper state of hydration. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Mode of action:
Norfloxacin has a rapid bactericidal action and inhibits synthesis of bacterial deoxyribonucleic acid (DNA). An enzyme called DNA gyrase plays a key role in this process. Norfloxacin has a broad spectrum of antibacterial activity against gram-positive and gram-negative aerobic bacteria.

Mechanisms of resistance:
Bacterial resistance against fluoroquinolones is usually based on mechanisms like reduction of quinolone accumulation and/or mutations in the genes that encode for DNA gyrase and topoisomerase IV, the targets of quinolone action.

Bacteria which are resistant to norfloxacin in-vitro are also resistant to the older quinolones. Several studies have shown that bacteria resistant to norfloxacin are also generally resistant to pefloxacin, ofloxacin, ciprofloxacin and enoxacin.

There is no cross-resistance to structurally unrelated substances such as penicillins, cephalosporins, tetracyclines, macrolide antibiotics, aminoglycosides and sulfonamides, 2,4-diaminopyrimidine or combinations of these (e.g. cotrimoxazole).

Infections caused by multiply-resistant organisms have been successfully treated with the usual doses of norfloxacin.

Pathogen Susceptible Resistant
Enterobacteriaceae £ 0.5 mg/l > 1 mg/l
Non-species-related breakpoints* £ 0.5 mg/l > 1 mg/l

* generally based on serum pharmacokinetics

Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species
Gram-negative aerobes
Aeromonas hydrophilia
Proteus vulgaris
Providencia rettgeri
Salmonella spp
Shigella spp.
Species for which acquired resistance may be a problem Gram-positive aerobes Enterococcus faecalis $
Stapylococcus aureus
(methicillin-susceptible)
Staphyllococcus saprophyticus
Gram-negative aerobes
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloaca Escherichia coli & Klebsiella oxytoca Klebsiella pneumoniae Morganella morganii Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens
Inherently resistant organisms
Gram-positive aerobes
Enterococcus faecium
Staphylococcus aureus
(methicillin resistant)
Streptococcus agalactiae
Gram-negative aerobes
Stenotrophomonas maltophilia
Anaerobes
Clostridium difficile
Others
Chlamydia trachomatis
Mycoplasma hominis
Ureaplasma urealyticum

$ The inherent susceptibility of most isolates is within the intermediate range.
& In female patients with uncomplicated cystitis the resistance rate is < 10%, otherwise ≥ 10%.

5.2 Pharmacokinetic properties
Absorption
Norfloxacin is rapidly absorbed after oral administration. In healthy volunteers, at least 30 to 40% of an oral dose is absorbed from the currently available pharmaceutical forms. The presence of food and/or dairy products may decrease absorption.

Distribution
Serum concentrations of 0.84 – 1.64 mg/L were obtained within 1 – 1.5 hours after oral administration of a dose of 400 mg. The time to peak concentration (tmax) ranged from 0.75-2.0 h. The average halflife in serum is three to four hours in healthy volunteers; it is independent of the dosage.

The apparent volume of distribution (Vdβ) is approximately 223 ± 97 I.

Protein binding
Norfloxacin is around 13.8% plasma protein bound at a concentration of 2.5 mgl/l in human serum.

Elimination
Norfloxacin absorbed from the gastrointestinal tract is eliminated by metabolization and by renal and biliary excretion.

Renal excretion occurs both by glomerular filtration and by tubular secretion, as indicated by the high renal clearance of approximately 236 ± 56 ml/min and the inhibition of probenacid excretion. Total body clearance is 506 ± 211ml/min.

Approximately 25-40% of the dose was recovered in the urine after administration of single and multiple doses of 400 mg PO to renally healthy adult volunteers.

In healthy elderly subjects (65-75 years of age, normal renal function for stated age), norfloxacin is excreted more slowly in keeping with the physiologically reduced renal function in this age group. Drug absorption appears to be unaffected. The elimination half-life in geriatric patients was 2.7 – 3.5 h after administration of 400 mg/day, and 5.3- 5.4 h after a dose of 400 mg twice daily.

Norfloxacin is recovered intact in the urine and in the form of six active metabolites whose antibacterial efficacy is lower than that of the parent compound. Over 70% of the excreted drug is recovered in non-metabolised form.

Norfloxacin’s antibacterial activity is not affected by changes in urinary pH.

Pharmacokinetics in patients with impaired renal function
After a single dose of 400 mg, norfloxacin is available in patients with a creatinine clearance above 30 ml/min x 1.73 m2 to a similar extent as in healthy volunteers. Renal norfloxacine excretion is markedly reduced in patients whose creatinine clearance is below 30 ml/min x 1.73 m2 . The average norfloxacin elimination half-life was 4.4, 6.6 and 7.6 h, respectively, in adults with a creatinine clearance of 30-80, 10-29, and below 10 ml/min x 1.73 m2 . Peak serum norfloxacin levels do not appear to be affected in the presence of renal insufficiency.

