Consumer medicine information

Aspen Ciprofloxacin

Ciprofloxacin

BRAND INFORMATION

Brand name

Aspen Ciprofloxacin Injection for Intravenous Infusion

Active ingredient

Ciprofloxacin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Aspen Ciprofloxacin.

SUMMARY CMI

Aspen Ciprofloxacin Injection for Intravenous Infusion

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I being given ASPEN CIPROFLOXACIN?

ASPEN CIPROFLOXACIN contains the active ingredient ciprofloxacin (as lactate). ASPEN CIPROFLOXACIN Injection for Intravenous Infusion is used to treat a range of different bacterial infections.

For more information, see Section 1. Why am I being given ASPEN CIPROFLOXACIN? in the full CMI.

2. What should I know before I am given ASPEN CIPROFLOXACIN?

You should not be given ASPEN CIPROFLOXACIN if you have ever had an allergic reaction to ciprofloxacin, any other quinolone antibiotics, 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 am given ASPEN CIPROFLOXACIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ASPEN 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 is ASPEN CIPROFLOXACIN given?

  • ASPEN CIPROFLOXACIN Injection for Intravenous Infusion is given as a slow infusion, over a period of not less than 60 minutes, into a vein. It must only be given by a nurse or doctor. Your doctor will decide what dose you receive.

More instructions can be found in Section 4. How is ASPEN CIPROFLOXACIN given? in the full CMI.

5. What should I know while I am being given ASPEN CIPROFLOXACIN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ASPEN CIPROFLOXACIN.
  • Drink plenty of water while you are being treated with ASPEN CIPROFLOXACIN.
  • Keep all of your doctor's appointments so that your progress can be checked.
  • Tell your doctor straight away if you become pregnant while being treated with this medicine.
Things you should not do
  • You must not be given this medicine if you have an allergy to ciprofloxacin, any other quinolone antibiotics such as grepafloxacin, moxifloxacin, nalidixic acid or norfloxacin
  • Do not have this medicine if you are also taking a medicine called tizanidine
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ASPEN CIPROFLOXACIN affects you. It may cause dizziness, light-headedness, tiredness and drowsiness in some people.
Drinking alcohol
  • Be careful when drinking alcohol while you are being given this medicine. If you drink alcohol, dizziness or light-headedness may be worse.
Looking after your medicine
  • This medicine is usually stored in the hospital pharmacy or on the ward.
  • The medicine is kept in a cool dry place, protected from light where the temperature stays below 25°C.

For more information, see Section 5. What should I know while being given ASPEN CIPROFLOXACIN? in the full CMI.

6. Are there any side effects?

Mild side effects of ASPEN CIPROFLOXACIN include headache, fever, dizziness or light-headedness, mild stomach upsets (e.g. stomach pains, flatulence or diarrhoea), loss of appetite or altered taste, heartburn (dyspepsia), nausea or vomiting, irritability, agitation or confusion, or difficulty sleeping. Serious side effects of ASPEN CIPROFLOXACIN may also occur. A list of these can be found in the full CMI.

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.

WARNINGS
Serious disabling and potentially irreversible side effects.
Some serious side effects may be long-lasting and disabling, such as tendonitis, tendon rupture, musculoskeletal disorders and other reactions affecting the nervous system including mental health disorders and disturbance of senses.



FULL CMI

Aspen Ciprofloxacin Injection for Intravenous Infusion

Active ingredient(s): Ciprofloxacin

Consumer Medicine Information (CMI)

This leaflet provides important information about using ASPEN CIPROFLOXACIN Injection for Intravenous Infusion. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ASPEN CIPROFLOXACIN.

Where to find information in this leaflet:

1. Why am I being given ASPEN CIPROFLOXACIN?
2. What should I know before I am given ASPEN CIPROFLOXACIN?
3. What if I am taking other medicines?
4. How is ASPEN CIPROFLOXACIN given?
5. What should I know while being given ASPEN CIPROFLOXACIN?
6. Are there any side effects?
7. Product details

1. Why am I being given ASPEN CIPROFLOXACIN?

ASPEN CIPROFLOXACIN Injection for Intravenous Infusion contains the active ingredient ciprofloxacin (as ciprofloxacin lactate). It belongs to a group of antibiotics called fluoroquinolones.

ASPEN CIPROFLOXACIN is used to treat many different conditions including:

  • Lung infections
  • Infections of the skin
  • Infections of bone and joints
  • Kidney and bladder infections
  • Infections in the blood
  • Inhalation of anthrax (post-exposure)

It works by killing many kinds of bacteria which cause infections in the body. ASPEN CIPROFLOXACIN will not work against infections caused by viruses such as cold and flu.

