Consumer medicine information

Roxin

Norfloxacin

BRAND INFORMATION

Brand name

Roxin

Active ingredient

Norfloxacin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Roxin.

What is in this leaflet

This leaflet answers some common questions about Roxin. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Roxin against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What Roxin is used for

Roxin contains norfloxacin as the active ingredient. It belongs to a group of antibiotics called quinolones. These medicines work by killing the bacteria that is causing infection.

Roxin is an antibiotic used to treat:

  • urinary tract infections
  • gastrointestinal infections.

Ask your doctor if you have any questions about why Roxin has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

Roxin is available only with a doctor's prescription.

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take Roxin if you are allergic to medicines containing:

  • norfloxacin
  • other quinolone antibiotics including nalidixic acid
  • any of the ingredients listed at the end of this leaflet.

Do not take Roxin if you are pregnant, or intend to become pregnant. Roxin may affect your developing baby if you take it during pregnancy.

Do not take this medicine if you are breastfeeding or intend to breastfeed. The active ingredient in Nufloxib may pass into breast milk and may affect your baby.

Do not give Roxin to children and to pre-pubertal adolescents, as there have been no studies of its effects in this age group.

Do not take Roxin if the expiry date (Exp.) printed on the pack has passed.

Do not take Roxin if the packaging shows signs of tampering or the tablets do not look quite right.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are breastfeeding or wish to breastfeed. Roxin should not be used during pregnancy or while breast-feeding.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • Kidney problems
  • Fits or seizures
  • Myasthenia gravis (a condition in which the muscles become weak and tire easily)
  • Glucose-6-phosphate dehydrogenase deficiency
  • Heart rhythm problems
  • Arthropathy
  • Crystalluria
  • Vision disorders
  • Tendon inflammation
  • Diabetes
  • Risk of aortic aneurysm and dissection.

If you have not told your doctor about any of the above, tell them before you start taking Roxin.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by Roxin, or may affect how well it works. These include:

  • theophylline (such as Nuelin), a medicine used to treat asthma
  • warfarin (such as Coumadin, Marevan), a medicine used to prevent blood clots
  • phenindione (such as Dindevan), a medicine also used to prevent blood clots
  • probenecid (Pro-Cid), a medicine used to treat gout
  • nitrofurantoin (Ralodantin, Macrodantin), a medicine used to treat urinary tract infections
  • cyclosporin (Neoral, Sandimmun, Cysporin), a medicine used to suppress the immune system
  • certain drugs that are metabolised by a specific enzyme: clozapine, ropinirole, tacrine, tizanidine
  • glibenclamide, a medicine used to treat diabetes
  • metronidazole (such as Flagyl, Metrogyl), a medicine used to treat various types of bacterial infections
  • non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis
  • erythromycin, a medicine used to treat infections
  • cisapride, a medicine used to treat gastric reflux, usually experienced as heartburn
  • some medicines used to treat irregular heart beats such as sotalol, amiodarone, quinidine and procainamide
  • antipsychotics, medicines used to treat certain mental and emotional conditions
  • tricyclic antidepressants, medicines used to treat depression such as amitriptyline and nortriptyline.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Some medicines may interfere with the absorption of Roxin. These include:

  • iron or zinc supplements, and multivitamins containing them
  • calcium preparations
  • antacids (such as Mylanta, AluTab, Gastrogel) used for indigestion
  • sucralfate (Ulcyte, Carafate), a medicine used to treat stomach ulcers
  • didanosine (Videx and Videx EC), a medicine used to treat HIV infections.

You can still take these medicines while you are taking Roxin, however, you must take Roxin at least 2 hours before or 2 hours after taking them to make sure there is no problem with absorption.

Roxin may prolong the effect of coffee and other drinks containing caffeine.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Roxin.

How to take it

How much to take

Follow all directions given to you by your doctor and pharmacist carefully.

Your doctor will tell you how many tablets you need to take each day and when to take them.

The usual dose is one tablet twice a day.

How to take it

Swallow the tablets with a glass of water.

Take Roxin on an empty stomach, one hour before or two hours after food. Food can interfere with the absorption of Roxin.

Do not take Roxin at the same time as taking iron or zinc supplements (or any multivitamins containing them), antacids, didanosine or sucralfate. Taking Roxin at the same time or even within two hours of taking these can interfere with the absorption of Roxin, so that the chance of Roxin fighting the infection won't be as good.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

How long to take it

Keep taking Roxin until you finish the pack, or for as long as your doctor recommends.

