Consumer medicine information

APO-Ciprofloxacin Tablets

Ciprofloxacin

BRAND INFORMATION

Brand name

APO-Ciprofloxacin

Active ingredient

Ciprofloxacin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Ciprofloxacin Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

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

The information in this leaflet was last updated on the date listed on the last page. Some more recent information on the medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with the medicine.

You may want to read it again.

What is this medicine used for

The name of your medicine is APO-Ciprofloxacin. It contains the active ingredient, ciprofloxacin.

It is used to treat:

  • urinary tract infections
  • kidney and bladder infections
  • bowel infections
  • lung infections
  • skin infections
  • bone and joint infections
  • prostate infections
  • inhalation of anthrax

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

This medicine works by killing the bacteria which cause these infections.

It will not work against viral infections such as colds or flu.

Ciprofloxacin belongs to a group of antibiotic medicines called quinolones.

There is no evidence that this medicine is addictive.

Use in children

This medicine is not recommended for use in children or pre-pubertal teenagers except for use in inhalational anthrax.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are taking a medicine called tizanidine (used for multiple sclerosis or spinal injuries)
  • You are hypersensitive to, or have had an allergic reaction to, ciprofloxacin, other quinolone antibiotics, nalidixic acid or any of the ingredients listed at the end of this leaflet
    Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, muscle pain or tenderness or joint pain or rash, itching or hives on the skin.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack.
    If you take this medicine after the expiry date has passed, it may not work as well.
  • The packaging is torn or shows signs of tampering or if it does not look quite right.
    If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking ciprofloxacin, talk to your doctor.

Before you start to take it

Tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • kidney disease
  • brain disease or stroke
  • epilepsy (seizures or fits)
  • arrhythmias (fast or irregular heartbeats)
    Ciprofloxacin may increase the risk of arrhythmias, especially in the elderly or patients with low potassium levels.
  • myasthenia gravis (disease of the muscles causing drooping eyelids, double vision, difficulty in speaking and swallowing and sometimes muscle weakness in the arms or legs)
  • liver disease
  • tendon disorders with the use of quinolones (e.g. moxifloxacin, norfloxacin, nalidixic acid).
  1. You are elderly or have previously taken corticosteroids such as prednisolone or cortisone, or have had problems with your tendons before, when taking quinolone medicines.
You may be at increased risk of swelling of or damage to the tendons. Symptoms include pain, tenderness and sometimes restricted movement.
  1. You are currently pregnant or plan to become pregnant.
Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  1. You are currently breast feeding or plan to breast feed. Do not take this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved.
Ciprofloxacin passes into human breast milk and may affect your baby, so your doctor will discuss with you what to do.
  1. You are planning to have surgery or an anaesthetic.
  2. You are currently receiving or are planning to receive dental treatment.
  3. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines must not be taken with ciprofloxacin.

Do not take ciprofloxacin if you are taking tizanidine, used for multiple sclerosis or spinal injuries.

Other medicines also interact with ciprofloxacin. These include:

  • certain anti-arrhythmics, antidepressants, antibiotics and antipsychotics
  • theophylline, and other methylxanthines, medicines used to help breathing. Caffeine is also a methylxanthine.
  • duloxetine, a medicine used for depression, incontinence or diabetic neuropathy
  • cyclosporin, used in organ transplants, or for severe arthritis or psoriasis
  • methotrexate, used to treat certain cancers, or for severe arthritis or psoriasis
  • warfarin or other medicines called anticoagulants, used to prevent blood clots
  • phenytoin, a medicine used to treat epilepsy
  • anti-viral medications such as didanosine
  • certain non-steroidal anti-inflammatory medicines (NSAIDs), used to treat muscular problems and arthritis. The combination of these medicines with ciprofloxacin may cause convulsions
  • clozapine, a medicine used to treat schizophrenia
  • ropinirole, used to treat restless legs syndrome
  • lidocaine, used in certain heart conditions and for local or spinal anaesthesia
  • sildenafil, a medicine used to treat erectile dysfunction
  • medicines containing iron, zinc, magnesium, aluminium or calcium such as antacids, multivitamins or mineral supplements
  • probenecid, used for gout, arthritis, or to raise levels of antibiotics
  • omeprazole, a medicine used to treat stomach ulcers.
  • sucralfate, a medicine used to treat stomach ulcers
  • metoclopramide, used to treat nausea and vomiting
  • oral anti-diabetic agents such as glibenclamide and glimepiride
  • antiretroviral medicines such as didanosine, used to treat HIV infections
  • medicines such as sevelamer, used to treat high blood levels of phosphate
  • oxpentifylline, used to treat circulation disorders
  • agomelatine, used to treat depression
  • zolpidem, used to treat sleep disorders

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with ciprofloxacin.