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 am given ASPEN CIPROFLOXACIN?

Warnings

You should not be given ASPEN CIPROFLOXACIN if:

  • You are allergic to ciprofloxacin, any other quinolone antibiotics (e.g. grepafloxacin, moxifloxacin, nalidixic acid, or norfloxacin), or any of the ingredients listed at the end of this leaflet.
    Some symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue, or any other parts of the body; rash, itching or hives on the skin.
  • Do not have this medicine if you are also taking a medicine called tizanidine.
  • Always check the ingredients to make sure you can use this medicine.
  • The expiry date on the pack has passed
  • The package shows signs of tampering

Check with your doctor if you:

  • Have any other medical conditions, especially the following:
    - epilepsy or seizures or fits
    - myasthenia gravis (a condition of extremely weak muscles)
    - kidney disease
    - liver disease
    - if you or your family have or have had any heart-related conditions, including heart-valves, or conditions affecting the veins or arteries such as Takayasu arteritis, giant cell arthritis, atherosclerosis, Behcet's disease
    - Sjögren's syndrome
    - high blood pressure
    - diarrhoea
    - decreased blood flow to parts of the brain (stroke)
    - tendon pain, inflammation or rupture of tendons or a history of tendon problems associated with quinolone antibiotics
    - connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, rheumatoid arthritis
    - sensitivity of the skin to sunlight
    - diabetes mellitus or sugar diabetes (too much sugar in the blood)
    - solid organ transplant.
  • Take any medicines for any other condition
  • Tell your doctor if you have previously taken or are currently taking corticosteroids such as prednisolone or cortisone. You may be at increased risk of aortic aneurysm and dissection and swelling of the tendons.
    - Symptoms of aortic aneurysm and dissection include sudden, severe pain in your abdomen, chest or back.
    - Symptoms of swelling of the tendons include pain, tenderness and sometimes restricted movement.

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

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor can discuss with you the risks and benefits involved.

Use in children

The use of this medicine in infants, children or growing teenagers is not recommended since fluoroquinolones may cause bone development problems. However, your doctor may choose to use this medicine if other medicines cannot be used

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 and ASPEN CIPROFLOXACIN may interfere with each other. These include:

  • medicines used to treat arrhythmias (fast or irregular heartbeats)
  • theophylline, a medicine used to treat asthma
  • glibenclamide or glimepiride, oral medicines used to treat diabetes
  • cyclosporin, an immunosuppressant
  • warfarin or anticoagulants, medicines used to stop the clotting of blood
  • non-steroidal anti-inflammatory drugs (NSAIDs), that are used for pain and inflammation
  • probenecid, a medicine used for gout
  • caffeine found in coffee, cola and some medications
  • methotrexate, a medicine used to treat certain types of cancers, severe psoriasis and severe rheumatoid arthritis
  • omeprazole, a medicine used to treat stomach ulcers and reflux
  • duloxetine, a medicine used to treat depression, anxiety and nerve pain due to high blood sugar levels
  • clozapine, a medicine used to treat schizophrenia
  • lidocaine (lignocaine), a local anaesthetic
  • ropinirole, a medicine used to treat Parkinson's disease and restless legs syndrome
  • pentoxifylline (oxypentifylline), a medicine used to improve the circulation of the blood
  • phenytoin, a medicine used to treat epilepsy and irregular heart beats
  • sildenafil, a medicine used to treat erectile dysfunction
  • zolpidem, a medicine used to treat sleep disorders
  • antibiotics known as macrolides (eg clarithromycin, roxithromycin, azithromycin and erythromycin)
  • some medicines used to treat depression (eg agomelatine, imipramine, amitriptyline, clomipramine)
  • some antipsychotics, (medicines used to treat certain mental and emotional conditions).

These medicines may be affected by ciprofloxacin or may affect how well it works. You may need different amounts of your medicines or you may need to take different medicines.

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

4. How is ASPEN CIPROFLOXACIN given?

How much is given

  • Your doctor will decide what dose you will receive.
    This depends on the condition being treated and your response to the treatment.

How it is given

  • ASPEN CIPROFLOXACIN Injection for Intravenous Infusion is given as a slow infusion, over a period of not less than 60 minutes, into a vein. It must only be given by a nurse or doctor.

If you receive too much ASPEN CIPROFLOXACIN

As ASPEN CIPROFLOXACIN Injection for Intravenous Infusion is given to you in a hospital under the supervision of your doctor, it is very unlikely that you will be given too much.

However if you experience any side effects after being given it, tell your doctor or nurse immediately.