Do not stop taking Roxin, even if you feel better after a few days, unless advised by your doctor. Your infection may not clear completely if you stop taking this medicine too soon.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Roxin. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Roxin, especially if you are about to start taking any new medicines.

Tell your doctor if you become pregnant while taking Roxin.

Tell your doctor or pharmacist immediately if you get severe diarrhoea. Do this even if it occurs several weeks after you have stopped taking Roxin. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care.

Do not take any diarrhoea medicine without checking with your doctor.

Drink plenty of water or fluids while you are taking Roxin. This will help prevent crystals forming in the urine, leading to kidney problems. This side effect is very rare.

Things you must not do

Do not take Roxin to treat any other conditions unless your doctor tells you to.

Do not give Roxin to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how Roxin affects you. This medicine may cause drowsiness, dizziness or lightheadedness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous while taking Roxin.

Protect your skin when you are in the sun, especially between 10 am and 3 pm. If outdoors, wear protective clothing and use a 30+ sunscreen. Roxin may cause your skin to be much more sensitive to sunlight than it is normally. This may cause a skin rash, itching, redness or severe sunburn.

If your skin does appear to be burning, stop taking Roxin and tell your doctor.

Try not to consume large amounts of caffeine while you are taking Roxin. Roxin may increase the chance of you getting side effects from caffeine, such as sleeplessness, anxiety, tremor, increased heartbeat and headache. Caffeine is contained within coffee, tea, cola and energy drinks.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Roxin.

Like all other medicines, Roxin may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • nausea, upset stomach, stomach pain
  • headache
  • dizziness
  • disturbances to vision
  • rash
  • tiredness, changes in sleep pattern
  • vaginal thrush - sore and itchy vagina or discharge.

These side effects are usually mild.

Tell your doctor as soon as possible if you notice any of the following:

  • increased sensitivity of the skin to the sun, with symptoms of sunburn (redness, blistering or itching) happening more quickly than usual
  • confusion, depression, hallucinations
  • bleeding or bruising more easily than usual
  • signs of anaemia such as tiredness, being short of breath and looking pale
  • numbness or tingling in the fingers or toes
  • worsening of the symptoms of myasthenia gravis
  • decreased feeling or sensitivity, especially in the skin
  • changes in your hearing.

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop taking Roxin and tell your doctor immediately, or go to Accident and Emergency at the nearest hospital:

  • severe abdominal cramps or stomach cramps
  • watery and severe diarrhoea, which may also be bloody
  • skin rash, itching or hives or peeling or blistering of the skin
  • asthma, wheezing or shortness of breath
  • swelling of the face, lips tongue or throat that may cause difficulty in swallowing or breathing
  • yellowing of the skin or eyes
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • sudden and severe pain or swelling of the muscles, joints or tendons
  • seizures, convulsions or fits
  • passing little or no urine, blood in the urine.

These are very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

After you have finished taking it

Tell your doctor immediately if you notice any of the following, even if they occur several weeks after stopping treatment with Roxin:

  • severe abdominal cramps or stomach cramps
  • watery and severe diarrhoea, which may also be bloody
  • fever, in combination with one or both of the above.

These are rare but serious side effects. You may have a serious condition affecting your bowel. You may need urgent medical attention. However, these side effects are rare.

Do not take any diarrhoea medicine without first checking with your doctor.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking it

Storage

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store Roxin or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Roxin, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Roxin is an oval, scored, white film coated tablet marked “N | F” on one side and “>” on the other.

Available in bottles of 14 tablets.

Ingredients

Active ingredient:

Each Roxin tablet contains 400 mg of norfloxacin.

Inactive ingredients:

  • microcrystalline cellulose
  • croscarmellose sodium
  • magnesium stearate
  • Opadry AMB OY-B-28920.

Roxin tablets do not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

Australian registration number: AUST R 93211

This leaflet was updated in August 2019.

Published by MIMS September 2019

BRAND INFORMATION

Brand name

Roxin

Active ingredient

Norfloxacin

Schedule

S4

 

1 Name of Medicine

Norfloxacin.

2 Qualitative and Quantitative Composition

Roxin tablets contain 400 mg of norfloxacin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Roxin tablets are white, film-coated, convex, oval shaped scored tablet, embossed with "N / F" on one side and ">" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of adults with complicated and uncomplicated urinary tract infections that are caused by susceptible strains of microorganisms.
Treatment of adults with gastrointestinal infections, in particular shigellosis and traveller's diarrhoea.