How to take this medicine

Follow carefully all directions given to you by your doctor.

Their instructions may be different to the information in this leaflet.

If you do not understand any written instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets you will need to take. This will depend on your condition and whether or not you are taking any other medicines.

The usual adult dosage for most infections is one tablet twice daily for 7 to 14 days. You may need to take your tablets for a longer period for some infections.

How to take it

Swallow the tablets whole with a full glass of water.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of ciprofloxacin.

How long to take it for

The length of treatment may vary from 1 to 28 days or longer depending on the type of infection.

Continue taking your medicine until you finish the pack or for as long as your doctor tells you.

Do not stop taking your tablets because you are feeling better.

If you do not complete the full course prescribed by your doctor, the infection may not clear completely or your symptoms may return.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the missed doses. This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 for Australia) or go to the Accident and Emergency Department at the nearest hospital, if you think that you or anyone else may have taken too much ciprofloxacin.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Drink plenty of water or fluids while taking this medicine. This will help to prevent crystals forming in the urine which can cause kidney problems. However, this is not a common problem.

Protect your skin when you are in the sun, especially between 10 am and 3 pm, or in the presence of artificial ultraviolet (UV) light. Wear protective clothing and use a 15+ sunscreen. If your skin does appear to be burning, stop taking this medicine and tell your doctor. Ciprofloxacin may cause your skin to be much more sensitive to sunlight and UV light than it is normally. This may cause a skin rash, itching, redness, or a severe sunburn.

Things you must not do

Do not:

Give this medicine to anyone else, even if their symptoms seem similar to yours.

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.
    If you do not complete the full course prescribed by your doctor, all of the bacteria causing your infection may not be killed. These bacteria may continue to grow and multiply so that your infection may not clear completely or it may return and be more difficult to treat.

Things to be careful of

Be careful while driving or operating machinery until you know how ciprofloxacin affects you. This medicine may cause dizziness, light-headedness or drowsiness in some people, or may change your reaction time. If you have any of these symptoms, do not drive or operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness, light-headedness or drowsiness may be worse.

Be careful when drinking beverages containing caffeine (e.g. coffee, cola drinks) while you are taking this medicine. Ciprofloxacin tablets may increase the stimulatory effects of caffeine.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking ciprofloxacin or if you have questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • nausea, vomiting, mild diarrhoea
  • loss of appetite
  • mild stomach pain or wind
  • agitation, anxiety or restlessness
  • sleeping disorders
  • headache
  • dizziness or light-headedness
  • tremor, twitching or weakness
  • purple or red spots on the skin
  • strange taste, smell or touch sensations.

Tell your doctor as soon as possible if you notice any of the following: These may be serious side effects and you may need medical attention.

  • vaginal itching or discharge
  • a sore white mouth or tongue
  • altered vision (specialist consult needed)
  • migraine
  • difficulty walking, uncoordinated, shaking
  • getting sunburnt very easily
  • joint or muscle pain, muscle cramps, or inflamed, painful or ruptured tendons such as the Achilles tendon
  • tinnitus (ringing in the ears), problems with hearing
  • symptoms of hypoglycaemia (low blood sugar) e.g. sweating, weakness, dizziness, trembling, headache, and having a fast, pounding heartbeat
  • symptoms of hyperglycaemia (high blood sugar): feeling hungry, thirsty and/or frequent or excessive urination
  • a worsening of the symptoms of myasthenia gravis, e.g. weaker muscles which tire more easily, drooping eyelids, double vision, difficulty in speaking and swallowing
  • confusion, hallucinations, depression.

In isolated instances, some serious side effects may be long-lasting (more than 30 days) and disabling, such as tendonitis, tendon rupture, musculoskeletal disorders and other reactions affecting the nervous system including mental health disorders and disturbance of senses.

If you experience any of the following, stop taking your medicine and either tell your doctor immediately or go to Accident and Emergency at your nearest hospital: These are very serious side effects.

You may need urgent medical attention or hospitalisation.

  • severe watery or bloody diarrhoea, even if it occurs several weeks after you have stopped taking this medicine
  • severe stomach pains
  • severe skin rashes or blistering
  • numbness, pain, burning, tingling or pins and needles in outer limbs
  • palpitations, or fast or irregular heart beats
  • chest pain
  • fainting
  • dark, bloody or cloudy urine
  • yellowing of the skin or eyes (jaundice)
  • fits (convulsions or seizures)
  • confusion, nightmares, hallucinations and psychotic reaction (even progressing to self-endangering behaviour)
  • ringing in the ear, loss of hearing
  • visual disturbances

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to ciprofloxacin, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

After finishing it

Tell your doctor immediately if you notice any of the following side effects, particularly if they occur several weeks after stopping treatment with ciprofloxacin:

  • 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.