5. What should I know while being given ASPEN CIPROFLOXACIN?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given ASPEN CIPROFLOXACIN.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are being given this medicine. It may affect other medicines used during surgery.
  • If you are about to have any blood tests, tell your doctor that you are being treated with this medicine. It may interfere with the results of some tests.
  • Drink plenty of water while you are being treated with this medicine. This will help prevent crystals forming in the urine.
  • Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you:

  • Develop severe diarrhoea. Do this even if it occurs several weeks after this medicine has been stopped. Do not take any diarrhoea medicine without first checking with your doctor. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care.
  • Become pregnant while you are being treated with this medicine.
  • Are experiencing symptoms of depression or self-endangering thoughts or behaviour.

Remind any doctor, dentist or pharmacist you visit that you are using ASPEN CIPROFLOXACIN.

Things to be careful of

  • This medicine may increase the stimulatory effects of caffeine.
  • This medicine may cause your skin to be much more sensitive to sunlight than it is normally.
    - Protect your skin when you are in the sun and avoid direct sunlight if possible. If outdoors, wear protective clothing.
    - Exposure to sunlight may cause a skin rash, itching, redness, or a severe sunburn
    - If your skin does appear to be burning, see your doctor as soon as possible. You may need alternative treatment.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ASPEN CIPROFLOXACIN affects you.

This medicine may cause dizziness, light-headedness, tiredness and drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

  • ASPEN CIPROFLOXACIN Injection for Intravenous Infusion will be stored in the hospital pharmacy or on the ward.
  • The medicine is kept in a cool dry place, protected from light where the temperature stays below 25°C.

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.

Less serious side effects

Less serious side effectsWhat to do
  • headache
  • fever
  • dizziness or light-headedness
  • mild stomach upsets such as stomach pains, flatulence or diarrhoea
  • loss of appetite or altered taste
  • heartburn (dyspepsia)
  • nausea or vomiting
  • irritability, agitation or confusion
  • difficulty sleeping
Speak to your doctor if you have any of these less serious side effects and they worry you.
These include the more common side effects of this medicine.

Serious side effects

Serious side effectsWhat to do
  • pain, swelling, redness or tenderness at site of injection.
  • increased feeling of sensitivity, such as pain, burning, tingling or numbness and/or muscle weakness
  • anxiety or nervousness
  • pain inflammation or rupture of the Achilles tendon (which extends from the calf to the heel of the foot) or other tendons
  • increased sensitivity of the skin to sunlight, resulting in getting sunburnt more easily than usual
  • symptoms of low blood sugar level (hypoglycaemia), which may include sweating, weakness, hunger, dizziness, trembling, headache, flushing or paleness and fast, pounding heart beat
  • symptoms of high blood sugar (hyperglycaemia), which may include passing large amounts of urine, excessive thirst and having a dry mouth and skin.
Tell your doctor as soon as possible if you notice any of these serious side effects. You may need medical attention.
  • swelling of the face, lips, mouth or throat
  • fainting
  • wheezing or difficulty breathing
  • severe skin rash, hives, itching or blistering or peeling of the skin
  • severe abdominal or stomach cramps, swelling of the abdomen or lower extremities (hips down to your toes)
  • sudden, severe pain in your abdomen, chest, back, which can be symptoms of aortic aneurysm and dissection
  • severe watery or bloody diarrhoea, even if it occurs several weeks after you have stopped taking this medicine
  • fits (convulsions or seizures)
  • depression, confusion, hallucinations or paranoia, selfendangering thoughts, psychosis – a severe mental condition in which the person loses contact with reality and is unable to think and judge clearly or behaviour
  • yellowing of the skin or eyes, also called jaundice
  • 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
  • palpitations or fast or irregular heart beats
  • joint/muscle pain or cramping
  • visual disturbances
  • ringing in the ear, loss of hearing
  • passing little or no urine
  • dark coloured urine.
Tell your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. You may need urgent medical attention or hospitalisation.
These side effects are very rare.

Tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with ASPEN CIPROFLOXACIN Injection for Intravenous Infusion.

If you are over 65 years of age you may have an increased chance of getting side effects.

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 only available with a doctor's prescription.

What ASPEN CIPROFLOXACIN Injection for Intravenous Infusion contains

Active ingredient
(main ingredient)
  • ciprofloxacin lactate
Other ingredients
(inactive ingredients)
  • glucose monohydrate
  • lactic acid
  • water for injections

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

What ASPEN CIPROFLOXACIN Injection for Intravenous Infusion looks like

ASPEN CIPROFLOXACIN Injection for Intravenous Infusion is a clear, colourless to slightly yellow solution (0.2% w/v) available in either 50 mL or 100 mL infusion bags. Available in packs of 10 infusion bags.

