Consumer medicine information

Ciprofloxacin Alphapharm

Ciprofloxacin

BRAND INFORMATION

Brand name

Ciprofloxacin Alphapharm

Active ingredient

Ciprofloxacin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

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

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

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

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

What CIPROFLOXACIN ALPHAPHARM is used for

CIPROFLOXACIN ALPHAPHARM is used to treat serious infections in the lungs, skin, blood, bone and joints, kidneys and bowel.

CIPROFLOXACIN ALPHAPHARM is also used to treat inhalational anthrax (an infection caused by breathing in the sports of bacteria).

CIPROFLOXACIN ALPHAPHARM contains the drug ciprofloxacin, which is an antibiotic belonging to a group of medicines called quinolones (pronounced kwin-o-lones). These antibiotics work by killing the bacteria which cause infections in the body.

CIPROFLOXACIN ALPHAPHARM is used in hospitalised patients where the use of ciprofloxacin tablets is inappropriate.

CIPROFLOXACIN ALPHAPHARM will not work against infections caused by viruses such as colds or the 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.

Before you are given CIPROFLOXACIN ALPHAPHARM

When you must not be given it

You must not be given CIPROFLOXACIN ALPHAPHARM if you have an allergy to:

  • ciprofloxacin
  • other quinolone antibiotics including nalidixic acid, moxifloxacin, norfloxacin
  • 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
  • skin rash, itching or hives

Do not be given CIPROFLOXACIN ALPHAPHARM if you are also taking a medicine called tizanidine, a muscle relaxant used to treat spasticity associated with multiple sclerosis or injury or diseases of the spinal cord. CIPROFLOXACIN ALPHAPHARM can interfere with tizanidine and can lead to undesirable side effects.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, inform your doctor.

The contents of the infusion bag are not to be used if it is cloudy or has little specks in it.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant. CIPROFLOXACIN ALPHAPHARM is not recommended if you are pregnant. Medicines similar to CIPROFLOXACIN ALPHAPHARM have caused joint disease in immature animals.

Your doctor will discuss the risks and benefits with you of taking this medicine during pregnancy.

Tell your doctor if you are breastfeeding. CIPROFLOXACIN ALPHAPHARM passes into breast milk. Your doctor will tell you whether you should be given it or temporarily stop breastfeeding while you are receiving CIPROFLOXACIN ALPHAPHARM.

CIPROFLOXACIN ALPHAPHARM is not recommended in children under 18 years of age except for use in inhalational anthrax.

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

Tell your doctor if you 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). CIPROFLOXACIN ALPHAPHARM 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. CIPROFLOXACIN ALPHAPHARM can worsen the 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

If you have not told your doctor about any of the above, tell them before you are given CIPROFLOXACIN ALPHAPHARM.

Taking other medicines

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

Some medicines may be affected by CIPROFLOXACIN ALPHAPHARM. 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
  • oral antidiabetic agents
  • ciclosporin, a medicine used to suppress the immune system
  • NSAIDs (non-steroidal anti-inflammatory drugs), used to treat pain, arthritis and other inflammatory conditions
  • methotrexate, a medicine used to treat certain types of cancers, severe psoriasis or severe rheumatoid arthritis
  • 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 (lignocaine), a local anaesthetic medicine used to numb pain or cause loss of sensation
  • pentoxifylline (oxpentifylline), 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

These medicines may be affected by CIPROFLOXACIN ALPHAPHARM 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 may interfere with CIPROFLOXACIN ALPHAPHARM. These include:

  • 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

You can still take these medicines while you are receiving CIPROFLOXACIN ALPHAPHARM.

However, you must be given CIPROFLOXACIN ALPHAPHARM at least 2 hours before or 2 hours after taking any of these medicines.

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

How CIPROFLOXACIN ALPHAPHARM is given

CIPROFLOXACIN ALPHAPHARM is given as a slow injection into a vein, usually as a drip, over a period of 60 minutes, by a doctor or a nurse.

CIPROFLOXACIN ALPHAPHARM is incompatible with alkaline drugs.

How much to receive

This depends on your condition, and will be decided by your doctor.

The usual adult dose is 200-300 mg twice a day for one to two weeks. Normally your doctor will put you on antibiotic tablets as soon as possible; but for difficult infections longer intravenous therapy may be required.

If you have not been given your next dose, tell the doctor or nurse on duty as soon as possible.

