Consumer medicine information

APO-Ciprofloxacin Tablets

Ciprofloxacin

BRAND INFORMATION

Brand name

APO-Ciprofloxacin

Active ingredient

Ciprofloxacin

Schedule

SUMMARY CMI

APO-CIPROFLOXACIN Tablets

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using APO-CIPROFLOXACIN?

APO-CIPROFLOXACIN contains the active ingredient ciprofloxacin (as hydrochloride). APO-CIPROFLOXACIN is used to treat certain infections of the lungs, skin, bones and joints, kidney and bladder, prostate and bowel.

For more information, see Section 1. Why am I using APO-CIPROFLOXACIN? in the full CMI.

2. What should I know before I use APO-CIPROFLOXACIN?

Do not take if you have ever had an allergic reaction to ciprofloxacin, other quinolone antibiotics including nalidixic acid, moxifloxacin, norfloxacin, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use APO-CIPROFLOXACIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-CIPROFLOXACIN and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use APO-CIPROFLOXACIN?

Your doctor will tell you how much and how often you should take APO-CIPROFLOXACIN. This will depend on the type of infection and any medical conditions you have. More instructions can be found in Section 4. How do I use APO-CIPROFLOXACIN? in the full CMI.

5. What should I know while using APO-CIPROFLOXACIN?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking APO-CIPROFLOXACIN. If you develop diarrhoea, tell your doctor or pharmacist immediately. Do this even if it occurs several weeks after you have stopped taking APO-CIPROFLOXACIN. Tell your doctor immediately if you experience symptoms of depression or self-endangering behaviour. Tell your doctor immediately if you develop pain, burning, tingling, numbness or weakness is any part of the body.
Things you should not do	Do not take APO-CIPROFLOXACIN to treat any other complaints unless your doctor tells you to. Do not stop taking your tablets because you are feeling better, unless your doctor told you to do so.
Driving or using machines	Be careful driving or operating machinery until you know how APO-CIPROFLOXACIN affects you. APO-CIPROFLOXACIN may cause dizziness in some people, especially after the first few doses.
Drinking alcohol	If you drink alcohol while taking this medicine, dizziness may be worse.
Looking after your medicine	Store APO-CIPROFLOXACIN in a cool dry place below 25°C. Keep your tablets in the pack until it is time to take them.

For more information, see Section 5. What should I know while using APO-CIPROFLOXACIN? in the full CMI.

6. Are there any side effects?

Less serious side effects: nausea or vomiting, diarrhoea. Serious side effects: severe skin rashes, peeling of the skin, yellowing of the skin and eyes also called jaundice, severe watery or bloody diarrhoea, nightmares, hallucinations and psychotic reaction, fast or irregular heartbeats, visual disturbances, abdominal pain/cramps, pain, burning, tingling, numbness and/or weakness in your limbs. This is not a complete list of all possible side effects

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

APO-CIPROFLOXACIN Tablets

Active ingredient(s): Ciprofloxacin (as hydrochloride)

Consumer Medicine Information (CMI)

This leaflet provides important information about taking APO-CIPROFLOXACIN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking APO-CIPROFLOXACIN.

Where to find information in this leaflet:

1. Why am I using APO-CIPROFLOXACIN?
2. What should I know before I use APO-CIPROFLOXACIN?
3. What if I am taking other medicines?
4. How do I use APO-CIPROFLOXACIN?
5. What should I know while using APO-CIPROFLOXACIN?
6. Are there any side effects?
7. Product details

1. Why am I using APO-CIPROFLOXACIN?

APO-CIPROFLOXACIN contains the active ingredient ciprofloxacin (as hydrochloride). APO-CIPROFLOXACIN is an antibiotic belonging to the group of medicines called quinolones (pronounced kwin-olones). These antibiotics work by killing the bacteria causing your infection.

APO-CIPROFLOXACIN does not work against infections caused by viruses, such as colds or flu.

APO-CIPROFLOXACIN is used to treat certain infections of the:

lungs
skin
bones and joints
kidney and bladder
prostate
bowel.

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

2. What should I know before I use APO-CIPROFLOXACIN?

Warnings

Do not use APO-CIPROFLOXACIN if:

you are allergic to ciprofloxacin, other quinolone antibiotics including nalidixic acid, moxifloxacin, norfloxacin, or any of the ingredients listed at the end of this leaflet.

