Ciprofloxacin hydrochloride Chemical Name: 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydro-quinoline-3- carboxylic acid hydrochloride Structural Formula: Molecular Formula: C17H18FN3O3.HCl.H2O Molecular Weight: 385.8 CAS Registry Number: 86393-32-0.
A pale yellow, crystalline powder, soluble in water, slightly soluble in methanol, very slightly soluble in ethanol, practically insoluble in acetone, in ethyl acetate and in methylene chloride. Ciprofloxacin hydrochloride is a synthetic carboxyquinolone derivative with broad spectrum antimicrobial activity. It is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1- piperazinyl)-3-quinolinecarboxylic acid.
Ciprofloxacin tablets are rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Serum concentrations increase in a dose-proportional manner and were, after multiple doses, as shown below:
| Dose (mg) | Maximum Serum Concentration ( g/mL) | Area Under Curve (AUC) ( g.hr/mL) |
| 250 | 1.4 | 5.4 |
| 500 | 2.6 | 10.6 |
| 750 | 3.4 | 15.0 |
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500 or 750 mg are 0.1, 0.2 and 0.4 ug/mL respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. During the first 2 hours after an oral dose of 250 mg, the urine concentration of ciprofloxacin usually exceeds 200 ug/mL. Eight to 12 hours after the same dose, urine levels are approximately 30 ug/mL. Urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin is approximately 18 L/h which exceeds the normal glomerular filtration rate of 7.2 L/h. Thus, active tubular secretion would seem to play a significant role in its elimination. Although bile concentrations of ciprofloxacin are 3 to 4 times higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile. Approximately 20 to 35% of an oral dose is recovered from the faeces within 5 days after dosing. Ciprofloxacin is also metabolised. Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have less antimicrobial activity than unchanged ciprofloxacin. Co-administration of ciprofloxacin with food appears to lower peak serum levels and delay the absorption of ciprofloxacin, resulting in peak concentrations closer to 2 hours after dosing rather than 1 hour. The overall absorption, however, is not substantially affected. Absorption also appears to be greatly reduced by prior administration of antacids. In patients with creatinine clearance between 21 to 40 mL/min, the half-life of ciprofloxacin is only slightly prolonged. Dosage adjustments are usually not required in such cases. However, in patients with severe renal impairment, with creatinine clearance less than 20 mL/min, the half life of ciprofloxacin is nearly doubled and dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION). After oral dosing ciprofloxacin is widely distributed throughout the body. The binding of ciprofloxacin to serum proteins is 20 to 40%.
Ciprofloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive organisms. The bactericidal action of ciprofloxacin appears to result from interference with the enzyme, DNA gyrase. Ciprofloxacin is usually active against the following organisms in vitro.
Gram-Negative
Escherichia coli; Klebsiella species (including Klebsiella pneumoniae and Klebsiella oxytoca); Enterobacter species; Citrobacter species; Salmonella species; Shigella species; Proteus mirabilis; Proteus vulgaris; Providencia stuartii; Providencia rettgeri (formerly Proteus rettgeri); Morganella morganii (formerly Proteus morganii); Serratia species * (including Serratia marcescens); Pseudomonas aeruginosa; Pseudomonas fluorescens; Campylobacter species; Haemophilus influenzae; Moraxella (Branhamella) catarrhalis.
Gram-Positive *
Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains); coagulase negative Staphylococcus species (including Staphylococcus epidermidis); Streptococcus pyogenes (group A); Streptococcus pneumoniae; Enterococcus faecalis. *Note:
Gram-positive organisms are generally less sensitive to ciprofloxacin than Gram-negative organisms.
Most strains of Streptococci are only moderately susceptible to ciprofloxacin. Clinical studies have shown the drug to be effective for urinary tract infections caused by Enterococcus faecalis; however failures and reinfections have been observed with prostatitis. Although bronchial infections caused by Streptococcus pneumoniae and skin infections caused by Streptococcus pyogenes have been shown to respond to ciprofloxacin, it is not the drug of first choice in such infections, particularly Streptococcus pneumoniae infection of the lower respiratory tract.
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 for ciprofloxacin or not. Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker (see PHARMACOLOGY). Ciprofloxacin is less active when tested at acidic pH and its antibacterial activity may be reduced by up to 100-fold in acidic urine. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) is generally 2-8 times the MIC. Resistance to ciprofloxacin in vitro develops slowly (multiple-step mutation). Rapid one-step development of resistance has not been observed. However, in practice resistance to ciprofloxacin may develop during the course of a treatment, particularly in a significant proportion of Pseudomonas aeruginosa infections, especially in patients with cystic fibrosis, and in Staphylococcus aureus infections. Ciprofloxacin does not exhibit cross resistance with non-quinolone antibacterial agents such as beta- lactams and aminoglycosides. However, organisms which are resistant to other quinolone agents (e.g. nalidixic acid, cinoxacin, etc) are usually less sensitive to ciprofloxacin.
In vitro
studies have shown that when ciprofloxacin is combined with other antimicrobial agents, particularly beta-lactams, the combination behaves either in an indifferent or additive manner. Synergism or antagonism have, however, been observed rarely.
Appropriate culture and susceptibility tests should be performed before treatment in order to determine organism susceptibility to ciprofloxacin and after treatment as warranted by the clinical condition. Therapy with Ciproxin may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.
Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be 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.
Ciprofloxacin is indicated for the treatment of infections caused by susceptible organisms in the conditions listed below:
Urinary tract infections
Gonorrhoeal urethritis and cervicitis
Gastroenteritis
Bronchial Infections
Skin and skin structure infections
Bone and joint infections
Chronic bacterial prostatitis of mild to moderate severity Note:
Typhoid and Paratyphoid infections and infections due to multi-resistant Staphylococcus aureus
are excluded from the above due to insufficient data. Because Gram-positive organisms are generally less sensitive to ciprofloxacin, it may not be the drug of choice in cases with Gram-positive infections, such as pneumonia due to Streptococcus pneumoniae. Chronic bacterial prostatitis should be demonstrated by microbiological evidence localising infection to the prostate. Strains of Neisseria gonorrhoea resistant to ciprofloxacin have been reported in Australia. Appropriate culture and susceptibility tests should be performed before treatment in order to determine organism susceptibility to ciprofloxacin and after treatment as warranted by the clinical condition. Therapy with Ciprofloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued. Ciprofloxacin is suitable to treat mixed infections caused by susceptible strains of both Gram-negative and Gram-positive aerobic bacteria. If anaerobic organisms are suspected as accompanying aetiologic agents, additional therapy should be considered.
A history of hypersensitivity to ciprofloxacin, any of the excipients as listed under "Description", or other quinolones, including nalidixic acid
Concurrent administration of ciprofloxacin and tizanidine, since an undesirable increase in serum tizanidine concentrations associated with clinically relevant tizanidine-induced side effects (hypotension, somnolence, drowsiness) can occur.
Antibiotic-associated colitis has been rarely reported with ciprofloxacin, but it should be considered in patients who develop diarrhoea. Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including ciprofloxacin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy such as oral antibacterial agents effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil), may prolong and/or worsen the condition and should not be used.
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. Ciprofloxacin should be used with caution in patients with a history of tendon disorders related to quinolone treatment. Therapy should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Care should be taken to keep the affected extremity at rest and avoid any inappropriate physical exercise due to the increased risk of tendon rupture.
Ciprofloxacin is associated with cases of QT prolongation (see ADVERSE EFFECTS). In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Precaution should be taken when using ciprofloxacin with concomitant drugs that can result in prolongation with the QT interval (e.g. class IA or III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g. known QT prolongation, uncorrected hypokalemia).
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.
Streptococcus pneumoniae
infections
Ciprofloxacin is not recommended for treatment of pneumococcal infections due to inadequate efficacy against Streptococcus pneumoniae.
Pseudomonas aeruginosa
Infections in Cystic Fibrosis
Although clinical improvement has been observed in patients with respiratory exacerbation of cystic fibrosis associated with Pseudomonas aeruginosa, bacterial eradication is usually not achieved. Resistance to ciprofloxacin has been shown to develop in a significant proportion of Pseudomonas aeruginosa infections in cystic fibrosis patients following a single course of the drug.
In some instances, hypersensitivity and allergic reactions may occur following a single dose, a physician should be informed immediately. Serious, and occasionally fatal, anaphylactoid reactions, some following the first dose, have been reported in patients receiving quinolones (including ciprofloxacin). In these cases ciprofloxacin should be discontinued and appropriate medical treatment given.
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.
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. Ciprofloxacin should be used with caution in patients with CNS disorders, such as severe cerebral arteriosclerosis or epilepsy. In some instances, the CNS reactions occurred after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to self-endangering behaviour.
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.
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.
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. Ciprofloxacin should be used with caution in epileptics and in patients who have suffered from previous CNS disorders (e.g. lowered convulsion threshold, previous history of convulsion, reduced cerebral blood flow, altered brain structure or stroke). Ciprofloxacin should only be used where the benefits of treatment exceed the risks, since these patients are endangered because of possible central-nervous side effects.
Alteration of the dosage regimen is necessary for patients with impairment of renal function (see DOSAGE AND ADMINISTRATION).
There can be a temporary increase in transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with previous liver damage.
Ciprofloxacin is known to be a moderate inhibitor of the CYP 1A2 enzymes. Care should be taken when other drugs are administered concomitantly which are metabolized via the same enzymatic pathway (e.g. theophylline, methylxantines, caffeine, duloxetine, clozapine). Increased plasma concentrations associated with drug specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin. (See also Interaction With Other Medicines)
Reproduction studies have been performed in rats and mice at doses up to 100 mg/kg/day (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and intravenous doses of up to 30 mg/kg and have revealed no evidence of impaired fertility or harm to the foetus due to ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally, 0.4 and 1.2 times the maximum daily human dose based upon body surface area, respectively) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, intra-uterine 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. Ciproxin 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).
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 fetus 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.
Ciprofloxacin is not recommended for use in pre-pubertal children. Toxicological studies have shown that ciprofloxacin and related drugs such as nalidixic acid and cinoxacin, can produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to paediatric patients are limited. The safety and effectiveness of ciprofloxacin in pre-pubertal children except for use in inhalational anthrax (post-exposure) have not been established.
Ciprofloxacin should be used with caution in the elderly after taking into account the severity of the illness and the creatinine clearance.
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.
Ciprofloxacin was mutagenic in the mouse lymphoma assay and the rat primary hepatocyte culture/DNA repair assay in vitro, but not in other mammalian systems in vitro or in microbial systems. In a small study on the chromosomal effects of ciprofloxacin on white blood cells, the drug did not exhibit any cytogenetic effect.
Carcinogenicity 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/m 2), 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.
Even when taken as prescribed, this drug can alter patients' responsiveness, impairing the ability to drive or operate machinery. This is even more applicable when the drug is taken in conjunction with alcohol.
Class IA or III antiarrhythmics
Precaution should be taken when using ciprofloxacin together with class IA or III antiarrhythmics 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 and prolongation of its elimination half-life. This can lead to theophylline-induced side effects; in very rare cases these side effects can be life threatening or fatal. If concomitant use cannot be avoided, the plasma levels of theophylline should be monitored and dosage adjustments made appropriately.
Omeprazole
Concomitant administration of ciprofloxacin and omeprazole results in a slight reduction of Cmax and area under the curve (AUC) of ciprofloxacin.
Probenecid
Co-administration of probenecid with ciprofloxacin results in a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its AUC, without altering the peak concentration, time to peak and half- life of elimination.
Caffeine
Quinolones have also been shown to interfere with the metabolism of caffeine. It may reduce the clearance of caffeine and prolong its plasma half-life. Patients are advised that ciprofloxacin may enhance the effects of caffeine.
Anticoagulants
Quinolones, including ciprofloxacin, have been reported to enhance the effects of oral anticoagulants, warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalised ratio) is difficult to assess.
Cyclosporin
Some quinolones, including ciprofloxacin, have been associated with transient elevations of serum creatinine in patients receiving cyclosporin concomitantly. Therefore, it is frequently (twice a week) necessary to control the serum creatinine concentrations in these patients.
Other xanthine derivatives
On concurrent administration of Ciproxin and caffeine or pentoxifylline (oxpentifylline) containing products, raised serum concentrations of these xanthine derivatives were reported.
Metoclopramide
Metoclopramide accelerates the absorption of ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.
Glibenclamide
In particular cases, concurrent administration of ciprofloxacin and glibenclamide can intensify the action of glibenclamide (hypoglycaemia).
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Animal studies have shown that the combination of very high doses of quinolones (gyrase inhibitors) and certain non-steroidal 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.
Other
Iron, sucralfate or highly buffered drugs (e.g. antiretrovirals), polymeric phosphate binders (e.g. sevelamer) and antacids containing magnesium, aluminium or calcium interfere with the absorption of ciprofloxacin; concurrent administration of these agents with ciprofloxacin should be avoided.
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 CONTRAINDICATIONS).
Duloxetine
In clinical studies, it was demonstrated that concurrent use of duloxetine with strong inhibitors of the CYP450 1A2 isoenzyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.
Ropinirole
In a clinical study it was shown that concomitant use of ropinirole with ciprofloxacin, a medium inhibitor of the CYP450 1A2 isozyme, resulted in increases in the Cmax and AUC of ropinirole of 60 and 84%, respectively. Although ropinirole treatment was well tolerated, case reports suggest that a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration. Ropinirole-related side effects should be monitored during and shortly after co-administration with Ciproxin; dose adjustment is recommended if necessary.
Lidocaine
It was demonstrated in healthy subjects that concomitant use of lidocaine with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.
Clozapine
Following concomitant administration of 250 mg Ciproxin 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 Ciproxin 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 Ciproxin. Therefore, caution should be used prescribing Ciproxin concomitantly with sildenafil taking into consideration the risks and the benefits.
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). Common:greater than or equal to 1% to < 10%; uncommon:greater than or equal to 0.1% to < 1%; rare:greater than or equal to 0.01% to < 0.1%; very rare:< 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, thrombocythaemia. 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:anorexia. Rare:hyperglycaemia.
Psychiatric disorders.
Uncommon:psychomotor hyperactivity/ agitation. Rare:confusion and disorientation, anxiety reaction, abnormal dreams, depression, hallucinations. Very rare:psychotic reactions.
Nervous system disorders.
Uncommon:headache, dizziness, sleep disorders, taste disorders. Rare:paraesthesia and dysaesthesia, hypoaesthesia, tremor, seizures, vertigo. Very rare:migraine, disturbed coordination, smell disorders, hyperesthesia, intracranial hypertension.
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.
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, unspecific blistering. Very rare:petechiae, erythema multiforme minor, 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).
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). Uncommon:unspecific pain, feeling unwell, fever. Rare:oedema, sweating (hyperhidrosis).
Investigations.
Uncommon:increase in blood alkaline phosphatase. Rare:prothrombin level abnormal, increased amylase.
Adverse drug reactions derived from postmarketing reports (status: 31 July 2005).
Blood and lymphatic system disorders.
Very rare:pancytopenia (life threatening), bone marrow depression (life threatening).
Immune system disorders.
Very rare:serum sickness-like reaction, anaphylactic shock (life threatening).
Nervous system disorders.
Very rare:hyperaesthesia, intracranial hypertension.
Cardiac Disorders. (Frequency unable to be estimated).
QT prolongation, ventricular arrhythmia, Torsades de pointes *
Hepatobiliary disorders.
Very rare:liver necrosis (very rarely progressing to life threatening hepatic failure).
Skin and subcutaneous tissue disorders.
Very rare:erythema nodosum, Stevens-Johnson syndrome (potentially life threatening), toxic epidermal necrolysis (potentially life threatening).
Musculoskeletal, connective tissue and bone disorders.
Very rare:exacerbation of symptoms of myasthenia gravis.
General disorders and administration site conditions.
Very rare:gait disturbance.
* These events were reported during the postmarketing period and were observed predominantly among patients with further risk factors for QT prolongation (see PRECAUTIONS). 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, thrombocythaemia, 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.
Urinary Tract Infections: The usual adult dosage is 250 mg every 12 hours. For patients with complicated infections caused by organisms not highly susceptible, such as Enterococcus faecalis, 500 mg may be administered every 12 hours.
Bronchial Infections, Skin and Skin Structure Infections: The usual dose is 500 mg every 12 hours. For more severe or complicated infections, a dosage of 750 mg may be given every 12 hours.
Bone and Joint Infections
: 750 mg every 12 hours.
Gastroenteritis (Infectious Diarrhoea)
: 500 mg every 12 hours.
Acute, Uncomplicated Gonorrhoeal Urethritis
: A single dose of 250 mg.
Chronic Bacterial Prostatitis
: 250 to 500 mg every 12 hours.
The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient's host- defence mechanisms, and the status of renal function. Because Gram-positive organisms are generally less sensitive than Gram-negative organisms, the use of higher doses should be considered in patients with Gram-positive infections. In such cases 8 hourly administration of 500 mg ciprofloxacin may be preferable.
The duration of treatment depends upon the severity of infection. Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration is 7 to 14 days, however for severe and complicated infections more prolonged therapy may be required. Bone and joint infections may require treatment for 4 to 6 weeks or longer. Gastrointestinal infections (infectious diarrhoea) need treatment for only 5 days. Chronic bacterial prostatitis should be treated for 14 to 28 days. In certain deep-seated infections involving abscess formation, appropriate surgical drainage should be performed in conjunction with antimicrobial therapy.
Dosage adjustments for patients with creatinine clearance between 31-60 mL/min/1.73m2 the maximum daily dose should be 1000 mg/day for oral administration. For creatinine clearance equal or less than 30 mL/min/1.73m2, the maximum daily dose should be 500 mg/day for oral administration. When only data for serum creatinine are available, the following formula (Cockroft's equation) may be used to estimate creatinine clearance.
| Men : Creatinine clearance = (mL/min) | Weight (kg) x (140 - age) x 0.0885 72 x serum creatinine (mmol/L) |
| Women : | 0.85 x the value calculated for men. |
In the event of acute, excessive oral overdosage, reversible renal toxicity has been reported in some cases.
Apart from routine emergency measures, it is recommended to monitor renal function and administer magnesium- or calcium- containing antacids, which reduce the absorption of ciprofloxacin. Only a small amount of ciprofloxacin (<10%) is removed from the body after haemodialysis or peritoneal dialysis.
white to off-white, round, film-coated tablets debossed with "250" on one side and plain on the other.
Blister packs of 14 tablets. Aust R Number: 135911
white to off-white, caplet shaped, film-coated tablets debossed with "500" on one side and plain on the other side.
Blister packs of 14 tablets. Aust R Number: 135912
white to off-white, caplet shaped, film-coated tablets debossed with "750" on one side and plain on the other side.
Blister packs of 14 tablets. Aust R Number: 135913
are intended for oral administration. Each tablet contains 250mg, 500mg or 750mg of ciprofloxacin.
In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, maize starch, magnesium stearate purified talc, colloidal anhydrous silica, sodium starch glycollate, purified water, and Opadry OY-S-58910 white. Store below 25degC.
Apotex Pty Ltd 16 Giffnock Avenue Macquarie Park, NSW 2113 Australia GenRx is a registered trade mark of Apotex Pty Ltd.
S4: Prescription Only Medicine.
16 May 2007