Note.

Specimens for culture and susceptibility testing should be obtained prior to and during treatment if clinical response warrants.
Consideration should be given to available official guidance on the appropriate use of antibacterial agents.

4.2 Dose and Method of Administration

Norfloxacin tablets should be taken one hour before or two hours after a meal with a glass of water. Patients receiving norfloxacin should be well hydrated. 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 two hours of administration of norfloxacin (see Section 4.4 Special Warnings and Precautions for Use).

Urinary tract infection.

Normal renal function.

The recommended dosage of norfloxacin for the treatment of urinary tract infection is 400 mg twice daily for seven to ten days.
For uncomplicated lower urinary tract infections, the recommended dosage is 400 mg twice daily for three days. In one study of uncomplicated lower urinary tract infections, treatment for seven days resulted in somewhat better eradication rates than treatment for three days.
Maximum total daily dosage should not exceed 800 mg per day.

Impaired renal function.

Norfloxacin may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/minute/1.73 m2 or less, the recommended dosage is one 400 mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/minute/1.73 m2. However, such patients should be observed carefully for adverse effects due to possible drug retention.
When only the serum creatinine level is available, the following formula (based on sex, weight and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

Use in the elderly.

Elderly patients with a creatinine clearance of greater than 30 mL/minute/1.73 m2 should receive the dosages recommended (see Normal renal function).
Elderly patients with a creatinine clearance of 30 mL/minute/1.73 m2 or less should receive 400 mg once daily as recommended (see Impaired renal function).

Gastrointestinal infection.

(Shigellosis, traveller's diarrhoea.) The recommended dosage is 400 mg twice daily for five days.

4.3 Contraindications

Hypersensitivity to any component of this product or any chemically related quinolone antibacterials.
Children; pregnancy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.4 Special Warnings and Precautions for Use

Fluoroquinolones, including Roxin, have been associated with disabling and persistent adverse reactions involving different body systems that have occurred together in the same patient. These include, but are not limited to, serious adverse reactions involving the nervous system (see Nervous system) and musculoskeletal system (see Effect on tendons).
Reserve fluoroquinolones for proven or suspected infections where alternative agents are ineffective or contraindicated.

Arthropathy.

The oral administration of single doses of norfloxacin 100 mg/kg caused lameness in immature dogs. Histological examination of the weight bearing joints of these dogs revealed permanent lesions of the cartilage. Related drugs (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.

Crystalluria.

Needle shaped crystals were found in the urine of some volunteers who received either placebo, norfloxacin 800 mg or norfloxacin 1,600 mg (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 twice daily, 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.

Antibiotic-associated colitis.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including norfloxacin. A toxin produced with Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life-threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Cl. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.

Dysglycaemia.

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. sulfonylurea) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.

Nervous system.

The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Convulsions have been reported rarely in patients receiving norfloxacin. As with other organic acids, norfloxacin should be used with caution in individuals with a history of convulsions or known factors that predispose to seizures.
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 norfloxacin, in patients with myasthenia gravis (see Section 4.8 Adverse Effects (Undesirable Effects)).
Cases of sensory or sensorimotor polyneuropathy resulting in paresthesias, hypoesthesias, dysesthesias, or weakness have been reported in patients receiving fluoroquinolones including norfloxacin. Norfloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see Section 4.8 Adverse Effects (Undesirable Effects)).

Psychiatric adverse reactions.

Fluoroquinolones, including norfloxacin have been associated with an increased risk of psychiatric adverse reactions including: toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations or paranoia; depression, or self-injurious behaviour such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These reactions may occur following the first dose. Advise patients receiving norfloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug and institute appropriate care.

Vision disorders.

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see Section 4.8 Adverse Effects (Undesirable Effects)).

Photosensitivity.

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.

Effect on tendons.

Tendon inflammation and rupture that required surgical repair or resulted in prolonged disability have been reported with fluoroquinolone therapy including norfloxacin. This risk is further increased in elderly patients and those treated concurrently with corticosteroids. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Norfloxacin should be discontinued at the first sign of pain, swelling, inflammation, or rupture of a tendon. Patients are advised to inform their health professional, rest the affected limb(s) and refrain from exercise.

Haemolytic reactions.

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 Adverse Effects (Undesirable Effects)).

Cardiac disorders.

Some quinolones have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmias. 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 yet 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 Ia 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.

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 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.

Information for patients.