Some of the 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
rash, itching or hives on the skin.
Always check the ingredients to make sure you can take this medicine.
you are also taking a medicine called tizanidine, a muscle relaxant used to treat spasticity associated with multiple sclerosis, injury or diseases of the spinal cord.
APO-CIPROFLOXACIN can interfere with tizanidine and can lead to undesirable side effects.
the expiry date printed on the pack has passed or if the packaging is torn or shows signs of tampering. If you are not sure whether you should start taking this medicine, talk to your doctor.

If you are not sure whether you should be taking APO-CIPROFLOXACIN, talk to your doctor.

Check with your doctor if you:

have allergies to any other medicines, foods, preservatives or dyes.
have or have had any of the following medical conditions:
- epilepsy, fits, seizures or convulsions
- stroke
- kidney disease
- liver disease
- arrhythmias (fast or irregular heartbeats). APO-CIPROFLOXACIN may increase the risk of arrhythmias, especially in the elderly or patients with low potassium levels
- conditions where you have taken corticosteroids. You may be at increased risk of swelling of the tendons. Symptoms include pain, tenderness and sometimes restricted movement
- myasthenia gravis, a condition where the muscles become weak. APO-CIPROFLOXACIN can worsen symptoms of this condition
- a history of tendon disorders with the use of quinolones (e.g. moxifloxacin, norfloxacin, nalidixic acid)
- have or have had a mental illness
- have diabetes..
Take any medicines for any other condition.
are pregnant or plan to become pregnant or breastfeeding

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given APO-CIPROFLOXACIN.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant.

APO-CIPROFLOXACIN is not recommended if you are pregnant. Medicines similar to APO-CIPROFLOXACIN have caused joint disease in immature animals. Your doctor will discuss the risks and benefits of taking APO-CIPROFLOXACIN during pregnancy.

Do not breast-feed if you are taking this medicine.

Tell your doctor if you are breastfeeding or plan to breastfeed. APO-CIPROFLOXACIN passes into breast milk and may affect your baby. Your doctor will tell you whether you should take APO-CIPROFLOXACIN or temporarily stop breastfeeding while you are taking the tablets.

Use in children

APO-CIPROFLOXACIN is not recommended for children under 18 years of age.

Use in elderly

APO-CIPROFLOXACIN should be used with caution in elderly patients as they are more prone to side effects.

3. What if I am taking other medicines?

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

Some medicines may be affected by APO-CIPROFLOXACIN or may affect how well it works. These include:

medicines used to treat arrhythmias (fast or irregular heartbeats)
theophylline, a medicine used to treat asthma
oral anticoagulants, medicines used to prevent blood clots such as warfarin and its derivatives
phenytoin, a medicine used to treat epilepsy
medicines used to control diabetes
didanosine, a medicine used to treat viral infections
ciclosporin, a medicine used to suppress the immune system following organ transplantation
NSAIDs (non-steroidal anti-inflammatory drugs), medicines used to treat pain, arthritis and other inflammatory conditions
methotrexate, a medicine used to treat severe rheumatoid arthritis, severe psoriasis or some types of cancer
duloxetine, a medicine used to treat depression, anxiety and nerve pain in people with diabetes
clozapine, a medicine used to treat schizophrenia ropinirole, a medicine used to treat Parkinson's disease or restless legs syndrome
lidocaine, a local anaesthetic medicine used to numb pain or cause loss of sensation
pentoxifylline, a medicine used to treat circulation disorders
sildenafil, a medicine used to treat erectile dysfunction
agomelatine, a medicine used to treat depression
zolpidem, a medicine used to treat sleep disorders.

These medicines may be affected by APO-CIPROFLOXACIN or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Some medicines that may interfere with the absorption of APO-CIPROFLOXACIN. These include:

multivitamins, mineral supplements, antacids (used for indigestion) and other medicines containing iron, zinc, magnesium, aluminium or calcium
sucralfate, a medicine used to treat duodenal or stomach ulcers
medicines used to treat HIV infection
probenecid, a medicine used to treat gout
omeprazole, a medicine used to treat stomach ulcers and other conditions where the stomach produces too much acid
sevelamer, a medicine used to treat high blood levels of phosphorus in patients with kidney disease who are on dialysis
metoclopramide, a medicine used to treat nausea and vomiting, heartburn and stomach pain.

You can still take these medicines while you are taking APO-CIPROFLOXACIN. However, you must take APO-CIPROFLOXACIN at least 2 hours before or 2 hours after taking any of these medicines.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APO-CIPROFLOXACIN.