If you are given too much (overdose)

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

While you are receiving CIPROFLOXACIN ALPHAPHARM

Things you must do

If you are about to be started on any new medicine, remind your doctor that you are receiving CIPROFLOXACIN ALPHAPHARM.

Tell any other doctors, dentists, nurses and pharmacists who are treating you that you are receiving CIPROFLOXACIN ALPHAPHARM.

If you are going to have surgery, tell your doctor, surgeon or anaesthetist that you are receiving CIPROFLOXACIN ALPHAPHARM.

The use of CIPROFLOXACIN ALPHAPHARM may affect the results of certain laboratory tests. If you are about to have any tests, tell your doctor that you are receiving this medicine.

Drink plenty of water while you are receiving CIPROFLOXACIN ALPHAPHARM. This helps to stop crystals forming in your urine.

If you become pregnant while you are receiving CIPROFLOXACIN ALPHAPHARM, tell your doctor immediately.

If you develop diarrhoea, tell your doctor, nurse or pharmacist immediately. Do this even if it occurs several weeks after you have stopped receiving CIPROFLOXACIN ALPHAPHARM.

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 first checking with your doctor, nurse or pharmacist.

Tell your doctor immediately if you experience symptoms of depression or self-endangering behaviour. CIPROFLOXACIN ALPHAPHARM should be discontinued immediately.

Tell your doctor immediately if you develop pain, burning, tingling, numbness or weakness in any part of your body. CIPROFLOXACIN ALPHAPHARM should be discontinued immediately.

Things you must not do

Do not receive CIPROFLOXACIN ALPHAPHARM 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 using CIPROFLOXACIN ALPHAPHARM 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.

What to be careful of

Avoid excessive exposure to direct sunlight. Your skin may become more prone to sunburn. If such a reaction occurs, tell your doctor.

Be careful driving or operating machinery until you know how CIPROFLOXACIN ALPHAPHARM affects you. CIPROFLOXACIN ALPHAPHARM may cause dizziness in some patients, especially after the first few doses. Your ability to drive and/or operate machinery may be impaired. If you drink alcohol while using this medicine, dizziness may be worse.

CIPROFLOXACIN ALPHAPHARM may increase the stimulating effect of caffeine.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are receiving CIPROFLOXACIN ALPHAPHARM.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

CIPROFLOXACIN ALPHAPHARM is usually well tolerated.

CIPROFLOXACIN ALPHAPHARM can cause redness, pain, oedema, hypersensitivity and inflammation at the injection site.

Vomiting and rash were common in patients switching from ciprofloxacin infusion to ciprofloxacin tablets.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

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

  • nausea
  • diarrhoea

These are the common side effects of CIPROFLOXACIN ALPHAPHARM. They are usually mild and short-lived.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • severe skin rashes, peeling of the skin and/or mucosal reactions
  • signs of allergy such as rash, swelling of the face, lips, mouth or throat or other parts of the body, shortness of breath, wheezing or difficulty in breathing
  • fainting
  • yellowing of the skin and eyes, also called jaundice
  • severe watery or bloody diarrhoea, even if it occurs several weeks after receiving CIPROFLOXACIN ALPHAPHARM
  • fits (seizures, convulsions)
  • confusion, nightmares, hallucinations and psychotic reaction (even progressing to self-endangering behaviour)
  • fast or irregular heart beats
  • visual disturbances (eye 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

These serious side effects are rare. If you have any of them, you may need urgent medical attention.

In isolated instances, some serious side effects may be long-lasting (> 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 ciprofloxacin. However, it is temporary and staying out of direct sunlight while receiving CIPROFLOXACIN ALPHAPHARM will prevent it 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 in the leg to the heel of the foot) or other tendons have been torn after CIPROFLOXACIN ALPHAPHARM therapy. This may occur even within the first 48 hours of treatment and up to several months after completing treatment with CIPROFLOXACIN ALPHAPHARM. 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 CIPROFLOXACIN ALPHAPHARM, tell your doctor, nurse or pharmacist immediately.

CIPROFLOXACIN ALPHAPHARM may need to be discontinued.

Tell your doctor, pharmacist or nurse if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After receiving CIPROFLOXACIN ALPHAPHARM

When treatment is to be stopped, your doctor may need to alter the dose of other medicines accordingly and monitor your condition.

Each infusion bag of CIPROFLOXACIN ALPHAPHARM is to be used once only. Any unused portion remaining in the bag must be discarded.

Storage

CIPROFLOXACIN ALPHAPHARM will be stored in the pharmacy or on the ward.

The infusion bag is kept in a cool, dry place away from sunlight, where the temperature stays below 25°C.

The infusion bag should not be stored in the refrigerator or freezer.

The infusion bag should be stored in the outer overwrap in order to protect it from light.

If you have any further questions on CIPROFLOXACIN ALPHAPHARM, or are unsure of the information given above, please ask your doctor or nurse, who will be able to assist you.

Product description

What it looks like

CIPROFLOXACIN ALPHAPHARM is a clear, colourless to slightly yellow solution containing ciprofloxacin in the following strengths:

  • 200 mg/100 mL infusion bag
  • 400 mg/200 mL infusion bag

Each carton of CIPROFLOXACIN ALPHAPHARM contains 10 infusion bags.

Ingredients

Active Ingredients:

CIPROFLOXACIN ALPHAPHARM - 200 mg ciprofloxacin /100 mL infusion bag

CIPROFLOXACIN ALPHAPHARM - 400 mg ciprofloxacin /200 mL infusion bag

Inactive ingredients:

  • lactic acid
  • glucose monohydrate
  • water for injections
  • small amounts of hydrochloric acid to adjust the acidity of the solution

CIPROFLOXACIN ALPHAPHARM contains sugars.

Supplier

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

CIPROFLOXACIN ALPHAPHARM 200 mg /100 mL - AUST R 154611

CIPROFLOXACIN ALPHAPHARM - 400 mg /200 mL - AUST R 154612

This leaflet was prepared in January 2020.

ciprofloxacin alphapharm_cmi\Jan20/00

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Ciprofloxacin Alphapharm

Active ingredient

Ciprofloxacin

Schedule

S4

 

1 Name of Medicine

Ciprofloxacin.

6.7 Physicochemical Properties

Ciprofloxacin (a fluoroquinolone) is a synthetic carboxyquinolone derivative with broad spectrum antimicrobial activity for intravenous administration. Ciprofloxacin is a faint to light yellow crystalline powder.
Chemical name: 1-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-7- (1-piperazinyl)-quinoline-3-carboxylic acid. Molecular formula: C17H18FN3O3. Molecular weight: 331.4.

Chemical structure.


CAS number.

85721-33-1.

2 Qualitative and Quantitative Composition

Ciprofloxacin Alphapharm is available as a ciprofloxacin (as lactate) 200 mg/100 mL and 400 mg/200 mL infusion solution.
Each intravenous infusion injection bag contains 200 mg in 100 mL or 400 mg in 200 mL of ciprofloxacin as the active ingredient.

Excipient with known effect.

Glucose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The solution is a clear, colourless to a slightly yellowish solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action (microbiology).

Ciprofloxacin has in vitro and in vivo 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.

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; 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.

Gram positive organisms and Pseudomonas aeruginosa are generally less sensitive to ciprofloxacin than other Gram negative organisms, which results in lower drug efficacy rates.
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 Strep. pneumoniae infection of the lower respiratory tract.
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.
Enterococcus faecium, Ureaplasma urealyticum and Nocardia asteroides are generally resistant. Ciprofloxacin is ineffective against Treponema pallidum.
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 to 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.
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 two to eight 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) 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 either behaves in an indifferent or additive manner. Synergism or antagonism have been observed very rarely.
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.

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

Distribution.

Immediately following a 30 minute intravenous infusion of ciprofloxacin 200 mg, 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 4 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 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 2 hours of a 200 mg intravenous dose, the urine concentration of ciprofloxacin usually exceeds 200 microgram/mL.

Protein binding.

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

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 three to four 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 5 days after dosing.

Factors influencing pharmacokinetics.

Impaired renal function.

In patients with creatinine clearance between 21 and 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.

Impaired hepatic 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.

Elderly patients.

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 (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 (approximately 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 (1 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.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Carcinogenicity studies in mice (oral doses up to 1,090 and 1,455 mg/kg/day in males and females, respectively; 1.4 and 1.8 times the highest recommended human dose of 1,500 mg/day based upon body surface area) and rats (241 and 328 mg/kg/day in males and females, respectively; 3.1 and 4.2 times the highest recommended human dose of 1,500 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.

Mutagenicity.

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Ciprofloxacin Alphapharm is indicated for use in the following.
Use in hospitalised adult patients in whom oral ciprofloxacin is indicated but cannot be administered or where the oral form is inappropriate.
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.
Inhalational anthrax (post-exposure). To reduce the incidence or progression of disease following exposure to aerosolised 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 Strep. pneumoniae.
If anaerobic organisms are suspected of contributing to the infection, use of other suitable drugs should be considered.
Strains of N. gonorrhoeae 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 aetiological agents, additional therapy should be considered.
Consideration should be given to available official guidance on the appropriate use of antibacterial agents.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially persistent adverse reactions involving different body systems that have occurred together in the same patient. These include, but are not limited to, serious adverse reactions involving the nervous system (see Section 4.4 Special Warnings and Precautions for Use, CNS effects, Psychiatric reactions) and musculoskeletal system (see Section 4.4 Special Warnings and Precautions for Use, Tendonitis and tendon rupture).
The use of ciprofloxacin in prepubertal children, except for use in inhalational anthrax (post-exposure), and during pregnancy is not recommended.
Antibiotic associated colitis has been rarely reported with ciprofloxacin, but it should be considered in patients who develop diarrhoea.

General.

Ciprofloxacin intravenous solution should be administered by slow infusion over a period of 60 minutes. Local intravenous 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.

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 Cl. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated.
Drugs that delay peristalsis, e.g. opiates and diphenoxylate with atropine (e.g. Lomotil), may prolong and/or worsen the condition and should not be used.

Myasthenia gravis.

Ciprofloxacin Alphapharm 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 doctor should be consulted.

Tendonitis and tendon rupture.

Tendonitis and tendon rupture (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.

Superinfection.

As with other broad spectrum antimicrobial agents, prolonged use of ciprofloxacin may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.
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 Ps. aeruginosa infections in cystic fibrosis patients following a single course of the drug.

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.

Hypersensitivity.

Serious and occasionally fatal anaphylactoid reactions, some following the first dose, have been reported in patients receiving quinolones (including ciprofloxacin). Some reactions are accompanied by cardiovascular collapse. Appropriate emergency measures for the management of such reactions should be readily available.

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.

Cardiac disorders.

Ciprofloxacin is associated with cases of QT prolongation. 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).

CNS effects.

As with other quinolones, ciprofloxacin may cause central nervous system (CNS) stimulation which may lead to transient tremor, restlessness, light-headedness, 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.

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. tizanidine, 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).

Epileptic patients.

Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower seizure threshold. Intravenous ciprofloxacin should be used with caution in epileptics and 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). Intravenous ciprofloxacin should only be used where the benefits of treatment exceed the risks, since these patients are endangered because of possible CNS side effects. Cases of status epilepticus have been reported. If seizures occur, intravenous ciprofloxacin should be discontinued.

Peripheral neuropathy.

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

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 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.

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)).

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 non-vegetarians 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.

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.

Use in hepatic impairment.

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.

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).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic and haematopoietic, is advisable during prolonged therapy.

Use in the elderly.

Intravenous 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 pre-pubertal children, except for use in inhalational anthrax (post-exposure). Toxicological studies have shown that ciprofloxacin and related drugs (e.g. nalidixic acid, norfloxacin 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 pre-pubertal 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.

Intravenous 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 anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).

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 central nervous system.
Serious and fatal reactions have been reported in patients receiving concurrent ciprofloxacin intravenously 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.

Omeprazole.

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

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.

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 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.

Oral antidiabetic agents.

Hypoglycaemia has been reported when intravenous ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (e.g. glibenclamide, glimepiride), where co-administered, 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 quinolones (gyrase inhibitors) and certain NSAIDs (but not aspirin) 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 intravenous 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 intravenous 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.

Tizanidine.

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

Duloxetine.

In clinical studies, it was demonstrated that concurrent use of duloxetine with strong inhibitors of the CYP450 1A2 isoenzyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration (see Section 4.4 Special Warnings and Precautions for Use).

Ropinirole.

In a clinical study, it was shown that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, resulted in increases in the Cmax and AUC of ropinirole of 60 and 84%, respectively. Although ropinirole treatment was well tolerated, case reports suggest that a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration. 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 (lignocaine) with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine (lignocaine) by 22%. Although lidocaine (lignocaine) 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 (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 (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 fetus 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 fetal 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 in rabbits.
There are, however, no adequate and well controlled studies in pregnant women. Like other drugs in its class, ciprofloxacin causes arthropathy in immature animals.
Intravenous 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 breast milk. Because of the potential for serious adverse reactions in breastfeeding infants from ciprofloxacin, a decision should be made to discontinue breastfeeding or to avoid using the drug, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

Adverse drug reactions (ADRs) based on all clinical studies with ciprofloxacin (oral, parenteral) sorted by CIOMS III categories of frequency are listed below (overall n = 51,721; data lock point: 15 May 2005).
The frequencies of ADRs reported with intravenous ciprofloxacin are summarised below. Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.
The frequencies of ADRs are defined as: common ≥ 1/100 to < 1/10 (≥ 1% to < 10%); uncommon ≥ 1/1000 to < 1/100 (≥ 0.1% to < 1%); rare ≥ 1/10,000 to < 1/1000 (≥ 0.01% to < 0.1%); very rare < 1/10,000 (< 0.01%).

Infections and infestations.

Uncommon: mycotic superinfections. Rare: antibiotic associated colitis (very rarely with possible fatal outcome).

Blood and lymphatic system disorders.

Uncommon: eosinophilia. Rare: leucopenia, anaemia, neutropenia, leucocytosis, thrombocytopenia, thrombocytaemia.
Very rare: haemolytic anaemia, agranulocytosis, pancytopenia (life threatening), bone marrow depression (life threatening).

Immune system disorders.

Rare: allergic reaction, allergic oedema/ angioedema.
Very rare: anaphylactic reaction, anaphylactic shock (life threatening), serum sickness-like reaction.

Metabolism and nutrition disorders.

Uncommon: decreased appetite and food intake.
Rare: hyperglycaemia, hypoglycaemia.

Psychiatric disorders.

Uncommon: psychomotor hyperactivity/ agitation.
Rare: confusion and disorientation, anxiety reaction, abnormal dreams, depression (potentially culminating in self injurious behaviour, such as suicidal ideations/ thoughts and attempted or completed suicide), hallucinations.
Very rare: psychotic reactions (potentially culminating in self injurious behaviour, such as suicidal ideations/ thoughts and attempted or completed suicide).

Nervous system disorders.

Uncommon: headache, dizziness, sleep disorders, taste disorders.
Rare: paraesthesia and dysaesthesia, hypoaesthesia, tremor, seizures (including status epilepticus), vertigo.
Very rare: migraine, disturbed coordination, smell disorders, hyperaesthesia, intracranial hypertension (pseudotumour cerebri).

Eye disorders.

Rare: visual disturbances.
Very rare: visual colour distortions.

Ear and labyrinth disorders.

Rare: tinnitus, hearing loss.
Very rare: hearing impaired.

Cardiac disorders.

Rare: tachycardia.

Vascular disorders.

Rare: vasodilatation, hypotension, syncope. Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders.

Rare: dyspnoea (including asthmatic condition).

Gastrointestinal disorders.

Common: nausea, diarrhoea.
Uncommon: vomiting, gastrointestinal and abdominal pains, dyspepsia, flatulence.
Very rare: pancreatitis.

Hepatobiliary disorders.

Uncommon: increase in transaminases, increased bilirubin.
Rare: hepatic impairment, jaundice, hepatitis (noninfective).
Very rare: liver necrosis (very rarely progressing to life threatening hepatic failure).

Skin and subcutaneous tissue disorders.

Uncommon: rash, pruritus, urticaria.
Rare: photosensitivity reactions, blistering.
Very rare: petechiae, erythema multiforme, erythema nodosum, Stevens-Johnson syndrome (potentially life threatening), toxic epidermal necrolysis (potentially life threatening).

Musculoskeletal, connective tissue and bone disorders.

Uncommon: arthralgia.
Rare: myalgia, arthritis, increased muscle tone and cramping.
Very rare: muscular weakness, tendonitis, tendon rupture (predominantly Achilles tendon), exacerbation of symptoms of myasthenia gravis.

Renal and urinary disorders.

Uncommon: renal impairment.
Rare: renal failure, haematuria, crystalluria, tubulointerstitial nephritis.

General disorders and administration site conditions.

Common: injection and infusion site reactions (only intravenous administration), e.g. phlebitis or thrombophlebitis.
Uncommon: unspecific pain, feeling unwell, fever.
Rare: oedema, sweating (hyperhidrosis).
Very rare: gait disturbance.

Investigations.

Uncommon: increase in blood alkaline phosphatase.
Rare: abnormal prothrombin level, increased amylase.
The incidence of arthropathy (arthralgia, arthritis), mentioned above, is referring to data collected in studies with adults. In children arthropathy is reported to occur commonly.

Post-marketing experience.

ADRs derived from postmarketing reports (status: 31 July 2005) and for which a frequency could not be estimated are as follows.

Blood and lymphatic system disorders.

Pancytopenia (life threatening), bone marrow depression (life threatening).

Immune system disorders.

Serum sickness-like reaction, anaphylactic shock (life threatening).

Nervous system disorders.

Hyperaesthesia, intracranial hypertension, peripheral neuropathy and polyneuropathy.

Cardiac disorders.

QT prolongation, ventricular arrhythmia, torsades de pointes*.

Hepatobiliary disorders.

Liver necrosis (very rarely progressing to life threatening hepatic failure).

Skin and subcutaneous tissue disorders.

Erythema nodosum, Stevens-Johnson syndrome (potentially life threatening), toxic epidermal necrolysis (potentially life threatening), acute generalised exanthematous pustulosis (AGEP).

Musculoskeletal, connective tissue and bone disorders.

Exacerbation of symptoms of myasthenia gravis.

General disorders and administration site conditions.

Gait disturbance.

Investigations.

International normalised ratio (INR) increased (in patients treated with vitamin K antagonists).
* 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).
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.

Common.

Vomiting, transient increase in transaminases, rash.

Uncommon.

Thrombocytopenia, thrombocythemia, confusion and disorientation, hallucinations, paraesthesia and dysaesthesia, seizures, vertigo, visual disturbances, hearing loss, tachycardia, vasodilatation, hypotension, transient hepatic impairment, jaundice, renal failure, oedema.

Rare.

Pancytopenia, bone marrow depression, anaphylactic shock, psychotic reactions, migraine, smell disorders, hearing impaired, vasculitis, pancreatitis, liver necrosis, petechiae, tendon rupture.

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.

4.2 Dose and Method of Administration

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).
Ciprofloxacin Alphapharm 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 defence 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 2 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 (intravenous or oral) for inhalational anthrax (post-exposure) is 60 days.
In certain deep seated infections involving abscess formation, appropriate surgical drainage should be performed in conjunction with antimicrobial therapy.

Impaired renal function.

For creatinine clearance less than or equal to 30 mL/minute/1.73 m2, the maximum daily dose should be 400 mg/day for the intravenous regimen.
When only data for serum creatinine are available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance (see Equation 1).

Administration.

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.
Osmolality of the infusion solution: 300 mOsmol/kg.
If intravenous ciprofloxacin is to be given concomitantly with another medicine, each medicine should be given separately in accordance with the recommended dosage and route of administration for each medicine.

Compatibility and stability.

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 3.9 to 4.5), especially when combined with alkaline solutions. Since ciprofloxacin is slightly light sensitive, the solutions should be protected from light during storage.

Instructions for handling.

At cool temperatures precipitation may occur, which will redissolve at room temperature. It is therefore recommended not to store the infusion solution in a refrigerator.

4.7 Effects on Ability to Drive and Use Machines

Fluoroquinolones including ciprofloxacin may result in an impairment of the patient's ability to drive or operate machinery due to CNS reactions. This is even more applicable when the drug is taken in conjunction with alcohol.

4.9 Overdose

In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Apart from routine emergency measures, it is recommended to monitor renal function, including urinary pH and acidify, if required to prevent crystalluria. 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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

It also contains the excipients lactic acid (as a solubilising agent), glucose monohydrate, hydrochloric acid (for pH adjustment) and water for injections.

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. Store in the outer overwrap in order to protect from light. Do not refrigerate or freeze.
The product is for single use in one patient only. Discard any residue.

6.5 Nature and Contents of Container

Container type: polyolefin bags fitted either with infusion and injection sites, presented in a sealed polyamide/polypropylene laminate overwrap and an opaque adhesive laminate of polyester, foil and polyethylene.
Pack size: 10.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

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

Summary Table of Changes