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

You may have a serious condition affecting your bowel, and may therefore need urgent medical attention. However, this side effect is rare.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging they may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car on hot days. Heat and dampness can destroy some medicines.

Keep it 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 this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Ciprofloxacin looks like

  • 250 mg - white to off-white, round, film-coated tablets marked with "250" on one side and plain on the other.

Blister packs of 14 tablets

  • 500 mg - white to off-white, caplet (oval) shaped, film-coated tablets marked with "500" on one side and plain on the other.\

Blister packs of 14 tablets

  • 750 mg - white to off-white, caplet (oval) shaped, film-coated tablets marked with "750" on one side and plain on the other.

Blister packs of 14 tablets

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 250 mg, 500 mg or 750 mg of ciprofloxacin.

It also contains the following inactive ingredients:

  • microcrystalline cellulose
  • maize starch
  • magnesium stearate
  • purified talc
  • colloidal anhydrous silica
  • sodium starch glycollate type A
  • purified water
  • hypromellose
  • titanium dioxide
  • macrogol 400.

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Ciprofloxacin 250mg Tablets
AUST R Number 135650

APO-Ciprofloxacin 500mg Tablets
AUST R Number 135651

APO-Ciprofloxacin 750mg Tablets
AUST R Number 135652

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was updated in: March 2020

Published by MIMS May 2020

BRAND INFORMATION

Brand name

APO-Ciprofloxacin

Active ingredient

Ciprofloxacin

Schedule

S4

 

1 Name of Medicine

Ciprofloxacin hydrochloride.

6.7 Physicochemical Properties

A pale yellow, crystalline powder, soluble in water, slightly soluble in methanol, very slightly soluble in ethanol, practically insoluble in acetone, in ethyl acetate and in methylene chloride.
Ciprofloxacin hydrochloride is a synthetic carboxyquinolone derivative with broad spectrum antimicrobial activity. It is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.

Chemical structure.


Chemical Name: 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride.
Molecular Formula: C17H18FN3O3.HCl.H2O.
Molecular Weight: 385.8.

CAS number.

86393-32-0.

2 Qualitative and Quantitative Composition

Each tablet contains 250 mg, 500 mg or 750 mg of ciprofloxacin.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Ciprofloxacin 250 mg tablets.

White to off-white, round, film-coated tablets debossed with "250" on one side and plain on the other.

APO-Ciprofloxacin 500 mg tablets.

White to off-white, caplet shaped, film-coated tablets debossed with "500" on one side and plain on the other side.

APO-Ciprofloxacin 750 mg tablets.

White to off-white, caplet shaped, film-coated tablets debossed with "750" on one side and plain on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Microbiology.

Ciprofloxacin has in vitro activity against a wide range of Gram negative and Gram positive organisms. The bactericidal action of ciprofloxacin appears to result from interference with the enzyme, DNA gyrase. Ciprofloxacin is usually active against the following organisms in vitro.

Gram negative.

Escherichia coli; Klebsiella species (including Klebsiella pneumoniae and Klebsiella oxytoca); Enterobacter species; Citrobacter species; Salmonella species; Shigella species; Proteus mirabilis; Proteus vulgaris; Providencia stuartii; Providencia rettgeri (formerly Proteus rettgeri); Morganella morganii (formerly Proteus morganii); Serratia species* (including Serratia marcescens); Pseudomonas aeruginosa; Pseudomonas fluorescens; Campylobacter species; Haemophilus influenzae; Moraxella (Branhamella) catarrhalis.

Gram positive*.

Staphylococcus aureus (including methicillin susceptible and methicillin resistant strains); coagulase negative Staphylococcus species (including Staphylococcus epidermidis); Streptococcus pyogenes (group A); Streptococcus pneumoniae; Enterococcus faecalis.

* Note.