4. How do I use APO-CIPROFLOXACIN?

Take Ciprofloxacin tablets exactly as your doctor has prescribed.

Follow all directions given to you by your doctor or pharmacist. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much and how often you should take APO-CIPROFLOXACIN. This will depend on the type of infection and any medical conditions you have.

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 of time for some types of infection.

Elderly people and people with kidney problems may need smaller doses.

When to take APO-CIPROFLOXACIN

APO-CIPROFLOXACIN tablets are usually taken twice a day.

Take your tablets at the same time each day, preferably on an empty stomach. However, APO-CIPROFLOXACIN can be taken with or without food.

How to take APO-CIPROFLOXACIN?

Swallow the tablet whole with a full glass of water.

How long to take APO-CIPROFLOXACIN for

Continue taking your medicine for as long as your doctor tells you.
The length of treatment may vary from 1 to 28 days or longer depending on the type of infection.
Do not stop taking APO-CIPROFLOXACIN even if you are feeling better, unless advised by your doctor.
If you stop taking your medicine too soon, the infection may not clear completely or your symptoms may return.

If you forget to use APO-CIPROFLOXACIN

If you forget to take APO-CIPROFLOXACIN tablets and it is:

6 hours or more until your next scheduled dose, take your missed dose right away. Then take the next dose at your regular time.
Less than 6 hours until your next scheduled dose, do not take the missed dose. Take the next dose at your regular time. Do not take a double dose to make up for the dose you missed.

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

If you use too much APO-CIPROFLOXACIN

If you think that you have used too much APO-CIPROFLOXACIN, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

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

5. What should I know while using APO-CIPROFLOXACIN?

Things you should do

Tell any other doctors, dentists and pharmacists who are treating you that you are taking APO-CIPROFLOXACIN.
If you are about to start any new medicine, tell your doctor or pharmacist that you are taking APO-CIPROFLOXACIN.
If you are going to have surgery, tell the surgeon or anaesthetist that you are taking APO-CIPROFLOXACIN.
If you are about to have any laboratory, blood or urine tests, tell your doctor that you are taking APO-CIPROFLOXACIN.
It may affect the results of some tests.
Drink plenty of water while you're taking APO-CIPROFLOXACIN. This helps to stop crystals forming in your urine.

Call your doctor straight away if you:

become pregnant while taking APO-CIPROFLOXACIN.
develop diarrhoea. Do this even if it occurs several weeks after you have stopped taking APO-CIPROFLOXACIN.
Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care.
Do not take any medicines for diarrhoea without checking with your doctor or pharmacist.
experience symptoms of depression or selfendangering behaviour. APO-CIPROFLOXACIN should be discontinued immediately.
develop pain, burning, tingling, numbness or weakness is any part of the body. APO-CIPROFLOXACIN should be discontinued immediately.

Things you should not do

Do not take APO-CIPROFLOXACIN to treat any other complaints unless your doctor tells you to.
Do not give your medicine to anyone else, even if they have the same condition as you.
Do not stop taking your tablets because you are feeling better, unless your doctor told you to do so.

If you do not complete the full course prescribed by your doctor, some 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 up completely or it may return.

Things to be careful of

Avoid excessive exposure to direct sunlight. Your skin may become more prone to sunburn. If such a reaction occurs, stop taking APO-CIPROFLOXACIN immediately and tell your doctor.
APO-CIPROFLOXACIN tablets may increase the stimulatory effects of caffeine.

Driving or using machines

Be careful driving or operating machinery until you know how APO-CIPROFLOXACIN affects you.

APO-CIPROFLOXACIN may cause dizziness in some people, especially after the first few doses. Your ability to drive and/or operate machinery may be impaired.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol while taking this medicine, dizziness may be worse.

Looking after your medicine

Keep APO-CIPROFLOXACIN tablets in the original pack until it is time to take them.
Keep APO-CIPROFLOXACIN tablets in a cool dry place where the temperature is below 25°C.

Do not store APO-CIPROFLOXACIN, or any other medicine, in the bathroom or near a sink.

Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

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

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

Less serious side effects

Less serious side effects	What to do
nausea or vomiting diarrhoea.	Speak to your doctor if you have any of these less serious side effects. These are the more mild and common side effects.

Serious side effects

Serious side effects

What to do

severe skin rashes, peeling of the skin and/or mucosal reactions
signs of allergy such as rash, swelling of the face, lips, mouth, throat or other parts of the body, shortness of breath, wheezing or trouble breathing
fainting
yellowing of the skin and eyes, also called jaundice
severe watery or bloody diarrhoea, even if it occurs several weeks after taking your tablets
fits (seizures, convulsions)
confusion, nightmares,
hallucinations and psychotic reaction (even progressing to self-endangering behaviour)
fast or irregular heartbeats
visual disturbances (eyesight problems)
ringing in the ear, loss of hearing
abdominal pain/cramps. Very rarely this can progress to a serious condition accompanied by fever and fatigue
pain, burning, tingling numbness and/or weakness in your limbs
hypersensitivity reaction called DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) which may include fever, extensive skin rash, swollen lymph nodes, blood abnormalities and inflammation of internal organs like liver, lung or kidney.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
These may be serious side effects that may need urgent medical attention

In isolated instance, some serious side effects may be longlasting (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.

Photosensitivity (getting sunburnt very easily) can occasionally occur with APO-CIPROFLOXACIN. However, it is temporary and staying out of direct sunlight while taking APO-CIPROFLOXACIN will prevent this from happening.

Rarely, there can be a worsening of the symptoms of myasthenia gravis. This is a condition in which the muscles become weak and tire easily, causing drooping eyelids, double vision, difficulty in speaking and swallowing, and sometimes muscle weakness in the arms or legs.

Rarely, the Achilles tendon (extending from the calf muscle in the leg to the heel of the foot) or other tendons have been torn after APO-CIPROFLOXACIN therapy. This may occur even within the first 48 hours of treatment and up to several months after completing treatment with APO-CIPROFLOXACIN. This risk of tendon damage may be increased in elderly patients, during strenuous physical activity, if you are currently being treated with a type of medicine called corticosteroids, if you have reduced kidney function or have received solid organ transplants.

Tell your doctor immediately if you feel any discomfort, pain or inflammation of a tendon.

Rarely, you may experience hyperglycaemia (high blood sugar) or hypoglycaemia (low blood sugar).

Symptoms of hyperglycaemia include increased thirst, appetite and urination. Symptoms of hypoglycaemia include weakness, shaking, sweating, light headedness, headache, behavioural changes, confusion, numbness/pins and needles in the lips, fingers or toes, irritability and hunger. Tell your doctor if you experience these symptoms.

If you experience any of these symptoms during treatment with APO-CIPROFLOXACIN, tell your doctor or pharmacist immediately. APO-CIPROFLOXACIN may need to be discontinued.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is available with a doctor's prescription.

What APO-CIPROFLOXACIN contains

Active ingredient
(main ingredient)

Ciprofloxacin hydrochloride

Other ingredients
(inactive ingredients)

APO-CIPROFLOXACIN tablets contain:

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

Potential allergens

None

Do not take this medicine if you are allergic to any of these ingredients.

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

What APO-CIPROFLOXACIN looks like

APO-CIPROFLOXACIN comes in 3 strengths of tablets:

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

AUST R 135650

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

AUST R 135651

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

AUST R 135652

Each pack contains 14 tablets.

Who distributes APO-CIPROFLOXACIN

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in January 2025

Published by MIMS March 2025

BRAND INFORMATION

Brand name

APO-Ciprofloxacin

Active ingredient

Ciprofloxacin

Schedule

1 Name of Medicine

Ciprofloxacin hydrochloride.

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.

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.

4.2 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. See Equation 1.

4.3 Contraindications

A history of hypersensitivity to ciprofloxacin, any of the excipients as listed under 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. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. These include, but are not limited to, serious adverse reactions involving the nervous system (see Effects on the central nervous system and Psychiatric reactions) and musculoskeletal system (see Tendonitis and tendon rupture) and psychiatric effects (see Psychiatric reactions).

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, dysaesthesias, 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 (post-exposure) 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 C_max 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.

Ciclosporin.

Some quinolones, including ciprofloxacin, have been associated with transient elevations of serum creatinine in patients receiving ciclosporin 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 C_max 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 C_max 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.

C_max 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 fetus (e.g. potential damage to articular cartilage in the immature fetal 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.

4.7 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.

4.8 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.

4.9 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).

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 T_max (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 co-carcinogenicity 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, maize starch, magnesium stearate, purified talc, colloidal anhydrous silica, sodium starch glycollate type A, Opadry complete film coating system 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.