5.3 Preclinical safety data
As with other quinolones, norfloxacin caused arthropathy in immature animals. Norfloxacin caused lesions and, in some cases, cartilage erosion in weight baring joints. No arthropathy was seen in monkeys receiving norfloxacin at doses below 500 mg/kg BW/day (Cmax 15.6 mg/l). Likewise, no such changes were seen in fully-grown animals.

In mice and rats, embryotoxicity was observed, but in rabbits and monkeys, high doses of norfloxacin resulted in increased embryolethality. Studies on fertility and perinatal and postnatal toxicity disclosed no adverse impact. Norfloxacin can be detected in the amniotic fluid and umbilical cord blood.

Based on the results of animal tests, damage to joint cartilage in the growing body can not entirely be ruled out. Animal studies have revealed no evidence of teratogenicity (see section 4.6).

In mice and rats, embryotoxicity was observed, but in rabbits and monkeys, high doses of norfloxacin resulted in increased embryolethality. Studies on fertility and perinatal and postnatal toxicity disclosed no adverse impact. Norfloxacin can be detected in the amniotic fluid and umbilical cord blood.

Cataractogenic potential
Specific studies investigating the cataractogenic potential of norfloxacin have not been conducted. As hitherto during therapeutic use no according adverse events have been observed, such studies are not considered necessary at present.

Carcinogenicity
Carcinogenicity studies in rats and mice provided no evidence to suggest carcinogenicity due to norfloxacin.

Genotoxicity and tumorigenic potential
Norfloxacin may be genotoxic due to its inhibition of topolsomerases in mammalian cells. This effect has a limiting value that is not exceeded in therapeutic use. Long-term studies in rats and mice failed to indicate tumorigenicity.
No photomutagenicity or photocarcinogenicity data are available on norfloxacin. Comparative data on other fluorquinolones suggest a low photomutagenic/photocarcinogenic potential of norfloxacin in vitro and in animal studies.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Povidone
Sodium starch glycolate (type A)
Microcrystalline cellulose
Colloidal anhydrous silica
Magnesium stearate
Hypromellose
Talc
Propylene glycol
Purified water
Titanium dioxide (E171)

6.2 Incompatibilities
Not applicable

6.3  Shelf life
3 years

6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container
Al/PVC/PVDC-blister: 6, 10, 14, 20 and 50 film-coated tablets
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
None.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Norfloxacin film-coated tablet USP 400mg Taj Pharma

Package leaflet: Information for the patient

Norfloxacin film-coated tablet USP 400mg Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What  Norfloxacin is and what it is used for
2. Before you are given Norfloxacin
3. How you will be given  Norfloxacin
4. Possible side effects
5. How Norfloxacin is stored
6. Further Information

1. What Norfloxacin is and what it is used for
Norfloxacin belongs to the so-called fluoroquinolones, a group of antibacterial medicines.

Norfloxacin is used for the treatment of infections caused by bacteria that are sensitive to norfloxacin, such as infections of the urinary system.

2. Before you are given Norfloxacin
Do not take Norfloxacin if:
§ you are allergic (hypersensitive) to norfloxacin or any of the other ingredients of Norfloxacin (listed in Section 6)
§ have had a history of tendon problems from using this type of medicine before
§ you are pregnant or think you could be pregnant (see Pregnancy and breast-feeding’ section below)
§ you are breast-feeding
§ you have had a reaction to a similar medicine in the past
§ the patient is a child or young person who is still growing.

Do not take Norfloxacin if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Norfloxacin.

Warnings and precautions
Talk to your doctor or pharmacist before taking Norfloxacin.
You should contact your doctor if:
§ you experience serious allergic reactions (an anaphylactic reaction) while starting or maintaining treatment with Norfloxacin(see section 4 ‘uncommon serious side effects: allergic reaction’).In such cases, therapy with Norfloxacin must be discontinued immediately and appropriate emergency action must be started, for example antihistamines, glucocorticosteroids, sympathomimetics and ventilation if necessary.
§ you experience symptoms of inflammation of tendons and tendon ruptures during the treatment.
§ you have ever had fits (convulsions or stroke)
§ you have ever had an illness that causes fits (convulsions), such as epilepsy
§ you have impaired kidney function. Your doctor may have to adjust the dose.
§ you have an illness called myasthenia gravis which causes muscle weakness
§ you or anyone in your family has anaemia caused by an illness called glucose-6-phosphate dehydrogenase deficiency (also called G-6-PD deficiency)
§ you experience diarrhoea, especially if you have severe, persistent and/or bloody diarrhoea.
§ If your eyesight becomes impaired or if your eyes seem to be otherwise affected whilst taking Norfloxacin, consult an eye specialist immediately (see sections Driving and using machines and 4. Possible side effects).
§ you have been diagnosed with an enlargement or “bulge” of a large blood vessel (aortic aneurysm or large vessel peripheral aneurysm).
§ you have experienced a previous episode of aortic dissection (a tear in the aorta wall).
§ you have a family history of aortic aneurysm or aortic dissection or other risk factors or predisposing conditions (e.g. connective tissue disorders such as Marfan syndrome, or vascular Ehlers-Danlos syndrome, or vascular disorders such as Takayasu arteritis, giant cell arteritis, Behcet’s disease, high blood pressure, or known atherosclerosis).

If you feel sudden, severe pain in your abdomen, chest or back, go immediately to an emergency room.

Heart problems
Caution should be taken when using this kind of medicine, if you were born with or have family history of prolonged QT interval (seen on ECG, electrical recording of the heart), have salt imbalance in the blood (especially low level of potassium or magnesium in the blood), have a very slow heart rhythm (called ‘bradycardia’), have a weak heart (heart failure), have a history of heart attack (myocardial infarction), you are female or elderly or you are taking other medicines that result in abnormal ECG changes (see section Other medicines and Norfloxacin).

When using norfloxacin, exposure to the sun or ultraviolet light should be avoided on the account of the possibility of the development of sensitivity to light.

Drink sufficient amounts during the treatment in order to prevent crystallisation of norfloxacin in the urine.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Norfloxacin.

Other medicines and Norfloxacin
You must tell your doctor if you are taking other medicines that can alter your heart rhythm: medicines that belong to the group of anti-arrhythmics (e.g. quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), tricyclic antidepressants, some antimicrobials (that belong to the group of macrolides), some antipsychotics.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because Norfloxacin can affect the way some other medicines work. Also some other medicines can affect the way Norfloxacin works.

Some medicines can reduce the amount of Norfloxacin that gets into the body.

If you take Norfloxacin, leave a gap of two hours before and at least four hours after taking one of these medicines:
§ antacids – used for indigestion or heartburn (this restriction does not apply to H2-receptor antagonist-type antacids).
§ sucralfate – used for stomach ulcers or an inflamed stomach (gastritis)
§ medicines containing calcium, magnesium, aluminium, iron, or zinc including multivitamins and minerals.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Norfloxacin.

It is also particularly important to tell your doctor or pharmacist if you take:
§ theophylline – used for breathing problems
§ medicines used to thin the blood, such as warfarin, phenprocoumon or acenocoumarol
§ fenbufen – used for joint pain
§ glibenclamide
§ didanosine – used for HIV or AIDS
§  ciclosporin or mycophenolic acid – used after transplants and for some other illnesses
§ probenecid – used for gout
§ nitrofurantoin – used for urinary tract infections, such as blatter infection
§ caffeine

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Norfloxacin.

Norfloxacin with food and drink
Take Norfloxacin with a glass of water. Take Norfloxacin at least one hour before or two hours after food or milk.

Pregnancy and breast-feeding
Do not take Norfloxacin if you are pregnant or think you might become pregnant. This is because it may affect the baby.

Do not breast-feed if you are taking Norfloxacin. This is because small amounts may pass into the mother’s milk. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines
Do not drive or use machines because Norfloxacin may adversely affect your reactivity, especially if you suffer from side effects such as dizziness, headache, fatigue or nausea. Reduced reactivity may occur to a greater degree at the start of treatment, when the dose is increased, when switching medication and in conjunction with alcohol.
You may experience a sudden, transient loss of vision, or you might faint for a short period. If you are affected in this way do not drive or operate machinery.
Therefore, make sure you know how you react to [nationally completed name] before driving a vehicle or operating machinery. If in doubt, talk to your doctor.

3. How you will be given Norfloxacin
Always take Norfloxacin exactly as your doctor told you. Check with your doctor or pharmacist if you are not sure.
Drink sufficient amounts during the treatment in order to prevent crystallisation of norfloxacin in the urine.

Taking this medicine
Take at least one hour before or two hours after food, milk or multivitamins. Swallow the tablets whole with a full glass of water in the morning and in the evening. If you have only one tablet per day this should always be taken at the same time of day.

The recommended dose is
§ for less serious infections – one tablet twice a day for 3 days
§ for more serious infection – one tablet twice a day for 7 to 10 days
§ for severe infections one tablet twice a day for 2 to 3 weeks
The dose depends on your illness and how bad it is.