1. Gram positive organisms are generally less sensitive to ciprofloxacin than Gram negative organisms.
2. Most strains of Streptococci are only moderately susceptible to ciprofloxacin. Clinical studies have shown the drug to be effective for urinary tract infections caused by Enterococcus faecalis; however failures and reinfections have been observed with prostatitis. Although bronchial infections caused by Streptococcus pneumoniae and skin infections caused by Streptococcus pyogenes have been shown to respond to ciprofloxacin, it is not the drug of first choice in such infections, particularly Streptococcus pneumoniae infection of the lower respiratory tract.
3. Most strains of Burkholderia cepacia and many strains of Stenotrophomonas maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
4. Enterococcus faecium, Ureaplasma urealyticum and Nocardia asteroides are generally resistant. Ciprofloxacin is ineffective against Treponema pallidum.
5. The in vitro minimal inhibitory concentration (MIC) of several strains of Serratia approaches or exceeds the peak plasma concentrations with the recommended doses of ciprofloxacin.
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. This information gives only an approximate guidance whether microorganisms will be susceptible for ciprofloxacin or not.
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker (see Section 5 Pharmacological Properties).
Ciprofloxacin is less active when tested at acidic pH and its antibacterial activity may be reduced by up to 100-fold in acidic urine. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) is generally 2-8 times the MIC.
Resistance to ciprofloxacin in vitro develops slowly (multiple step mutation). Rapid one step development of resistance has not been observed. However, in practice resistance to ciprofloxacin may develop during the course of a treatment, particularly in a significant proportion of Pseudomonas aeruginosa infections, especially in patients with cystic fibrosis, and in Staphylococcus aureus infections.
Ciprofloxacin does not exhibit cross resistance with nonquinolone antibacterial agents such as beta-lactams and aminoglycosides. However, organisms which are resistant to other quinolone agents (e.g. nalidixic acid, cinoxacin, etc.) are usually less sensitive to ciprofloxacin.
In vitro studies have shown that when ciprofloxacin is combined with other antimicrobial agents, particularly beta-lactams, the combination behaves either in an indifferent or additive manner. Synergism or antagonism have, however, been observed rarely.
Appropriate culture and susceptibility tests should be performed before treatment in order to determine organism susceptibility to ciprofloxacin and after treatment as warranted by the clinical condition. Therapy with ciprofloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.

Disc susceptibility test.

Dilution or infusion 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 considered 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 situations 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.

Note.

The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Ciprofloxacin tablets are rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Coadministration of ciprofloxacin with food appears to lower peak serum levels and delay the absorption of ciprofloxacin, resulting in peak concentrations closer to 2 hours after dosing rather than 1 hour. The overall absorption, however, is not substantially affected. Absorption also appears to be greatly reduced by prior administration of antacids.

Distribution.

After oral dosing, ciprofloxacin is widely distributed throughout the body. The binding of ciprofloxacin to serum proteins is 20 to 40%. Serum concentrations increase in a dose proportional manner and were, after multiple doses, as shown in Table 4.
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500 or 750 mg are 0.1, 0.2 and 0.4 microgram/mL respectively.

Metabolism.

Ciprofloxacin is also metabolised. Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have less antimicrobial activity than unchanged ciprofloxacin.

Excretion.

The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. During the first 2 hours after an oral dose of 250 mg, the urine concentration of ciprofloxacin usually exceeds 200 microgram/mL. Eight to 12 hours after the same dose, urine levels are approximately 30 microgram/mL. Urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin is approximately 18 L/h which exceeds the normal glomerular filtration rate of 7.2 L/h. Thus, active tubular secretion would seem to play a significant role in its elimination.
In patients with creatinine clearance between 21 to 40 mL/min, the half-life of ciprofloxacin is only slightly prolonged. Dosage adjustments are usually not required in such cases. However, in patients with severe renal impairment, with creatinine clearance less than 20 mL/min, the half-life of ciprofloxacin is nearly doubled and dosage adjustment is necessary (see Section 4.2 Dose and Method of Administration).
Although bile concentrations of ciprofloxacin are 3 to 4 times higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile. Approximately 20 to 35% of an oral dose is recovered from the faeces within 5 days after dosing.

Inhalational anthrax.

The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and paediatric patients receiving oral and intravenous regimens (see Section 4.2 Dose and Method of Administration). Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady state in human adults receiving 500 mg orally every 12 hours is 2.97 microgram/mL, and 4.56 microgram/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady state for both of these regimens is 0.2 microgram/mL. In a study of 10 paediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 microgram/mL and trough concentrations range from 0.09 to 0.26 microgram/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 microgram/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to paediatric patients are limited. (For additional information, see Section 4.4 Special Warnings and Precautions for Use, Paediatric use.) Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105) spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was
0.08 microgram/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady state ranged from 0.98 to 1.69 microgram/mL. Mean steady state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 microgram/mL. Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.

5.3 Preclinical Safety Data

Genotoxicity.

Ciprofloxacin was mutagenic in the mouse lymphoma assay and the rat primary hepatocyte culture/DNA repair assay in vitro, but not in other mammalian systems in vitro or in microbial systems.
In a small study on the chromosomal effects of ciprofloxacin on white blood cells, the drug did not exhibit any cytogenetic effect.

Carcinogenicity.

Carcinogenicity studies in mice (oral doses up to 1090 mg/kg/day and 1455 mg/kg/day in males and females, respectively; 1.4 and 1.8 times the highest recommended human dose of 1500 mg/day based upon body surface area) and rats (241 mg/kg/day and 328 mg/kg/day in males and females, respectively; 3.1 and 4.2 times the highest recommended human dose of 1500 mg/day based upon body surface area) showed no evidence of carcinogenicity.
Results from photo cocarcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV induced skin tumours as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumours was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumours ranged from 16 to 32 weeks in mice treated concomitantly with UVA and other quinolones. In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumours. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.

4 Clinical Particulars

4.1 Therapeutic Indications

Ciprofloxacin is indicated for the treatment of infections caused by susceptible organisms in the conditions listed below.
Urinary tract infections.
Gonorrhoeal urethritis and cervicitis.
Gastroenteritis.
Bronchial infections.
Skin and skin structure infections.
Bone and joint infections.
Chronic bacterial prostatitis of mild to moderate severity.
Inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.

Note.

1. Typhoid and paratyphoid infections and infections due to multiresistant Staphylococcus aureus are excluded from the above due to insufficient data.
2. Because Gram positive organisms are generally less sensitive to ciprofloxacin, it may not be the drug of choice in cases with Gram positive infections, such as pneumonia due to Streptococcus pneumoniae.
3. Chronic bacterial prostatitis should be demonstrated by microbiological evidence localising infection to the prostate.
Strains of Neisseria gonorrhoea resistant to ciprofloxacin have been reported in Australia.
Appropriate culture and susceptibility tests should be performed before treatment in order to determine organism susceptibility to ciprofloxacin and after treatment as warranted by the clinical condition. Therapy with ciprofloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.
Ciprofloxacin is suitable to treat mixed infections caused by susceptible strains of both Gram negative and Gram positive aerobic bacteria. If anaerobic organisms are suspected as accompanying aetiologic agents, additional therapy should be considered.
Consideration should be given to available official guidance on the appropriate use of antibacterial agents.

4.3 Contraindications

A history of hypersensitivity to ciprofloxacin, any of the excipients as listed (see Section 6.1 List of Excipients), or other quinolones, including nalidixic acid.
Concurrent administration of ciprofloxacin and tizanidine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially 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 Effects on the central nervous system, Psychiatric reactions) and musculoskeletal system (see Tendonitis and tendon rupture).

Streptococcus pneumoniae infections.

Ciprofloxacin is not recommended for treatment of pneumococcal infections due to inadequate efficacy against Streptococcus pneumoniae.

Cardiac disorders.

Ciprofloxacin is associated with cases of QT prolongation (see Section 4.8 Adverse Effects (Undesirable Effects)). In general, elderly patients may be more susceptible to drug associated effects on the QT interval. Women may also be more sensitive to QT prolongation medicine compared to men as they tend to have a longer baseline QTc interval. Precaution should be taken when using ciprofloxacin with concomitant drugs that can result in prolongation with the QT interval (e.g. class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) or in patients with risk factors for QT prolongation or torsade de pointes (e.g. congenital long QT syndrome, uncorrected electrolyte imbalance such as hypokalaemia or hypomagnesaemia and cardiac disease such as heart failure, myocardial infarction, or bradycardia).

Antibiotic associated colitis.

Antibiotic associated colitis has been rarely reported with ciprofloxacin, but it should be considered in patients who develop diarrhoea.
Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including ciprofloxacin. A toxin produced by 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 such as oral antibacterial agents effective against Clostridium 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.

Effects on the liver.

Cases of hepatic necrosis and life threatening hepatic failure have been reported with ciprofloxacin. In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued (see Section 4.8 Adverse Effects (Undesirable Effects)). There can be a temporary increase in transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin.

Tendonitis and tendon rupture.

Tendonitis and tendon ruptures (predominantly Achilles tendon), sometimes bilateral, that required surgical repair or resulted in prolonged disability have been reported with ciprofloxacin and other quinolones. This may occur even within the first 48 hours of treatment, and cases occurring up to several months after completion of therapy have been reported. The risk of tendinopathy may be increased in elderly patients, during strenuous physical activity, in patients treated concomitantly with corticosteroids, in patients with renal impairment and in patients with solid organ transplants. Ciprofloxacin should be used with caution in patients with a history of tendon disorders related to quinolone treatment. At any sign of tendonitis (e.g. painful swelling, inflammation), the affected extremity should be kept at rest, any inappropriate physical exercise should be avoided, a physician should be consulted and the antibiotic treatment should be discontinued.

Superinfections.

As with other broad spectrum antimicrobial agents, prolonged use of ciprofloxacin may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pseudomonas aeruginosa infections in cystic fibrosis.

Although clinical improvement has been observed in patients with respiratory exacerbation of cystic fibrosis associated with Pseudomonas aeruginosa, bacterial eradication is usually not achieved. Resistance to ciprofloxacin has been shown to develop in a significant proportion of Pseudomonas aeruginosa infections in cystic fibrosis patients following a single course of the drug.

Anaphylactoid reactions.

In some instances, hypersensitivity and allergic reactions may occur following a single dose, a physician should be informed immediately.
Serious, and occasionally fatal, anaphylactoid reactions, some following the first dose, have been reported in patients receiving quinolones (including ciprofloxacin). In these cases ciprofloxacin should be discontinued and appropriate medical treatment given.

Phototoxicity.

Ciprofloxacin has been shown to be phototoxic in a number of in vitro and in vivo studies. Nalidixic acid (the prototype quinolone antibiotic) and other quinolone antibiotics, produce photosensitivity reactions. Patients taking ciprofloxacin should avoid direct exposure to sunlight. Therapy should be discontinued if photosensitisation occurs.

Effects on the central nervous system.

As with other quinolones, ciprofloxacin may cause central nervous system (CNS) stimulation which may lead to transient tremor, restlessness, lightheadedness, confusion, and very rarely to hallucinations or convulsive seizures. In some instances, CNS reactions may occur even after the first administration of fluoroquinolones, including ciprofloxacin.

Psychiatric reactions.

Fluoroquinolones, including ciprofloxacin, 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 ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug and institute appropriate care.

Myasthenia gravis.

Ciprofloxacin should be used with caution in patients with myasthenia gravis because symptoms can be exacerbated. Therefore, at any clinical sign or symptom of an exacerbation of myasthenia gravis, a physician should be consulted.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaethesias, or weakness have been reported in patients receiving fluoroquinolones including ciprofloxacin. Ciprofloxacin 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)).

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)).

Cytochrome P450.

Ciprofloxacin is known to be a moderate inhibitor of the CYP450 1A2 enzymes. Care should be taken when other drugs are administered concomitantly which are metabolised via the same enzymatic pathway (e.g. theophylline, methylxanthines, caffeine, duloxetine, clozapine, olanzapine, ropinirole, agomelatine). Increased plasma concentrations associated with drug specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

Dysglycaemia.

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported with Ciprofloxacin. In Ciprofloxacin-treated patients, dysglycaemia occurred predominantly in elderly 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 (see Section 4.8 Adverse Effects (Undesirable Effects)).

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 the 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.

Crystalluria.

The solubility of ciprofloxacin is pH dependent and is greatly reduced between pH 5 and 9. Crystals of ciprofloxacin have been observed in the urine of laboratory animals given high doses of the drug, but also in some patients receiving standard therapeutic doses. Crystalluria seems to occur under alkaline conditions of the urine and is less likely in nonvegetarians who usually have an acidic urine. Patients receiving ciprofloxacin should be well hydrated and alkalinity of the urine should be avoided. It should, however, be noted that the activity of ciprofloxacin is significantly reduced in acid media.

Epileptic patients.

Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower seizure threshold.
Ciprofloxacin should be used with caution in epileptics and in patients who have suffered from previous CNS disorders (e.g. lowered convulsion threshold, previous history of convulsion, reduced cerebral blood flow, altered brain structure or stroke). Ciprofloxacin should only be used where the benefits of treatment exceed the risks, since these patients are endangered because of possible central nervous system adverse effects. Cases of status epilepticus have been reported. If seizures occur, ciprofloxacin should be discontinued.

Use in renal impairment.

Alteration of the dosage regimen is necessary for patients with impairment of renal function (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Ciprofloxacin should be used with caution in the elderly after taking into account the severity of the illness and the creatinine clearance. (See Section 4.2 Dose and Method of Administration).

Paediatric use.

Ciprofloxacin is not recommended for use in prepubertal children except for use in inhalational anthrax (post-exposure). Toxicological studies have shown that ciprofloxacin and related drugs such as nalidixic acid and cinoxacin, can produce erosions of cartilage of weight bearing joints and other signs of arthropathy in immature animals of various species. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to paediatric patients are limited.
For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients is appropriate. For information regarding paediatric dosing in inhalational anthrax (post-exposure), (see Section 4.2 Dose and Method of Administration).
The safety and effectiveness of ciprofloxacin in prepubertal children except for use in inhalational anthrax (postexposure) have not been established.

Effects on laboratory tests.

Ciprofloxacin in vitro potency may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth, causing false negative results in specimens from patients currently taking ciprofloxacin.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs known to prolong QT interval.

Ciprofloxacin, 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).

Theophylline.

Concurrent administration of ciprofloxacin with theophylline may lead to elevated plasma concentrations of theophylline and prolongation of its elimination half-life. This can lead to theophylline induced side effects; in very rare cases these side effects can be life threatening or fatal. If concomitant use cannot be avoided, the plasma levels of theophylline should be monitored and dosage appropriate adjustments should be made.

Omeprazole.

Concomitant administration of ciprofloxacin and omeprazole results in a slight reduction of Cmax and area under the curve (AUC) of ciprofloxacin.

Probenecid.

Coadministration of probenecid with ciprofloxacin results in a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its AUC, without altering the peak concentration, time to peak and half-life of elimination.

Anticoagulants.

Quinolones, including ciprofloxacin, have been reported to enhance the effects of oral anticoagulants, warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalised ratio) is difficult to assess.

Cyclosporin.

Some quinolones, including ciprofloxacin, have been associated with transient elevations of serum creatinine in patients receiving cyclosporin concomitantly. Therefore, it is frequently (twice a week) necessary to control the serum creatinine concentrations in these patients.

Metoclopramide.

Metoclopramide accelerates the absorption of ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.

Oral antidiabetic agents.

Hypoglycaemia has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (e.g. glibenclamide, glimepiride), where coadministered, presumably by intensifying the action of the oral antidiabetic agent.

Non-steroidal anti-inflammatory drugs (NSAIDs).

Animal studies have shown that the combination of very high doses of fluoroquinolones (gyrase inhibitors) and certain non-steroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.

Other xanthine derivatives.

On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline) containing products, raised serum concentrations of these xanthine derivatives were reported. Quinolones may reduce the clearance of caffeine and prolong its plasma half-life, and therefore may enhance the effects of caffeine.

Phenytoin.

Altered (decreased or increased) serum levels of phenytoin were observed in patients receiving ciprofloxacin and phenytoin simultaneously. To avoid the loss of seizure control associated with decreased phenytoin levels, and to prevent phenytoin overdose related adverse effects when ciprofloxacin is discontinued in patients receiving both agents, monitoring of phenytoin therapy, including phenytoin serum concentration measurements, is recommended during and shortly after coadministration of ciprofloxacin with phenytoin.

Methotrexate.

Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.

Chelation complex formation.

The simultaneous administration of ciprofloxacin and multivalent cation-containing medicinal products and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer, lanthanum carbonate), sucralfate or antacids, and highly buffered drugs (e.g. antiretrovirals) containing magnesium, aluminium or calcium reduce the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1-2 hours before or at least 4 hours after these preparations.

Tizanidine.

Tizanidine serum concentrations increase with concomitant administration with ciprofloxacin. Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect. Tizanidine must not be administered together with ciprofloxacin (see Section 4.3 Contraindications).

Duloxetine.

In clinical studies, it was demonstrated that concurrent use of duloxetine with strong inhibitors of the CYP450 1A2 isoenzyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.

Ropinirole.

In a clinical study it was shown that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, resulted in increases in the Cmax and AUC of ropinirole of 60% and 84%, respectively. Although ropinirole treatment was well tolerated, case reports suggest that a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration. Ropinirole related side effects should be monitored during and shortly after coadministration with ciprofloxacin; dose adjustment is recommended if necessary.

Lidocaine.

It was demonstrated in healthy subjects that concomitant use of lidocaine with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.

Clozapine.

Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.

Sildenafil.

Cmax and AUC of sildenafil were increased approximately twofold in healthy subjects after an oral dose of 50 mg given concomitantly with 500 mg ciprofloxacin. Therefore, caution should be used prescribing ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.

Agomelatine.

Agomelatine In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a large increase in agomelatine exposure. Although no clinical data are available, ciprofloxacin is a moderate inhibitor of CYP450 1A2 and similar effect can be expected upon concomitant administration. Therefore concurrent use of ciprofloxacin with agomelatine is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Cytochrome P450).

Zolpidem.

Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
Reproduction studies have been performed in rats and mice at doses up to 100 mg/kg/day (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and intravenous doses of up to 30 mg/kg and have revealed no evidence of impaired fertility or harm to the foetus due to ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally, 0.4 and 1.2 times the maximum daily human dose based upon body surface area, respectively) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, intrauterine deaths and foetal retardation, but no teratogenicity was observed at either dose.
After intravenous administration, at doses up to 20 mg/kg, no maternal toxicity was produced in the rabbit and no embryotoxicity or teratogenicity was observed. There are, however, no adequate and well controlled studies in pregnant women.
Like other drugs in its class, ciprofloxacin causes arthropathy in immature animals.
Ciprofloxacin should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus (e.g. potential damage to articular cartilage in the immature foetal organism).
Ciprofloxacin is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ciprofloxacin, a decision should be made to discontinue nursing or to avoid using the drug, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions (ADRs) based on all clinical studies with ciprofloxacin (oral, parenteral) sorted by CIOMS III categories of frequency are listed in Table 1 (overall n = 51,721; data lock point: 15 May 2005).

Note.

The incidence of arthropathy (arthralgia, arthritis), mentioned in Table 1, refers to data collected in studies with adults. In children, arthropathy is reported to occur commonly.
ADRs derived from post marketing reports (status: 31 July 2005) for which a frequency could not be estimated are listed in Table 2:
In isolated instances, some serious adverse drug reactions may be long-lasting (> 30 days) and disabling; such as tendonitis, tendon rupture, musculoskeletal disorders, and other reactions affecting the nervous system including psychiatric disorders and disturbance of senses.
The following undesirable effects have a higher frequency category in the subgroups of patients receiving intravenous or sequential (intravenous to oral) treatment (see Table 3):

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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

APO-Ciprofloxacin tablets are intended for oral administration.

Dosage.

Urinary tract infections.

The usual adult dosage is 250 mg every 12 hours. For patients with complicated infections caused by organisms not highly susceptible, such as Enterococcus faecalis, 500 mg may be administered every 12 hours.

Bronchial infections, skin and skin structure infections.

The usual dose is 500 mg every 12 hours. For more severe or complicated infections, a dosage of 750 mg may be given every 12 hours.

Bone and joint infections.

750 mg every 12 hours.

Gastroenteritis (infectious diarrhoea).

500 mg every 12 hours.

Acute, uncomplicated gonorrhoeal urethritis.

A single dose of 250 mg.

Chronic bacterial prostatitis.

250 to 500 mg every 12 hours.

Inhalational anthrax (post-exposure).

For adults, the recommended dose is 500 mg every 12 hours. For paediatric patients, the recommended dose is 15 mg/kg per dose (not to exceed 500 mg per dose), every 12 hours. Drug administration should begin as soon as possible after suspected or confirmed exposure.
The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient's host defence mechanisms, and the status of renal function.
Because Gram positive organisms are generally less sensitive than Gram negative organisms, the use of higher doses should be considered in patients with Gram positive infections. In such cases 8 hourly administration of 500 mg ciprofloxacin may be preferable.

Duration.

The duration of treatment depends upon the severity of infection. Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration is 7 to 14 days, however for severe and complicated infections more prolonged therapy may be required. Bone and joint infections may require treatment for 4 to 6 weeks or longer. Gastrointestinal infections (infectious diarrhoea) need treatment for only 5 days. Chronic bacterial prostatitis should be treated for 14 to 28 days.
Inhalational anthrax (post exposure) should be treated for 60 days. Drug administration should begin as soon as possible after suspected or confirmed exposure.
In certain deep seated infections involving abscess formation, appropriate surgical drainage should be performed in conjunction with antimicrobial therapy.

Missed dose.

If a dose is missed, it should be taken as soon as the patient remembers and then treatment should be continued as prescribed. Double doses should not be taken to compensate for a missed dose.

Renal impairment.

Dosage adjustments for patients with creatinine clearance between 31-60 mL/min/1.73 m2 the maximum daily dose should be 1000 mg/day for oral administration. For creatinine clearance equal or less than 30 mL/min/1.73 m2, the maximum daily dose should be 500 mg/day for oral administration.
When only data for serum creatinine are available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance.

4.7 Effects on Ability to Drive and Use Machines

Even when taken as prescribed, this drug can alter patients' responsiveness, impairing the ability to drive or operate machinery. This is even more applicable when the drug is taken in conjunction with alcohol.

4.9 Overdose

Symptoms.

In the event of acute, excessive oral overdosage, reversible renal toxicity has been reported in some cases.

Treatment.

Apart from routine emergency measures, it is recommended to monitor renal function, including urinary pH and acidify if required to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids reduce the absorption of ciprofloxacin in overdoses.
Only a small quantity of ciprofloxacin (< 10%) is removed from the body after haemodialysis or peritoneal dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, maize starch, magnesium stearate, purified talc, colloidal anhydrous silica, sodium starch glycollate, purified water, Opadry OY-S-58910 white.

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 25°C.

6.5 Nature and Contents of Container

APO-Ciprofloxacin 250 mg tablets.

Blister packs of 14 tablets.
Aust R Number: 135650.

APO-Ciprofloxacin 500 mg tablets.

Blister packs of 14 tablets.
Aust R Number: 135651.

APO-Ciprofloxacin 750 mg tablets.

Blister packs of 14 tablets.
Aust R Number: 135652.
APO is a registered trade mark of Apotex Inc.
Not all strengths may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes