1. Name Of The Medicinal Product
UTINOR® 400 mg Tablets
2. Qualitative And Quantitative Composition
'Utinor' contains 400 mg of the active ingredient, norfloxacin.
For excipients, see 6.1
3. Pharmaceutical Form
'Utinor' is supplied as off-white oval tablets marked 'MSD 705'.
4. Clinical Particulars
4.1 Therapeutic Indications
Norfloxacin is a broad-spectrum, quinolone bactericidal agent indicated for the treatment of:
Upper and lower, complicated and uncomplicated, acute and chronic urinary tract infections. These infections include cystitis, pyelitis, chronic prostatitis and those urinary infections associated with urological surgery, neurogenic bladder or nephrolithiasis caused by bacteria susceptible to 'Utinor'.
Consideration should be given to official local guidance (e.g. national recommendations) on the appropriate use of bacterial agents.
Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.
4.2 Posology And Method Of Administration
'Utinor' should be taken with a glass of water at least one hour before or two hours after a meal or milk ingestion. Multivitamins, products containing iron or zinc, antacids containing magnesium and aluminium, sucralfate or products containing didanosine should not be taken within 2 hours of administration of norfloxacin.
Susceptibility of the causative organism to 'Utinor' should be tested. However, therapy may be initiated before obtaining the results of these tests.
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* Trials in over 600 patients have demonstrated the efficacy and tolerability of 'Utinor' in the three
** If adequate suppression is obtained within the first four weeks of therapy, the dose of 'Utinor' may be reduced to 400 mg daily.
Patients with renal impairment
'Utinor' is suitable for the treatment of patients with renal impairment. In studies involving patients whose creatinine clearance was less than 30 ml/min/1.73m2, but who did not require haemodialysis, the plasma half2, compared to patients with creatinine clearance of 102. 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 MICs for most pathogens sensitive to norfloxacin.
Use in the elderly
Pharmacokinetic studies have shown no appreciable changes when compared to younger patients, apart from a slight prolongation of half
4.3 Contraindications
Hypersensitivity to any component of this product or any chemically related quinolone antibacterials.
'Utinor' is contra
4.4 Special Warnings And Precautions For Use
As with other drugs in this class, 'Utinor' should not be used in patients with a history of convulsions or known factors that predispose to seizures unless there is an overwhelming clinical need. Convulsions have been reported rarely with norfloxacin.
Tendinitis and/or tendon rupture, particularly affecting the Achilles tendon, may occur with quinolone antibiotics. Such reactions have been observed, particularly in older patients and in those treated concurrently with corticosteroids. At the first sign of pain or inflammation, patients should discontinue 'Utinor' and rest the affected limbs.
Photosensitivity reactions have been observed in patients who are exposed to excessive sunlight while receiving some members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if photosensitivity occurs.
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 'Utinor', in patients with myasthenia gravis (see section 4.8 'Undesirable effects').
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 4.8 'Undesirable effects').
Very rarely, some quinolones have been associated with prolongation of the QTc interval on the electrocardiogram and infrequent cases of arrhythmia (including extremely rare cases of torsade de pointes) have been observed. As with other agents associated with prolongation of the QTc interval, caution should be exercised when using 'Utinor' in patients with hypokalaemia, significant bradycardia or undergoing concurrent treatment with class Ia or class III anti-arrhythmics.
Some quinolones including 'Utinor' should be used with caution in patients using cisapride, erythromycin, antipsychotics, tricyclic antidepressants or who have any personal or family history of QTc prolongation.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including 'Utinor', 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 indicte 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.
Use in children
As with other quinolones, 'Utinor' has been shown to cause arthropathy in immature animals. The safety of 'Utinor' in children has not been adequately explored and therefore the use of 'Utinor' in prepubertal children or growing adolescents is contra
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Co
As with other organic acid antibacterials, antagonism has been demonstrated in vitro between 'Utinor' 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, theophylline, tizadine) may result in increased levels of these drugs, with the potential risk of increased toxicity. Patients taking any concomitant drugs metabolised by CYP1A2 should be carefully monitored.
Specifically in relation to this interaction:
Monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required.
The dose of clozapine or ropinirole may need to be adjusted in patients already taking these medications if norfloxacin is introduced or withdrawn.
Co-administration of tizanidine and norfloxacin is not recommended.
Elevated serum levels of ciclosporin have been reported with concomitant use of norfloxacin. Ciclosporin serum levels should be monitored and appropriate ciclosporin dosage adjustments made when these drugs are used concomitantly.
Quinolones, including norfloxacin, may enhance the effects of the anticoagulant warfarin, or its derivatives, by displacing significant amounts from serum albumin
The concomitant administration of quinolones including norfloxacin with glibenclamide (a sulphonylurea agent) has, on 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 two hours of, the administration of norfloxacin because they may interfere with absorption, resulting in lower serum and urine levels of norfloxacin.
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.
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 'Utinor' 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.
4.6 Pregnancy And Lactation
There is no evidence from animal studies that norfloxacin has any teratogenic or mutagenic effects. Embryotoxicity secondary to maternotoxicity was observed after large doses in rabbits. Embryonic losses were observed in cynomolgus monkeys without any teratogenic effects. The relevance of these findings for humans is uncertain.
The safe use of 'Utinor' in pregnant women has not been established; however, as with other quinolones, norfloxacin has been shown to cause arthropathy in immature animals and therefore its use during pregnancy is not recommended.
It is not known whether 'Utinor' is excreted in human milk; administration to breast
4.7 Effects On Ability To Drive And Use Machines
Norfloxacin may cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they drive or operate machinery or engage in activities requiring mental alertness and coordination.
4.8 Undesirable Effects
The overall incidence of drug
The most common side effects have been gastro
Less commonly, other side effects such as anorexia, sleep disturbances, depression, anxiety/nervousness, irritability, euphoria, disorientation, hallucination, tinnitus, and epiphora have been reported.
Abnormal laboratory side effects observed during clinical trials included:
leucopenia, elevation of ALAT (SGPT), ASAT (SGOT), eosinophilia, neutropenia, thrombocytopenia.
With more widespread use the following additional side effects have been reported:
Hypersensitivity reactions
Hypersensitivity reactions including anaphylaxis, angioedema, dyspnoea, vasculitis, urticaria, arthritis, myalgia, arthralgia and interstitial nephritis.
Skin
Photosensitivity, Stevens
Gastro
Pseudomembranous colitis, pancreatitis (rare), hepatitis, jaundice including cholestatic jaundice and elevated liver-function tests.
Musculoskeletal
Tendinitis, tendon rupture, exacerbation of myasthenia gravis, elevated creatinine kinase (CK).
Nervous system/psychiatric
Polyneuropathy including Guillaine-Barré syndrome, confusion, paraesthesia, hypoaesthesia, psychic disturbances including psychotic reactions, convulsions, tremors, myoclonus.
Haematological
Agranulocytosis, haemolytic anaemia, sometimes associated with glucose-6-phosphate dehydrogenase deficiency.
Genito-urinary
Vaginal candidiasis.
Renal function
Renal failure.
Special senses
Dysgeusia, visual disturbances, hearing loss.
Cardiovascular
Very rarely: prolonged QTc interval and ventricular arrhythmia (including torsade de pointes) may occur with some quinolones including norfloxacin.
4.9 Overdose
No information is available at present.
In the event of recent acute overdosage, the stomach should be emptied by induced vomiting or by gastric lavage and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Fluoroquinolone
ATC code
JO1MA06
Mode of Action
Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events were attributed to norfloxacin in Escherichia coli cells:
(1) Inhibition of the ATP
(2) Inhibition of the relaxation of supercoiled DNA
(3) Promotion of double
'Utinor' has a broad spectrum of antibacterial activity against Gram
PK/PD relationship
Efficacy is mainly dependent upon the Cmax (maximum serum concentration): MIC (minimum inhibitory concentration) ratio of the pathogen and the AUC ( area under the curve): MIK ratio of the pathogen, respectively.
Mechanism/s of Resistance
The major mechanism of resistance to the quinolones, including norfloxacin, is through mutations in the genes that encode for DNA gyrase and topoisomerase IV, the targets of quinolone action. Additional mechanisms of resistance include mutations in the cell membrane proteins, which alter membrane permeability and the development of efflux pumps.
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. co-trimoxazole).
Break points
EUCAST clinical MIC breakpoints to separate susceptible (S) pathogens from resistant (R) pathogens are:
Entero-bacteriaceae S<0.5mcg/ml, R>1mcg/ml
For Neisseria gonorrhoeae and other species MIC breakpoint not defined.
Susceptibility
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. The information below gives only approximate guidance on the probability as to whether the micro-organism will be susceptible to norfloxacin or not.
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5.2 Pharmacokinetic Properties
Norfloxacin is rapidly absorbed following oral administration. In healthy volunteers, at least 30
The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post
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Norfloxacin is eliminated through metabolism, biliary excretion and renal excretion. After a single 400 mg dose of norfloxacin, mean antimicrobial activities equivalent to 278, 773 and 82 mcg of norfloxacin/g of 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 (approximately 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
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 norfloxacin is not affected by the pH of urine.
Protein binding is less than 15%.
5.3 Preclinical Safety Data
Norfloxacin, when administered to 3- to 5-month-old dogs at doses four or more times the usual human dose, produced blister formation and eventual erosion of the articular cartilage of the weight-bearing joints. Similar changes have been produced by other structurally related drugs. 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 the drug was not teratogenic in cynomolgus monkeys at several times the therapeutic human dosage, an increased percentage of embryonic losses was observed.
6. Pharmaceutical Particulars
6.1 List Of Excipients
'Utinor' contains the following inactive ingredients:
Croscarmellose sodium USNF
Magnesium stearate Ph Eur
Microcrystalline cellulose Ph Eur
Hydroxypropylcellulose Ph Eur
Hypromellose Ph Eur
Titanium dioxide Ph Eur
Carnauba wax Ph Eur
6.2 Incompatibilities
None
6.3 Shelf Life
36 months shelf-life for blister packs.
6.4 Special Precautions For Storage
Store below 25°C, in a dry place protected from light.
6.5 Nature And Contents Of Container
'Utinor' is available as blister packs of 6, 7 and 14 tablets.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK
8. Marketing Authorisation Number(S)
PL 0025/0254
9. Date Of First Authorisation/Renewal Of The Authorisation
Authorisation first granted 3 August 1990. Licence last renewed 4 December 2001.
10. Date Of Revision Of The Text
October 2009
® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
© Merck Sharp & Dohme Limited 2009. All rights reserved.
SPC.NRX.09.UK.3160
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