100 mg/50 mL bag: AUST R 114731

200 mg/100 mL bag: AUST R 114735

Who distributes ASPEN CIPROFLOXACIN Injection for Intravenous Infusion

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

This leaflet was revised in October 2024.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Aspen Ciprofloxacin Injection for Intravenous Infusion

Active ingredient

Ciprofloxacin

Schedule

S4

 

1 Name of Medicine

Ciprofloxacin.

2 Qualitative and Quantitative Composition

Aspen Ciprofloxacin Injection for Intravenous Infusion is available as a ciprofloxacin (as lactate) 100 mg/50 mL and a 200 mg/100 mL infusion solution. It also contains the excipients lactic acid (as a solubilising agent), glucose monohydrate (55 mg/mL) and water for injections.

3 Pharmaceutical Form

Aspen Ciprofloxacin Injection for Intravenous Infusion is a synthetic carboxyquinolone derivative with broad spectrum antimicrobial activity for intravenous (IV) administration.
Ciprofloxacin is a faint to light yellow crystalline powder.
Aspen Ciprofloxacin Injection for Intravenous Infusion is a clear, colourless to a slightly yellowish solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Aspen Ciprofloxacin Injection for Intravenous Infusion is indicated for use in the following:
1. Hospitalised adult patients in whom oral ciprofloxacin is indicated but cannot be administered or where the oral form is inappropriate.
2. For the treatment of serious or life threatening infections due to sensitive organisms involving the following organ systems: lower respiratory tract infections (Gram negative organisms); skin and skin structure; septicaemia; bone and joint; urinary tract.
3. Inhalational anthrax (postexposure). 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.

Because Gram positive organisms are generally less sensitive to ciprofloxacin, it may not be the drug of choice in cases with Gram positive infections due to Streptococcus pneumoniae.
If anaerobic organisms are suspected of contributing to the infection, use of other suitable drugs should be considered.
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 isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. 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.

4.2 Dose and Method of Administration

Aspen Ciprofloxacin Injection for Intravenous Infusion contains no antimicrobial preservative. Product is for single use in one patient only. Discard any residue.

Dosage.

Intravenous therapy, for the indications mentioned below, should be used only when oral therapy is contraindicated. The usual dosage for adults is 200 to 300 mg every 12 hours. For complicated infections or for those caused by organisms not highly susceptible, 300 mg should be administered every 12 hours. (See Table 1.)
Aspen Ciprofloxacin Injection for Intravenous Infusion should be administered only by intravenous infusion over a period of 60 minutes. Slow infusion of a dilute solution into a large vein will minimise patient discomfort and reduce the risk of venous irritation.
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 defense mechanisms, and the status of renal and hepatic function.
The serum creatinine should represent a steady state of renal function.

Duration.

The duration of treatment depends upon the severity of infection. Generally, ciprofloxacin should be continued for at least two days after the signs and symptoms of infection have disappeared. The usual duration is 7 to 14 days (parenteral therapy should be changed to oral ciprofloxacin tablets as soon as the condition warrants). In general, intravenous ciprofloxacin should not normally be given for greater than 14 days. However, for severe and complicated infections more prolonged therapy may be required. Total duration of ciprofloxacin administration (IV or oral) for inhalational anthrax (postexposure) is 60 days.
In certain deep seated infections involving abscess formation, appropriate surgical drainage should be performed in conjunction with antimicrobial therapy.

Dosage adjustment in renal impairment.

For creatinine clearance equal or less than 30 mL/min/1.73 m2, the maximum daily dose should be 400 mg/day for IV regimen.
When only data for serum creatinine are available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance.

Method of administration.

Aspen Ciprofloxacin Injection for Intravenous Infusion solutions (0.2%) are available in 50 mL or 100 mL infusion bags.
The solution should be infused over a period of not less than 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in place. If this method or the "piggyback" method of administration is used, it is advisable to discontinue temporarily the administration of any other solutions during the intravenous infusion of ciprofloxacin.
If Aspen Ciprofloxacin Injection for Intravenous Infusion is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each drug.

4.3 Contraindications

A history of hypersensitivity to ciprofloxacin or other quinolones (including nalidixic acid) or any of the excipients is a contraindication to its use.
Concurrent administration of ciprofloxacin and tizanidine is contraindicated since an undesirable increase in serum tizanidine concentrations associated with clinically relevant tizanidine-induced side effects (hypotension, somnolence, drowsiness) can occur (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Identified precautions.

Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious 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 Central nervous system (CNS) disorders), musculoskeletal system (see Tendon rupture) and psychiatric effects (see Psychiatric reactions).
The use of ciprofloxacin in prepubertal children [except for use in inhalational anthrax (postexposure)] and during pregnancy is not recommended.

Duration of use.

Increased toxicity of intravenous ciprofloxacin has been associated with increased duration of use, hence, oral ciprofloxacin should be substituted as soon as practicable.

Superinfection.

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.
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.

Severe infections and/or infections due to Gram-positive or anaerobic bacteria.

For the treatment of severe infections, staphylococcal infections and infections involving anaerobic bacteria, ciprofloxacin should be used in combination with an appropriate antibacterial agent.

Streptococcus pneumoniae infections.

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

Antibiotic-associated colitis.

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.

Hypersensitivity reactions.

Serious, and occasionally fatal hypersensitivity (anaphylactoid) reactions, some following the first dose, have been reported in patients receiving quinolones (including ciprofloxacin). Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnea, urticaria and itching. Appropriate emergency measures for the management of such reactions should be readily available.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with fatal outcome have also been reported extremely rarely in patients receiving ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity.

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.

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.

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 medicines that can result in prolongation with the QT interval (e.g. class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) 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).

Aortic aneurysm and dissection, and heart valve regurgitation/incompetence.

Studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones,. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/ incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or dissection or heart valve disease, or in presence of other risk factors or conditions predisposing for both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behcet's disease, hypertension or rheumatoid arthritis) or additionally for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjogren's syndrome) or additionally for heart valve regurgitation/incompetence (e.g. infective endocarditis).
The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.

Central nervous system (CNS) disorders.

As with other quinolones, ciprofloxacin may cause central nervous system (CNS) stimulation which may lead to transient tremor, restlessness, dizziness, lightheadedness, confusion, and very rarely to hallucinations or convulsive seizures. These reactions may occur following the first dose. If these reactions do occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. Increased intracranial pressure and toxic psychosis have also been reported in patients receiving quinolones, including ciprofloxacin.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoesthesias, dysethesias, or weakness have been reported in patients receiving fluoroquinolones including ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy such as pain, burning, tingling, numbness and/or weakness develop in order to prevent the development of an irreversible condition (see Section 4.8 Adverse Effects (Undesirable Effects)).

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.

Epileptic patients.

Ciprofloxacin, like other fluoroquinolones is known to trigger seizures or lower seizure threshold. Ciprofloxacin should be used with caution in epileptic patients 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 side effects. Cases of status epilepticus have been reported. If seizures occur, ciprofloxacin should be discontinued.

Myasthenia gravis.

Ciprofloxacin might exacerbate symptoms of myasthenia gravis. Therefore, at any clinical sign or symptom of an exacerbation of myasthenia gravis, a physician should be consulted.

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)).

Tendon rupture.

Fluoroquinolones may cause tendonitis or tendon rupture. The risk of tendonitis or tendon rupture is increased in patients: over the age of 60 years; on concomitant systemic steroid therapy; who have received a kidney, heart or lung transplant. Fluoroquinolones should not be used in patients with a history of fluoroquinolone associated tendinopathy. Tendonitis and tendon rupture risk is present during use and for 6 months following use of fluoroquinolone. Prescribers should advise patients that at the first sign of tendon pain, inflammation or tendon rupture, to stop taking the fluoroquinolone, avoid exercise or use of the affected area and immediately contact their doctor.

Diabetes mellitus.

Note that Aspen Ciprofloxacin Injection for Intravenous Infusion contains 55 mg/mL of glucose. The amount of glucose in the solution exceeds 100 mg per recommended daily dose. This may have a significant glycaemic effect on diabetes mellitus patients.

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)).

Effects on the liver.

There can be a temporary increase in transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with previous liver damage.
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. There can be temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin.

Administration.

Ciprofloxacin intravenous solution should be administered by slow infusion over a period of 60 minutes. Local IV site reactions have been reported with the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 60 minutes or less or if small veins of the hand are used. These may appear as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic and haematopoietic, is advisable during prolonged therapy.

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.

Paediatric use.

Ciprofloxacin is not recommended for use in prepubertal children, except for use in inhalational anthrax (postexposure). Toxicological studies have shown that ciprofloxacin and related drugs such as nalidixic acid, norfloxacin and cinoxacin, can produce erosions of cartilage of weightbearing 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 (postexposure), the risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients is appropriate. For information regarding paediatric dosing in inhalational anthrax (postexposure), 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.

Changes in laboratory parameters listed as adverse events without regard to drug relationship.

Hepatic.

Elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, serum bilirubin.

Renal.

Elevations of serum creatinine, serum urea, uric acid.

Urinalysis.

Crystalluria, haematuria and albuminuria have been reported.

Haematologic.

Eosinophilia, decreased blood platelets (thrombocytopenia), elevated blood platelets (thrombocytosis), decreased haemoglobin/ haematocrit, leukopenia, leukocytopenia, granulocytopenia.

Other.

Elevations of serum creatinine, phosphokinase, elevations of serum theophylline (in patients receiving theophylline concomitantly), blood glucose, triglycerides.
Changes occurring in 0.1% or less of courses: Decreased serum urea, elevated serum potassium, decreased serum potassium, decreased uric acid, elevated serum calcium, decreased total serum protein, elevated atypical lymphocyte count, decreased lymphocyte count, elevation of serum gamma-glutamyl transpeptidase (gamma-GT), decrease in platelet count, increase in blood monocytes, hyperglycaemia, immature WBCs, decreased serum albumin, cylindruria, elevated serum cholesterol.
Other changes occurring rarely during the administration of ciprofloxacin were elevation of serum amylase, increase in lipase, decrease in blood glucose, pancytopenia (life threatening), marrow depression (life threatening), leukocytosis, elevated sedimentation rate, elevation of serum phenytoin (in patients receiving phenytoin concomitantly), decreased prothrombin time, haemolytic anaemia and bleeding diathesis.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs known to prolong the QT interval.

Precaution should be taken when using ciprofloxacin together with drugs known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) as ciprofloxacin may have an additive effect on the QT interval.

Theophylline.

Concurrent administration of ciprofloxacin with theophylline may lead to elevated plasma concentrations of theophylline, prolongation of its elimination half-life and increased adverse reactions, particularly those involving the CNS.
Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin IV and theophylline.
These reactions include cardiac arrest, convulsive seizures, status epilepticus and respiratory failure. Similar serious adverse events have been noted with administration of theophylline alone, however the possibility that ciprofloxacin may potentiate these reactions cannot be eliminated.
If concomitant use cannot be avoided, the plasma levels of theophylline should be monitored and appropriate dosage adjustments should be made.

Caffeine and xanthine derivatives.

Quinolones have also been shown to interfere with the metabolism of caffeine and pentoxifylline (oxpentifylline). It may reduce the clearance of caffeine and prolong its plasma half-life. Patients are advised that ciprofloxacin may enhance the effects of caffeine.

Probenecid.

Probenecid interferes with the renal excretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin results in a 50% reduction in the ciprofloxacin renal clearance, a 50% increase in AUC but without altering peak concentration or time to peak.

Cyclosporin.

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

Oral antidiabetic agents.

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

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 co-administration of ciprofloxacin with phenytoin.

Anticoagulants.

Quinolones, including ciprofloxacin, have been reported to enhance the effects of oral anticoagulants, warfarin or its derivatives such as acenocoumarol, phenprocoumon, or fluindione. 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 normalized ratio) is difficult to assess.

NSAIDs.

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

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.

Levothyroxine.

There are limited case reports that oral ciprofloxacin may decrease the absorption of levothyroxine.

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).

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 metabolized via the same enzymatic pathway (e.g. tizanidine [see Section 4.3 Contraindications], 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.

Omeprazole.

Concomitant administration of ciprofloxacin and omeprazole results in a slight reduction of Cmax and AUC of ciprofloxacin.

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 increase 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. Monitoring ropinirole-related adverse effects and/or dose adjustment as appropriate is recommended during and shortly after co-administration with ciprofloxacin.

Lidocaine (lignocaine).

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 oral 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 co-administration with oral 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 oral tablet. Therefore, caution should be used prescribing oral ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.

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.

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 (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and IV 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.
Australian categorisation definition of:
Category B3 - Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
 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 may cause dizziness and lightheadedness and alter patients' responsiveness. It may therefore impair the ability to drive, operate machinery, or engage in activities requiring mental alertness or coordination. This is even more applicable when the drug is taken in conjunction with alcohol.

4.8 Adverse Effects (Undesirable Effects)

Ciprofloxacin IV was generally well tolerated in the reported clinical trials at the recommended doses. Adverse events that were considered likely to be drug related occurred in 7.1% of courses, possibly related in 8.6%, and remotely related in 3.4%. The overall incidence of adverse reactions (29%) was higher than after oral ciprofloxacin (19%). Incidence increased progressively with increase in duration of treatment beyond 7 days.
The most frequently reported events, drug related or not, were nausea, diarrhoea, vomiting, rash, CNS disturbances, injection site reactions (e.g. oedema, hypersensitivity, inflammation, pain), abnormalities of liver enzymes and eosinophilia.
Additional events, drug related or not, that occurred in 1% or less of ciprofloxacin courses are listed below.

Gastrointestinal.

Mouth dryness, oral candidiasis, plaque on dentures, painful oral mucosa, dysphagia, anorexia, flatulence, constipation, vomiting, dyspepsia, epigastric pain, gastric irritation, ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhoea, life threatening pseudomembranous colitis with possible fatal outcome, pancreatitis, hepatic necrosis, intestinal perforation.

Hepatic.

Allergic hepatitis, cholestatic jaundice, very rarely major liver disorders including hepatic necrosis.

CNS.

Hallucinations, confusion, convulsive seizures, nightmares, tremor, psychotic reaction (even progressing to self endangering behaviour), depression, lethargy, drowsiness, somnolence, anxiety, nervousness, headache, dizziness, weakness, paraesthesia, dysphasia, manic reaction, sweating, unsteady gait, paranoia, ataxia, irritability, depersonalisation, insomnia, increase in intracranial pressure, peripheral paralgesia, hypoaesthesia, hyperaesthesia, hypertonia, twitching.

Skin/ hypersensitivity.

Erythema, burning, increased perspiration, urticaria, fever, photosensitivity reactions, angioedema, flushing, pruritus, chills, cutaneous candidiasis, anaphylactic reactions, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, hyperpigmentation, erythema nodosum, erythema multiforme exudativum (minor), papules, petechiae, Lyell syndrome, haemorrhagic bullae, serum sickness-like reaction, fixed eruption, drug reaction with eosinophilia and systemic symptoms (DRESS).
Ciprofloxacin has been shown to be phototoxic in a number of in vitro and in vivo studies. Nalidixic acid, the prototype quinolone antibiotic, produces photosensitivity reactions. Patients taking ciprofloxacin should avoid direct exposure to sunlight. Therapy should be discontinued if photosensitisation occurs.

Body as a whole.

Fatigue, malaise, aches, hot flushes, pain, pain in extremities, back pain, chest pain, injection site reaction (e.g. oedema/ hypersensitivity/ inflammation/ pain).

Special senses.

Disturbed vision (blurred vision, colour vision, flashing lights, overbrightness of lights, diplopia), decreased visual acuity, retro-ocular pain, transient impairment of hearing especially at high frequencies, tinnitus, bad taste, impaired smell, loss of smell (usually reversible on discontinuation).

Respiratory.

Epistaxis, laryngeal oedema, wheezing, dyspnoea, hiccough, coughing, pulmonary embolism, respiratory arrest, respiratory distress, pleural effusion.

Metabolic or renal.

Interstitial nephritis, nephritis, renal failure, flare up of gout, acidosis, hyperglycaemia.

Urogenital.

Crystalluria, dysuria, polyuria, candiduria, vaginitis, haemorrhagic cystitis, urethral bleeding.

Cardiovascular**.

Cardiovascular collapse, cardiopulmonary arrest, myocardial infarction, arrhythmia, tachycardia, cerebral thrombosis, palpitations, cardiac murmur, hypertension, hot flushes, migraine, syncope, hypotension, angina pectoris, thrombophlebitis (at infusion site). QT prolongation, ventricular arrhythmia, torsades de pointes - unknown frequency. These events were reported during the post-marketing period and were observed predominantly among patients with further risk factors for QT prolongation (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal.

Muscular pain, myasthenia, joint pain, joint swelling, tenosynovitis, tendovaginitis, tendinitis, predominantly affecting the achilles tendon, exacerbation of symptoms of myasthenia gravis. Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported with ciprofloxacin and other quinolones. Patients who are elderly or have had prior systemic treatment with corticosteroids are thought to be at particular risk. Therapy should be discontinued if the patient experiences pain, inflammation or rupture of a tendon.

Intravenous infusion site.

Burning, pain, erythema, swelling, paraesthesia, pruritus. Thrombophlebitis accounted for half the local reactions at the site of intravenous infusion, with the remainder being erythema, pruritus or burning pain. These reactions are more frequent with infusion time of 60 minutes or less. Most of these events which were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment.

Other.

In several instances nausea, vomiting, tremor, restlessness, agitation or palpitations were judged by investigators to be related to elevated plasma levels of theophylline possibly as a result of a drug interaction with ciprofloxacin.
Also reported were agranulocytosis, prolongation of prothrombin time and possible exacerbation of myasthenia gravis.
** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

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

4.9 Overdose

In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The patient should be carefully observed and given appropriate supportive treatment. Adequate hydration must be maintained. Only a small amount 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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The bactericidal action of ciprofloxacin appears to result from interference with the enzyme, DNA gyrase.

Microbiology.

Ciprofloxacin has in vitro and in vivo activity against a wide range of Gram-negative and Gram-positive organisms.

Gram negative organisms.

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; Haemophilus influenzae; Neisseria gonorrhoeae; Moraxella (Branhamella) catarrhalis; Campylobacter species.

Gram positive organisms*.

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 and Pseudomonas aeruginosa are generally less sensitive to ciprofloxacin than other Gram negative organisms which results in lower drug efficacy rates.
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. 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 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 guidance whether or not microorganisms will be susceptible to ciprofloxacin.
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker.
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 to 8 times the minimal inhibitory concentration (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 additive activity often results when ciprofloxacin is combined with other antimicrobial agents. The combination behaves either in an indifferent or additive manner. Synergism or antagonism have been observed very rarely.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

Immediately following a 30 minute intravenous infusion of 200 mg ciprofloxacin, serum concentrations average 3 microgram/mL. During the first hour after completion of infusion, serum concentration decreases to approximately 30% of the peak value, but thereafter serum concentrations decline with a half-life of approximately four hours. Mean concentrations observed after a 200 mg dose are given in Table 2.
The pharmacokinetics of intravenously administered ciprofloxacin are near linear over the dosage range of 100 mg to 300 mg, as no substantial dose dependent changes in clearance or serum half-life are observed.
Approximately 50 to 70% of the intravenous dose is excreted in the urine as unchanged drug. During the first two hours of a 200 mg intravenous dose, the urine concentration of ciprofloxacin usually exceeds 200 microgram/mL.

Metabolism.

Four metabolites, desethyleneciprofloxacin (M1), sulphociprofloxacin (M2), oxociprofloxacin (M3) and formylciprofloxacin (M4), have been identified in human urine which, together, account for approximately 12% of an intravenous dose. The metabolites have less antimicrobial activity than unchanged ciprofloxacin.

Excretion.

Urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin is approximately 18 L/hr which exceeds the normal glomerular filtration rate of 7.2 L/hr. Thus, active tubular secretion would seem to play a significant role in its elimination.
Although bile concentrations of ciprofloxacin are 3 to 4 times higher than serum concentrations after intravenous dosing, only a small amount of the dose administered (< 1%) is recovered from bile as unchanged drug.
An additional 1 to 2% of the dose is recovered from bile in the form of metabolites.
Approximately 15% of an intravenous dose is recovered from the faeces within five days after dosing.

Protein binding.

Binding of ciprofloxacin to serum protein is 20 to 40%.

Factors influencing pharmacokinetics.

Impaired renal/hepatic function.

In patients with creatinine clearance between 21 to 40 mL/min, the half-life of ciprofloxacin is slightly prolonged, but 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). Serum metabolite concentrations, particularly sulfociprofloxacin (M2) and oxociprofloxacin (M3), are higher in renally impaired patients than in patients with normal renal function.
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics were observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated.

Age (elderly).

The higher levels of ciprofloxacin and its metabolites seen in elderly patients are possibly due to reduced renal function and volume of distribution.

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 to 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 (one hour postdose) following oral dosing to steady state ranged from 0.98 to 1.69 microgram/mL. Mean steady-state trough concentrations at 12 hours postdose 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 postexposure 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.

Pharmacokinetic drug interactions.

The potential for pharmacokinetic drug interactions between ciprofloxacin and theophylline, caffeine, cyclosporin, sulfonylurea, warfarin, probenecid and methotrexate has been evaluated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Susceptibility tests.

Dilution or diffusion techniques - either quantitative (Minimal Inhibitory Concentration - 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 micro-organisms 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.

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 chromosomal abnormalities.

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 tumors. 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

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Ciprofloxacin solutions are incompatible with all infusion solutions/drugs (e.g. penicillins, heparin solutions), which are physically or chemically unstable at the pH of ciprofloxacin (pH 3.5 to 4.6), especially when combined with alkaline solutions.

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

Since ciprofloxacin is slightly light sensitive, the solutions should be protected from light during storage.
Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Aspen Ciprofloxacin Injection for Intravenous Infusion is a clear, colourless, to slightly yellowish solution, available in infusion bags.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Ciprofloxacin, a fluoroquinolone, is a 1-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and it has a molecular weight of 331.4.

CAS number.

85721-33-1.

7 Medicine Schedule (Poisons Standard)

S4 Prescription Only Medicine.

Summary Table of Changes