People with kidney disease:
It can be necessary to adjust the dose.

Elderly:

It is not necessary to adjust the dose.

Children:
This medicine is not recommended for children and growing adolescents.

If you take more Norfloxacin than you should
If you take more Norfloxacin than you should, talk to your doctor straight away.

If you forget to take Norfloxacin
If you forget to take a tablet, skip the missed dose. Take the next dose as usual. Do not take a double dose to make up for a forgotten dose.

If you stop taking Norfloxacin
Keep taking these tablets until the course is finished. Keep taking them, even if you start to feel better after a few days.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines this medicine can cause side effects, although not everybody gets them.

Serious side effects
If any of the following happens, stop taking this medicine and tell your doctor immediately or go to the casualty department at your nearest hospital:

Uncommon: may affect up to 1 in 100 people
§ fits (convulsions)
§ severe pain in the abdomen and back (signs of inflamed pancreas)

Rare serious side effects: may affect up to 1 in 1,000 people
§ inflammation of the bowels, called colitis (or antibiotic-associated colitis), causing severe longlasting watery diarrhoea with stomach cramps and fever.
§ allergic reaction – the signs may include swelling of your face, lips, tongue and throat (This may make it difficult to breathe or swallow),
§ a serious skin reaction that causes blisters and bleeding called ‘Stevens-Johnson’ syndrome
§ yellowing of the skin and eyes, unusual tiredness or fever, dark coloured urine (signs of inflamed liver and liver damage)
§ kidney disorder

Very rare serious side effects: may affect up to 1 in 10,000 people
§ low white blood cells which may cause frequent infections, fever, severe chills, sore throat or mouth

Not known: frequency cannot be estimated from the available data
§ Abnormal fast heart rhythm, life-threatening irregular heart rhythm, alteration of the heart rhythm (called ‘prolongation of QT interval’, seen on ECG, electrical activity of the heart)
§ purple skin patches, itching, burning
§ transient loss of vision

Other possible side effects:
Tell your doctor if any of the following side effects bother you:

Common: may affect up to 1 in 10 people
§ changes in blood tests that check for liver problems
§  feeling sick (nausea)
§  abnormal kidney function test results

Uncommon: may affect up to 1 in 100 people
§ low or high levels of a specific type of white blood cells
§ short of breath, labored breathing
§ bleed for a long time after a cut or bruise very easily
§ tiredness, insomnia, not sleeping very well
§ mood swings, depression, feeling nervous (anxiety)
§ pins and needles
§ headache, dizziness, lightheadedness, drowsiness
§ bitter, weird or funny taste
§ stomach pain and cramps
§ heartburn, dry mouth, flatulence, stomach discomfort after meal, constipation
§ loss of appetite, vomiting
§ changes in your eyesight, overflow of tears
§ rash, itching
§ thrush (vaginal)

Rare: may affect up to 1 in 1,000 people
§ rupture of the Achilles’ tendon
§ being pale and tired. This may be due to anaemia especially in patients with something called ‘glucose-6-phosphate dehydrogenase deficiency’ due to a red cell loss
§ swelling mainly of the face and throat
§ feeling restless (irritability), feeling disorientated, confusion, loss of contact with reality (psychosis), problems of behavior and personality , seeing things that are not really there (hallucination)
§ uncontrolled shaking
§ an illness called ‘Gullain-Barré’ syndrome. This makes you weak and can make it difficult to breath.
§ making worse the illness called ‘myasthenia gravis’ (this illness causes muscle weakness)
§ ringing in the ears
§ severe upper stomach pain due to inflamed pancreas
§ red or purple, flat, pinhead spots under the skin; red blisters and papules; dermatitis; skin reactions to sunlight
§ pain and swelling of joints and muscles

Very rare: may affect up to 1 in 10,000 people
§ loss of hearing
§ pain and swelling of tendons, often around your ankles. This is more common if you are an older person, or are taking steroid medicines such as prednisolone, dexamethasone or hydrocortisone. Try to rest the painful areas until a doctor is seen.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5. How Norfloxacin is stored
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.

No special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Further information

What Norfloxacin contains
– The active substances is norfloxacin.
Each film-coated tablet contains: Norfloxacin USP  400 mg
– The other ingredients are:
Tablet core
Povidone, sodium starch glycolate (type A), microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, purified water

Coating:
hypromellose, talc, titanium dioxide (E 171), propylene glycol

What Norfloxacin looks like and contents of the pack
Round, slightly biconvex, white film-coated tablet with one side scored.
Al/PVC/PVDC-blister: 6, 10, 14, 20 and 50 film-coated tablets
Not all pack sizes may be marketed.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com