Gerard Laboratories

Cifloxager 250 mg Film-coated Tablets

Cifloxager 500 mg Film-coated Tablets

Each tablet contains ciprofloxacin hydrochloride equivalent to 250 mg or 500mg ciprofloxacin.

Excipient: Polydextrose (containing not more than 173 or 346 micrograms glucose and sorbital (E420) per tablet).

For a full list of excipients, see section 6.1.

Film-coated tablet.

250mg:White, biconvex, round tablets marked "CF 250" on either side of a score line on one side and "G" on the other.

500mg:White, biconvex, capsule-shaped tablets marked "CF 500" on either side of a score line on one side and "G" on the other.

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Ciprofloxacin is indicated for the treatment of the following infections caused by sensitive bacteria.

Adults:

Respiratory tract infections: e.g. lobar and bronchopneumonia, acute and chronic bronchitis, acute exacerbation of cystic fibrosis, bronchiectasis, emphysema. Ciprofloxacin is not recommended as first line therapy for the treatment of pneumococcal pneumonia (see Special warnings and precautions for use). In circumstances where a physician considers it appropriate to use ciprofloxacin in patients with pneumococcal pneumonia a dose of 750 mg twice daily should provide adequate cover in the majority of cases (see Posology and method of administration). Ciprofloxacin may be used for treating Gram-negative pneumonia.

Urinary tract infections: e.g. uncomplicated and complicated urethritis, cystitis, pyelonephritis, prostatitis, epididymitis.

Gastro-Intestinal Infections: e.g. enteric fever, infective diarrhoea.

Gonorrhoea: including urethral, rectal and pharyngeal gonorrhoea caused by beta-lactamase producing organisms or organisms moderately sensitive to penicillin.

Children and adolescents:

Ciprofloxacin may be used for the 2^nd and 3^rd line treatment of complicated urinary tract infections and pyelonephritis in children and adolescents 1-17 years of age and for the treatment of acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa infection in children and aolescents 5-17 years of age. The use of Cifloxager in paediatric patients with complicated urinary tract infections and pyelonephritis should be restricted to infections caused by organisms, for which Cifloxager is the drug of choice, based on the results of antimicrobial susceptibility testing. Treatment should be initiated by a physician, who is experienced in the treatment of severe infections in children and adolescents and after careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissues (see 4.4. and 5.1.).

Inhalation Anthrax in Adults and in Children: To reduce the incidence or progression of disease following confirmed or suspected exposure to aerosolised Bacillus anthracis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

General Dosage Recommendations: the dosage of ciprofloxacin tablets is determined by the severity and type of infection, the sensitivity of the causative organism(s) and the age, weight and renal function of the patient. Cifloxager Film-Coated Tablets should be swallowed whole with an adequate amount of liquid.

Adults:

The dosage range for adults is 100 – 750 mg twice daily. The following dosages for specific types of infection are recommended.

Table 1: Recommended Adult Dosage

*As the pharmacokinetics of ciprofloxacin remain unchanged in patients with cystic fibrosis, the low bodyweight of these patients should be taken into consideration when determining dosage.

Impaired renal function:

Where creatinine clearance is between 31 and 60 ml/min/1.73m² or where the serum creatinine concentration is between 1.4 and 1.9 mg/100 ml the maximum daily dose should be 1000 mg per day for oral administration.

Where creatinine clearance is equal or is less than 30 ml/min/1.73m² or where the serum creatinine concentration is equal or higher than 2.0 mg/100 ml the maximum daily dose should be 500 mg per day for oral administration.

For patients with impaired renal function undergoing haemodialysis the maximum daily dose should be 500 mg per day. Ciprofloxacin should be administered on dialysis days after dialysis.

For patients with impaired renal function and on continuous ambulatory peritoneal dialysis (CAPD), the dose should be 1 x 500 mg film coated tablet (or 2 x 250mg film coated tablets).

Impaired hepatic function

No adjustment of dosage is necessary. In cases of impaired renal and liver function follow instructions as for renal impairment function.

Elderly: Elderly patients should receive a dose as low as possible depending on the severity of their illness and the creatinine clearance.

Children and adolescents

Cystic fibrosis

Clinical and pharmacokinetic data support the use of ciprofloxacin in paediatric cystic fibrosis patients (aged 5-17 years) with acute pulmonary exacerbation associated with P. aeruginosa infection, at a dose of 20mg/kg orally twice daily (maximum daily dose 1500mg).