Patients should be advised to take norfloxacin 1 hour before or 2 hours after a meal. Patients should also be advised to drink fluids liberally and not to take antacids concomitantly or within 2 hours after dosing.

Use in renal impairment.

Norfloxacin is suitable for the treatment of patients with renal impairment; however, since norfloxacin is primarily excreted by the kidney, urinary levels may be significantly compromised by severe renal dysfunction. Alteration in dosage regimen is necessary for patients with impaired renal function (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

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 is not to be used in children less than 18 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin.
The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonise the antibacterial effect of norfloxacin in the urinary tract.
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 side 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 drugs are used concomitantly.
Quinolones, including norfloxacin, may enhance the effects of the oral anticoagulant warfarin or its derivatives and phenindione 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, calcium preparations, 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.
Videx (didanosine) chewable/ buffered tablets or the paediatric powder for oral solution should not be administered concomitantly with, or within two 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 its 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, norfloxacin 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.
Lowered bioavailability of mycophenolic acid was observed in healthy volunteers receiving combined treatment with norfloxacin and metronidazole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 500 mg/kg/day.
(Category B3)
Norfloxacin has been shown to produce embryonic loss in cynomolgus monkeys when given in doses of 150 mg/kg/day with peak plasma levels that are two to three 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 100 to 800 mg/kg/day. There were no adequate and well controlled studies in pregnant women. Since norfloxacin, like other drugs in this class, causes arthropathy in immature animals, it should not be used in pregnant women.
 It is not known whether norfloxacin is excreted in human milk.
When a 200 mg dose of norfloxacin was administered to breastfeeding 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 breastfed infants, a decision should be made to discontinue breastfeeding or to discontinue the drug at least 24 to 48 hours before restarting breastfeeding, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

Norfloxacin may cause dizziness or light-headedness; therefore, patients should know how they react to norfloxacin before they operate a vehicle or machinery or engage in activities requiring mental alertness and coordination.

4.8 Adverse Effects (Undesirable Effects)

In clinical trials, norfloxacin was generally well tolerated.
The incidence of subjects reporting drug related adverse experiences in clinical trials involving 1,127 subjects was 3.4%. However, the overall incidence was 10.7% and the figures below were calculated without reference to drug relationship. Most adverse reactions occur within the first few days of therapy.
The most common adverse experiences (1 to 3%) were either gastrointestinal or neurological: nausea 2.8%, headache 2.7% and dizziness 1.8%.
Additional reactions (0.3 to 1%) were: fatigue, rash, abdominal pain, dyspepsia, somnolence, depression, insomnia, constipation, flatulence and heartburn.
Less frequent reactions included: dry mouth, diarrhoea, fever, vomiting, erythema, euphoria, anxiety, irritability, hallucinations, altered taste, vaginal swelling and tendinitis.
Visual disturbances have been reported with drugs in this class.
Abnormal laboratory values observed in these 1,127 subjects in clinical trials were eosinophilia 1.8%, elevation of ALT and AST 1.8%, increased alkaline phosphatase 1.4%, and decreased white blood cell or neutrophil count 1.2%. Those occurring less frequently included increased serum urea, serum creatinine and lactate dehydrogenase (LDH), and decreased haematocrit.

Postmarketing.

The following additional adverse effects have been reported since the drug was marketed.

Hypersensitivity reactions.

These include anaphylaxis, angioedema, dyspnoea, vasculitis, urticaria, arthritis, myalgia, arthralgia, interstitial nephritis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Skin.

Photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, pruritus, and leukocytoclastic vasculitis.

Central nervous system.

Confusion, paraesthesia, polyneuropathy including Guillain-Barre syndrome, hypoesthesia, psychic disturbances including psychotic reactions, convulsions, tremors and myoclonus.

Liver, gastrointestinal.

Pseudomembranous colitis, pancreatitis (rare), hepatitis, including jaundice and cholestatic jaundice, elevated liver function tests.

Musculoskeletal.

Tendinitis, tendon rupture, exacerbation of myasthenia gravis, elevated creatine kinase (CK), muscle spasms.

Haematological.

Agranulocytosis, thrombocytopenia, haemolytic anaemia, sometimes associated with glucose-6-phosphate dehydrogenase deficiency.

Genitourinary.

Vaginal candidiasis.

Renal function.

Renal failure.

Metabolic.

Dysglycaemia.

Special senses.

Dysgeusia, visual disturbances, hearing loss.

Causal relationship unknown.