Complicated urinary tract infections and pyelonephritis

For complicated urinary tract infections or pyelonephritis the dose is 10 to 20 mg/kg orally every 12 hours with a maximum of 750 mg per dose.

Inhalation anthrax

For the indication of inhalation anthrax, the risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients at a dose of 15 mg/kg orally twice daily (maximum daily dose of 1000 mg) is appropriate.

Dosing in children with impaired renal and/or hepatic function has not been studied.

Duration of Treatment:

The duration of treatment depends upon the severity of infection, clinical response and bacteriological findings.

In acute and uncomplicated cystitis the treatment period is three days with Cifloxager Film-Coated 250 mg Tablets.

In other acute infections the usual treatment period is 5 to 10 days with Cifloxager Film-Coated Tablets. Generally, treatment should be continued for at least three days after the signs and symptoms of infection have disappeared.

Prolonged treatment or use in chronic conditions should only be initiated under consultant direction with regular surveillance.

For acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa infection in paediatric patients (aged 5 – 17 years), the duration of treatment is 10-14 days.

For complicated urinary tract infections and pyelonephritis in paediatric patients the duration of treatment is 10-21 days.

For inhalation anthrax, drug administration should begin as soon as possible after confirmed or suspected exposure and should be continued for 60 days.

Ciprofloxacin is contraindicated in patients who have shown hypersensitivity to ciprofloxacin or any of the excipients, or similar quinolone drugs.

Ciprofloxacin is contraindicated in patients with a history of quinolone-induced tendon disorder.

Concurrent administration of ciprofloxacin and tizanidine is contraindicated since an undesirable increase in serum tizanidine concentrations associated with clinically relevant tizanidine-induced side-effects (hypotension, somnolence) can occur.

In the event of hypersensitivity, which in some instances can occur after the first administration, therapy should be discontinued.

Ciprofloxacin should be used with caution in epileptics and patients with existing central nervous system disorders or a history of convulsive disorders and only if the benefits of treatment are considered to outweigh the risk of possible CNS side-effects. CNS side-effects have been reported after first administration of ciprofloxacin in some patients. Treatment should be discontinued if the side-effects, depression or psychoses lead to self-endangering behaviour (see also Section 4.8).

Crystalluria related to the use of ciprofloxacin has been reported. Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.

Persons with latent or actual defects in glucose-6-phosphate dehydrogenase activity are prone to haemolytic reactions with quinolone antibacterials and so ciprofloxacin should be used with caution in these patients.

Ciprofloxacin is not recommended as first-line therapy for the treatment of pneumococcal pneumonia. Streptococcus pneumoniae is the most frequent pathogen responsible of community acquired pneumonia.

Tendon inflammation and rupture may occur with quinolone antibiotics. Such reactions have been observed particularly in older patients and in those treated concurrently with corticosteroids. At the first sign of pain or inflammation, patients should discontinue ciprofloxacin and rest the affected limbs.

Patients with pre-existent significant renal or hepatic disorders should be carefully monitored to detect any deterioration in function. It should only be administered with great caution to persons with renal insufficiency or severe dehydration.

There is a risk of pseudomembranous colitis with broad-spectrum antibiotics possibly leading to a fatal outcome. It is important to consider this in patients suffering from severe, persistent diarrhoea. With ciprofloxacin this effect has been reported rarely. If pseudomembranous colitis is suspected treatment with ciprofloxacin should be stopped and appropriate treatment given (e.g. oral vancomycin). Drugs that inhibit peristalsis must not be given.

Ciprofloxacin has been shown to produce photosensitivity reactions. Patients taking ciprofloxacin should avoid direct exposure to excessive sunlight or UV-light. Therapy should be discontinued if photosensitisation (i.e., sunburn-like skin reactions) occur.

Laboratory tests may give abnormal findings if performed whilst patients are receiving ciprofloxacin e.g. increased alkaline phosphatase; increases in liver function tests e.g. transaminases and cholestatic jaundice, especially in patients with previous liver damage.

Eradication of infection due to Pseudomonas in persons with cystic fibrosis only occurs in a minority of cases, particularly after repeat courses of treatment with ciprofloxacin. Cyclical or alternating antibacterial therapies may help reduce the number of resistant strains.

Children and adolescents

Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. Safety data from a randomised double blind study on ciprofloxacin use in children (ciprofloxacin: n=335, mean age = 6.3 years; comparators: n=349, mean age = 6.2 years; age range = 1 to 17 years) revealed an incidence of suspected drug related arthropathy (discerned from joint-related clinical signs and symptoms) by Day +42 of 7.2% and 4.6%. Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug related arthropathy over the time was not statistically significant between groups. Treatment should only be initiated after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.

The use of ciprofloxacin for indications other than the treatment of acute pulmonary exacerbation of cystic fibrosis caused by P. aeruginosa infection (children aged 5 – 17 years), complicated urinary tract infections and pyelonephritis (children aged 1 – 17 years) and for the use in inhalational anthrax (post-exposure) has not been evaluated in clinical trials and the clinical experience is limited. The use of ciprofloxacin should follow the official guidance.

The simultaneous administration of ciprofloxacin (oral) and multivalent cationic drugs and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer), sucralfate or antacids and highly buffered drugs (e.g.didanosine tablets), containing magnesium, aluminium or calcium reduce the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1-2 hours before, or at least 4 hours after these preparations. The restriction does not apply to antacids belonging to the class of H2 receptor blockers.

The concurrent administration of dairy products or fortified drinks alone (e.g. milk, yoghurt, calcium fortified orange juice) and ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced. However a normal diet, that will contain small amounts of calcium, does not significantly affect ciprofloxacin absorption.

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

In a crossover study, 10 healthy subjects were given ciprofloxacin 500mg or placebo twice daily for three days, at the end of which a single dose of tizanidine 4mg was given. There was an increase in tizanidine serum concentrations (Cmax increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin compared to placebo. Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect. Tizanidine must not be administered together with ciprofloxacin (refer to Section 4.3).

Increased plasma levels of theophylline have been observed following concurrent administration with ciprofloxacin. It is recommended that the dose of theophylline should be reduced and plasma levels of theophylline monitored. Where monitoring of plasma levels is not possible the use of ciprofloxacin should be avoided in patients receiving theophylline. Particular caution is advised in those patients with convulsive disorders.

Prolongation of bleeding time has been reported during concomitant administration of ciprofloxacin and oral anti-coagulants.

Ciprofloxacin may interfere with estimations of urinary 17-ketosteroids, or vanillylmandelic acid.

Animal data have shown that high doses of quinolones in combination with some non-steroidal anti-inflammatory drugs (e.g. fenbufen but not acetylsalicylic acid) can lead to convulsions.

Transient increases in serum creatinine have been seen following concomitant administration of ciprofloxacin and cyclosporin. Therefore monitoring of serum creatinine levels is advisable (twice a week)

Concomitant use with some phenylpropionic acid derived non-steroidal anti-inflammatory drugs may lead to toxicity possibly because of renal effects.

The simultaneous administration of quinolones and glibenclamide can on occasion potentiate the effect of glibenclamide resulting in hypoglycaemia.

Concomitant use with probenecid reduces the renal clearance of ciprofloxacin, resulting in increased quinolone plasma levels.

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

The use of metoclopramide with ciprofloxacin may accelerate the absorption of ciprofloxacin.

In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme 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.

Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, tacrine, ropinirole, tizanidine, duloxetine). Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations, especially of theophylline, may be necessary.

Phenytoin levels may be altered when Cifloxager is used concomitantly.

Ciprofloxacin should not be used during pregnancy, or in women at risk of pregnancy, nor during lactation.

Reproduction studies performed in mice, rats and rabbits using parenteral and oral administration did not reveal any evidence of teratogenicity, impairment of fertility or impairment of peri-/post-natal development. However, as with other quinolones, ciprofloxacin has been shown to cause arthropathy in immature animals, and therefore its use during pregnancy or in women capable of child-bearing is not recommended. Studies have indicated that ciprofloxacin is secreted in breast milk. Administration to nursing mothers is thus not recommended.

Ciprofloxacin could result in impairment of the patient's ability to drive or operate machinery particularly in conjunction with alcohol.

Adverse drug reactions based on all clinical studies with ciprofloxacin (oral, parenteral) sorted by CIOMS III categories of frequency using MedDRA terminology are listed below. The most frequently reported adverse reactions are nausea, diarrhoea and injection and infusion site reactions (intravenous administration only).

Adverse drug reactions derived from post-marketing reports are included in the column frequency “not known”.

The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children arthropathy is reported to occur more commonly (See also 4.4 Special warning and precautions for use).

Based on the limited information available in two cases of ingestion of over 18g of ciprofloxacin reversible renal toxicity has occurred. Therefore apart from routine emergency measures, it is recommended to monitor renal function, including urinary pH and acidity, if required to prevent crystalluria. Patients must be kept well hydrated and in the case of renal damage resulting in prolonged oliguria, dialysis should be initiated.

Calcium or magnesium antacids may be administered as soon as possible after ingestion of Cifloxager Film-Coated Tablets in order to reduce the absorption of ciprofloxacin.

Serum levels of ciprofloxacin are reduced by dialysis.

Pharmacotherapeutic group: Fluoroquinolone antibacterials,ATC code: J01 MA 02

Mechanism of action

As a fluoroquinolone antibacterial agent, ciprofloxacin acts on the bacterial enzymes DNA-gyrase and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination.

Mechanism of resistance

In vitro investigations have shown that resistance to ciprofloxacin is commonly due to mutations in bacterial topoisomerases and usually develops slowly and gradually ('multiple-step' type). Cross-resistance between fluoroquinolones may occur when the mechanism of resistance is due to mutations in bacterial gyrases. However, single mutations may not result in clinical resistance, but multiple mutations generally do result in clinical resistance to all active substances within the class. Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physiochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. Plasmid mediated resistance encoded by qnr-genes have been reported. Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines do not interfere with the antibacterial activity of ciprofloxacin.

In vitro Susceptibility Data

In accordance to the guidance document CPMP/EWP/558/95 rev 1 EUCAST clinical MIC breakpoints for moxifloxacin are listed together with Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) interpretative criteria for the susceptibility testing of ciprofloxacin where breakpoints differ. CLSI disc breakpoints are also included since the majority of susceptibility testing in Europe is performed by this method.

Table 2: EUCAST clinical MIC breakpoints for ciprofloxacin (excerpt from 2006-01-31 v2.2, www.escmid.org/sites/index_f.aspx?par=2.4)

Clinical and Laboratory Standards Institute™ (CLSI), formerly NCCLS breakpoints are presented in the table below for MIC testing (mg/L) or disc diffusion testing (zone diameter [mm]) using a 5-μg ciprofloxacin disc.

Table 3: Clinical and Laboratory Standards Institute™ (CLSI) MIC, (mg/L) and disc diffusion breakpoints (mm) (M100-S16, 2006):

The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought where the local prevalence of resistance is such that utility of the agent in at least some types of infections is questionable.

Table 4: Groupings of relevant species according to ciprofloxacin susceptibility

Absorption of oral doses of ciprofloxacin tablet formulation occurs rapidly, mainly from the small intestine, the half-life of absorption being 2-15 minutes. Plasma levels are dose–related and peak 0.5-2.0 hours after dosing. The AUC also increases dose proportionately after administration of both single and repeated oral (tablet) and intravenous doses. Plasma levels peak approximately 1.5 – 2.5 hours after dosing and the AUC_0ω is in the range of 5 – 12mg.h/l. The absolute bioavailability is approximately 70-80% and ciprofloxacin is subject to only slight first pass metabolism.

The intake of food at the same time as administration of oral ciprofloxacin has a marginal but clinically not relevant effect on the pharmacokinetic parameters C_max and AUC. No specific recommendations are necessary with regard to time to administration of oral ciprofloxacin relative to food intake.

Distribution of ciprofloxacin within issues is wide and the volume of distribution high, though slightly lower in the elderly. Protein binding is low (between 19 – 40%).

Only 10-20% of a single oral or intravenous dose is eliminated as metabolites (which exhibit lower activity than the parent drug). Four different antimicrobially active metabolites have been reported desethyleneciprofloxacin (M1), sulphociprofloxacin (M2),oxaciprofloxacin (M3) and formylciprofloxacin (M4). M2 and M3 account for one third each of metabolised substance and M1 is found in small amounts (1.3-2.6% of the dose). M4 has been found in very small quantities (<0.1% of the dose). M1-M3 have antimicrobial activity comparable to nalidixic acid and M4 found in the smallest quantity has antimicrobial activity similar to that of norfloxacin.

Elimination of ciprofloxacin and its metabolites occurs rapidly, primarily by the kidney. After single oral and intravenous doses of ciprofloxacin, 55% and 75% respectively are eliminated by the kidney and 39% and 14% in the faeces within 5 days. Renal elimination takes place mainly during the first 12 hours after dosing and renal clearance levels suggest that active secretion by the renal tubules occurs in addition to normal glomerular filtration. Renal clearance is between 0.18-0.3 l/h.kg and total body clearance is between 0.48-0.60 l/h.kg. Approximately 1% of a ciprofloxacin dose is excreted via the biliary route. The elimination kinetics are linear and after repeated dosing at 12 hourly intervals no further accumulation is detected after the distribution equilibrium is attained (at 4.5 half-lives). The elimination half-life of unchanged ciprofloxacin over a period of 24 – 48 hours post dose is 3.1-5.1 hours.

Some studies carried out with ciprofloxacin in severely renally impaired patients (serum creatinine> 265 micromole/l or creatinine clearance <20 ml/minutes) demonstrated either a doubling of the elimination half-life or fluctuations in half-life in comparison with healthy volunteers, whereas other studies showed no significant correlation between elimination half-life and creatinine clearance. However, it is recommended that in severely renally impaired patients, the total daily dose should be reduced by half, although monitoring of drug serum levels provides the most reliable basis for dose adjustment as necessary.

Children and adolescents

The data available to substantiate the pharmacokinetic data in children are limited. In a study in children Cmax and AUC were not age-dependent (above one year of age). No notable increase in Cmax and AUC upon multiple dosing (10 mg/kg three times daily) was observed. In 10 children with severe sepsis, less than 1 year of age Cmax was 6.1 mg/L (range 4.6 – 8.3 mg/L) after a 1-hour intravenous infusion at a dose level of 10 mg/kg; and 7.2 mg/L (range 4.7 – 11.8 mg/L) for children between 1 and 5 years of age. The AUC values were 17.4 mg*h/L (range 11.8 – 32.0 mg*h/L) and 16.5 mg*h/L (range 11.0 – 23.8 mg*h/L) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of paediatric patients with various infections, the predicted mean half-life in children is approx. 4 –5 hours and the bioavailability of the oral suspension ranges from 50 to 80%.

Inhalation anthrax: Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for the recommended doses.

Following extensive oral and intravenous toxicology testing with ciprofloxacin only two findings which may be considered relevant to the use of ciprofloxacin in man were observed. Crystalluria was noted in those species of animals which had normally alkaline urine. Kidney damage without the presence of crystalluria was not observed. This effect is considered a secondary inflammatory foreign-body reaction due to the precipitation of crystalline complex of ciprofloxacin, magnesium and protein in the distal tubule system of the kidneys. This is considered not to be a problem in man because the urine is normally acidic. However to avoid the occurrence of crystalluria, patients should be well hydrated and excessive alkalinity of the urine avoided.

Articular tolerability studies

As reported for other gyrase inhibitors, ciprofloxacin causes damage to the large weight-bearing joints in immature animals. The extent of the cartilage damage varies according to age, species and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) revealed no evidence of cartilage lesions. In a study in young beagle dogs ciprofloxacin caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months. Additionally, because of the potential of arthropathy, the use of ciprofloxacin during pregnancy, in women capable of child bearing and in nursing mothers is not recommended.

Microcrystalline cellulose

Maize starch

Crospovidone

Pregelatinised maize starch

Colloidal anhydrous silica

Magnesium stearate

Coating:

Opadry II White Y-22-7719 consisting of:

Hypromellose

Titanium dioxide

Polydextrose (contains glucose and sorbital (E420)

Triacetin

Macrogol 8000

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVDC/PVC Aluminium Foil blisters of 10 tablets packed in cartons

Cartons contain a total of 10 or 20 tablets

Not all pack sizes may be marketed.

No special requirements.

McDermott Laboratories Ltd

T/A Gerard Laboratories

35-36 Baldoyle Industrial Estate

Grange road,

Dublin 13

PA 577/69/1-2

Date of first authorisation: 04^th February 2005

Date of last authorisation: 30 September 2007

September 2008