A definite causal relationship could not be established with regard to the following adverse effects: conjunctivitis, eye pain/irritation and asthenia. On very rare occasions, hypertonia, ataxia, dysarthria, dysphasia, haemophthalmia, nystagmus, periorbital erythema, proteinuria and transient hearing loss have been reported.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

The acute oral LD50 values in male and female mice and male and female rats were greater than 4 g/kg.

Treatment.

In the event of acute overdosage, absorption may be decreased by giving active charcoal, the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Microbiology.

Norfloxacin has in vitro activity against a broad spectrum of Gram-negative and some Gram-positive aerobic bacteria. Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level three specific events are attributed to norfloxacin 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 in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistance of the organism has developed during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter sp., Enterococci. For this reason, when there is a lack of satisfactory clinical response, culture and susceptibility testing should be repeated.
Norfloxacin is active in vitro against the following organisms:
Bacteria found in urinary tract infections. Aerobic bacteria: Gram-positive bacteria including Streptococcus faecalis (Enterococcus), Staphylococcus aureus, Staph. epidermidis, Staph. saprophyticus. Gram-negative bacteria including Citrobacter diversus, C. freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa. Bacteria found in gastrointestinal infections: Shigella, E. coli, Salmonella typhi.
In addition, norfloxacin is active against Neisseria gonorrhoeae.
Norfloxacin is not generally active against obligate anaerobes.
Nalidixic acid resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MIC) to norfloxacin than nalidixic acid susceptible strains. There is generally no cross resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin often demonstrates activity against indicated organisms resistant to the aminoglycosides (including gentamicin), penicillins, cephalosporins, tetracyclines, macrolides and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin.

Susceptibility tests.

Dilution or diffusion techniques - either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated.
This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in sites where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Animal pharmacology.

Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested.
Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day.
Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher.
Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin treated animals.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

In fasting healthy volunteers, approximately 30 to 40% of an oral dose of norfloxacin is absorbed. Absorption is rapid following single doses of 200 and 400 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8 and 1.5 microgram/mL are attained approximately one hour after dosing. The presence of food may decrease absorption. The effective half-life of norfloxacin in serum and plasma is three to four hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing.

Distribution.

The serum protein binding of norfloxacin is between 10 and 15%.

Metabolism.

Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5 to 8% being recovered in the urine as six metabolites of considerably less antimicrobial potency.

Excretion.

The absorbed norfloxacin is eliminated mainly through renal excretion. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/minute). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5 to 8% being recovered in the urine as six metabolites of considerably less antimicrobial potency. However, urinary recovery may occasionally be very low. Only a small percentage (less than 1%) of the dose is recovered thereafter.
Two to three hours after a single 400 mg dose, urinary concentrations of 200 microgram/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 microgram/mL for approximately twelve hours following a 400 mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with solubility increasing at pHs above and below this value.
The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/minute/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/minute/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 8.6 to 11.5 hours. In these patients, alteration of dosage is necessary (see Section 4.2 Dose and Method of Administration). Drug absorption appears unaffected by decreasing renal function.
In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Drug absorption appears unaffected. The effective half-life of norfloxacin in these elderly subjects is four hours.
Faecal recovery accounts for another 30% of the administered dose. This represents the unabsorbed drug along with a small contribution through biliary excretion. After a single 400 mg dose of norfloxacin, mean antimicrobial activities equivalent to norfloxacin 278, 773 and 82 microgram/g of faeces were obtained at 12, 24 and 48 hours, respectively.

5.3 Preclinical Safety Data

Genotoxicity.

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 500 to 1000 mg/kg/day. Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test 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).

Carcinogenicity.

Information is not available at present on the carcinogenic potential of norfloxacin.

6 Pharmaceutical Particulars

6.1 List of Excipients

Roxin tablets contain the following excipients: microcrystalline cellulose, croscarmellose sodium, magnesium stearate and Opadry AMB OY-B-28920.
The tablets are gluten free.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Roxin tablets are available in bottle (HDPE) and blister* packs of 2*, 6* and 14 tablets.
* Currently not marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Norfloxacin is a white to pale yellow crystalline powder. It is freely soluble in glacial acetic acid, and slightly soluble in ethanol, methanol and water.
The chemical name for norfloxacin is 1-ethyl-6-fluoro-4-oxo-7- (piperazin-1-yl)-1,4- dihydroquinoline-3-carboxylic acid. C16H18FN3O3. Molecular weight: 319.34.

Chemical structure.


CAS number.

CAS No.: 70458-96-7.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes