Document: spc-doc_PL 21880-0033 change

• spc-doc_PL 00289-0495
• spc-doc_PL 00289-1436
• spc-doc_PL 04569-0514
• spc-doc_PL 08553-0175
• spc-doc_PL 11311-0414
• spc-doc_PL 20075-0050
• spc-doc_PL 20532-0013
• spc-doc_PL 21880-0033
• spc-doc_PL 40378-0056
• spc-doc_PL 40378-0164

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ciprofloxacin 750 mg, film coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 873.0mg ciprofloxacin hydrochloride equivalent to 750mg Ciprofloxacin (INN).

For excipients see 6.1

3 PHARMACEUTICAL FORM

Film-coated tablets

Off-white capsule shaped biconvex film coated tablets with CP/750 on one side and k on the other

4.1 Therapeutic Indications

Ciprofloxacin is indicated for the treatment of the following infections caused by sensitive bacteria. Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy.

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

Adults:

•Lower respiratory tract infections due to Gram-negative bacteria

-    exacerbations of chronic obstructive pulmonary disease

-    broncho-pulmonary infections in cystic fibrosis or in bronchiectasis

-    pneumonia

•Chronic suppurative otitis media

•Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria

•Urinary tract infections

•Genital tract infections

-    gonococcal uretritis and cervicitis due to susceptible Neisseria

gonorrhoeae

-    epididymo-orchitis including cases due to susceptible Neisseria

gonorrhoeae

-    pelvic inflammatory disease including cases due to susceptible

Neisseria gonorrhoeae

•    Infections of the gastro-intestinal tract (e.g. travellers’ diarrhoea)

•    Intra-abdominal infections

•    Infections of the skin and soft tissue caused by Gram-negative bacteria

•    Malignant external otitis

•    Infections of the bones and joints

•    Prophylaxis of invasive infections due to Neisseria meningitidis • Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Ciprofloxacin may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Children and adolescents

•    Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa

•    Complicated urinary tract infections and pyelonephritis

•    Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.

Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents (see sections 4.4 and 5.1).

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

4.2 Posology and Method of Administration

General dosage recommendations: The dosage of Ciprofloxacin film coated 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. Ciprofloxacin film coated tablets should be swallowed whole with an adequate amount of liquid.

If Ciprofloxacin film coated Tablets are taken on an empty stomach, the active substance is absorbed more rapidly. In this case, the tablets should not be taken concurrently with dairy products or with mineral fortified drinks alone (e.g. milk, yogurt, calcium fortified orange juice). However, a normal diet that will contain small amounts of calcium, does not significantly affect ciprofloxacin absorption.

In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous ciprofloxacin until a switch to oral administration is possible.

Treatment of infections due to certain bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter or Staphylococci) may require higher ciprofloxacin doses and coadministration with other appropriate antibacterial agents.

Treatment of some infections (e.g. pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients and infections of bones and joints) may require co-administration with other appropriate antibacterial agents depending on the pathogens involved.

Adults

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

Table 1 : Recommended Adult Dosage

Indications		Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Infections of the lower respiratory tract		500 mg twice daily to 750 mg twice daily	7 to 14 days
Infections of the upper respiratory tract	Acute exacerbation of chronic sinusitis	500 mg twice daily to 750 mg twice daily	7 to 14 days
	Chronic suppurative otitis media	500 mg twice daily to 750 mg twice daily	7 to 14 days
	Malignant external otitis	750 mg twice daily	28 days up to 3 months

Indications		Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Urinary tract infections (see section 4.4)	Uncomplicated cystitis	250 mg twice daily to 500 mg twice daily	3 days
		In pre-menopausal women, 500 mg single dose may be used
	Complicated cystitis, Uncomplicated pyelonephritis	500 mg twice daily	7 days
	Complicated pyelonephritis	500 mg twice daily to 750 mg twice daily	at least 10 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses)
	Prostatitis	500 mg twice daily to 750 mg twice daily	2 to 4 weeks (acute) to 4 to 6 weeks (chronic)
Genital tract infections	Gonococcal urethritis and cervicitis	500 mg as a single dose	1 day (single dose)
	Epididymo-orchitis and pelvic inflammatory diseases	500 mg twice daily to 750 mg twice daily	at least 14 days
Infections of the gastro-intestinal tract and intraabdominal infections	Diarrhoea caused by bacterial pathogens including Shigella spp. other than Shigella dysenteriae type 1 and empirical treatment of severe travellers' diarrhoea	500 mg twice daily	1 day
	Diarrhoea caused by Shigella dysenteriae type 1	500 mg twice daily	5 days
	Diarrhoea caused by Vibrio cholerae	500 mg twice daily	3 days
	Typhoid fever	500 mg twice daily	7 days
	Intra-abdominal infections due to Gram-negative bacteria	500 mg twice daily to 750 mg twice daily	5 to 14 days
Infections of the skin and soft tissue		500 mg twice daily to 750 mg twice daily	7 to 14 days
Bone and joint infections		500 mg twice daily to 750 mg twice daily	max. of 3 months
Neutropenic patients with fever suspected to be due to a bacterial infection. Ciprofloxacin should be co-administered with appropriate antibacterial agent(s) in accordance to official guidance.		500 mg twice daily to 750 mg twice daily	Therapy should be continued over the entire period of neutropenia
Prophylaxis of invasive infections due to Neisseria meningitidis		500 mg as a single dose	1 day (single dose)

Indications	Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure.	500 mg twice daily	60 days from the confirmation of Bacillus anthracis exposure

Impaired Renal Function

Recommended starting and maintenance doses for patients with impaired renal function:

Creatinine Clearance [mL/min/1.73 m2]	Serum Creatinine [pmol/L]	Oral Dose [mg]
> 60	< 124	See Usual Dosage.
30-60	124 to 168	250-500 mg every 12 h
< 30	> 169	250-500 mg every 24 h
Patients on haemodialysis	> 169	250-500 mg every 24 h (after dialysis)
Patients on peritoneal dialysis	> 169	250-500 mg every 24 h

Impaired Hepatic Function No adjustment of dosage is necessary. Geriatric patients

Geriatric patients should receive a dose selected according to the severity of the infection and the patient's creatinine clearance

Adolescents and children

Indications	Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Cystic fibrosis	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	10 to 14 days
Complicated urinary tract	10 mg/kg body weight twice daily	10 to 21 days

infections and pyelonephritis	to 20 mg/kg body weight twice daily with a maximum of 750 mg per dose.
Inhalation anthrax postexposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure.	10 mg/kg body weight twice daily to 15 mg/kg body weight twice daily with a maximum of 500 mg per dose.	60 days from the confirmation of Bacillus anthracis exposure
Other severe infections	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	According to the type of infections

As with other drugs in its class, ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. Although analysis of available safety data from ciprofloxacin use in patients less than 18 years of age, the majority of whom had cystic fibrosis, did not disclose any evidence of drug-related cartilage or articular damage, its use in the paediatric population is generally not recommended.

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.

4.3 Contraindications

Ciprofloxacin is contra-indicated in patients who have shown hypersensitivity to ciprofloxacin or any of its excipients, or other quinolone anti-infectives.

Except in cases of exacerbations of cystic fibrosis associated with P. aeruginosa (in patients aged 5-17 years), and inhalation anthrax, ciprofloxacin is contra-indicated in children and growing adolescents unless the benefits of treatment are considered to outweigh the risks.

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.

4.4 Special warnings and precautions for use

Severe infections and mixed infections with Gram-positive and anaerobic pathogens

Ciprofloxacin monotherapy is not suited for treatment of severe infections and infections that might be due to Gram-positive or anaerobic pathogens. In such infections ciprofloxacin must be co-administered with other appropriate antibacterial agents.

Streptococcal Infections (including Streptococcus _pneumoniae)

Ciprofloxacin is not recommended for the treatment of streptococcal infections due to inadequate efficacy.

Genital tract infections

Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Ciprofloxacin should be coadministered with another appropriate antibacterial agent unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Urinary tract infections

Resistance to fluoroquinolones of Escherichia coli - the most common pathogen involved in urinary tract infections - varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in Escherichia coli to fluoroquinolones. The single dose of ciprofloxacin is expected to be associated with lower efficacy than with the longer treatment duration. This is all the more to be taken into account as regards the increasing resistance level of Escherichia coli to quinolones.

Intra-abdominal infections

There are limited data on the efficacy of ciprofloxacin in the treatment of postsurgical intra-abdominal infections.

Travellers' diarrhoea

The choice of ciprofloxacin should take into account information on resistance to ciprofloxacin in relevant pathogens in the countries visited.

Infections of the bones and _ joints

Ciprofloxacin should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.

Inhalational anthrax

Use in humans is based on in-vitro susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.

Children and adolescents

The use of ciprofloxacin in children and adolescents should follow available official guidance. Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in 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 cases over time was not statistically significant between groups.

Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.

Broncho-pulmonary infections in cystic fibrosis

Clinical trials have included children and adolescents aged 5 to 17 years. More limited experience is available in treating children between 1 and 5 years of age.

Complicated urinary tract infections and pyelonephritis

Ciprofloxacin treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation.

Clinical trials have included children and adolescents aged 1 to 17 years.

Other specific severe infections

Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify a ciprofloxacin use.

The use of ciprofloxacin for specific severe infections other than those mentioned above has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.

Hypersensitivity

Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose (see section 4.8) and may be life-threatening. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required.

Musculoskeletal System

Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances,

after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.

Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, as soon as the first 48 hours of treatment. Inflammation and ruptures of tendon may occur even up to several months after discontinuation of ciprofloxacin therapy. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).

At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest.

Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).

Photosensitivity

Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment (see section 4.8).

Central Nervous System

Ciprofloxacin like other Quinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8).

Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to self-endangering behavior, suicidal ideations/thoughts culminating in attempted suicide or completed suicide.. In the occurrence of such cases, ciprofloxacin should be discontinued.

Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).

Cardiac disorders

Since ciprofloxacin is associated with cases of QT prolongation (see section 4.8), caution should be exercised when treating patients at risk for torsades de pointes arrhythmia. For Example:

• congenital long QT syndrome

•    concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

•    uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)

•    cardiac disease ( e.g. heart failure, myocardial infarction, bradycardia)

Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including Ciprofloxacin tablets, in these populations.

Gastrointestinal System

The occurrence of severe and persistent diarrhoea during or after treatment (including several weeks after treatment) may indicate an antibiotic-associated colitis (life-threatening with possible fatal outcome), requiring immediate treatment (see section 4.8). In such cases, ciprofloxacin should immediately be discontinued, and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this situation.

Renal and urinary system

Crystalluria related to the use of ciprofloxacin has been reported (see section 4.8). Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.

Impaired renal function

Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment is needed in patients with impaired renal function as described in section 4.2 to avoid an increase in adverse drug reactions due to accumulation of ciprofloxacin.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (see section 4.8). 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.

Glucose-6-phosphate dehydrogenase deficiency

Haemolytic reactions have been reported with ciprofloxacin in patients with glucose-6-phosphate dehydrogenase deficiency. Ciprofloxacin should be avoided in these patients unless the potential benefit is considered to outweigh the possible risk. In this case, potential occurrence of haemolysis should be monitored.

Resistance

During or following a course of treatment with ciprofloxacin bacteria that demonstrate resistance to ciprofloxacin may be isolated, with or without a clinically apparent

superinfection. There may be a particular risk of selecting for ciprofloxacin-resistant bacteria during extended durations of treatment and when treating nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450

Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine). Co-administration of ciprofloxacin and tizanidine is contra-indicated. Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary (see section 4.5).

Methotrexate

The concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).

Interaction with tests

The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.

Contains lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interactions with Other Medicaments and Other Forms of Interaction

Effects of other products on ciprofloxacin:

Drugs known to _prolong QT interval

Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).

Chelation Complex Formation

The simultaneous administration of ciprofloxacin (oral) and multivalent cation-containing 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 reduces the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1 to 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.

Food and Dairy Products

Dietary calcium as part of a meal does not significantly affect absorption. However, the concurrent administration of dairy products or mineral-fortified drinks alone (e.g. milk, yoghurt, calcium-fortified orange juice) with ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced.

Probenecid

Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.

Omeprazole

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

Effects of ciprofloxacin on other medicinal products:

Tizanidine

Tizanidine must not be administered together with ciprofloxacin (see section 4.3). In a clinical study with healthy subjects, there was an increase in serum tizanidine concentration (C_max increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Increased serum tizanidine concentration is associated with a potentiated hypotensive and sedative effect.

Methotrexate

Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and increased risk of methotrexate-associated toxic reactions. The concomitant use is not recommended (see section 4.4).

Theophylline

Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration. This can lead to theophylline-induced side effects that may rarely be life threatening or fatal. During the combination, serum theophylline concentrations should be checked and the theophylline dose reduced as necessary (see section 4.4).

Other xanthine derivatives

On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.

Phenytoin

Simultaneous administration of ciprofloxacin and phenytoin may result in increased or reduced serum levels of phenytoin such that monitoring of drug levels is recommended.

Cyclosporin

A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and cyclosporin containing medicinal products were administered simultaneously. Therefore, it is frequently (twice a week) necessary to control the serum creatinine concentrations in these patients.

Vitamin K antagonists

Simultaneous administration of ciprofloxacin with a vitamin K antagonist may augment its anti-coagulant effects. 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. The INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with a vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).

Glibenclamide

In particular cases, concurrent administration of ciprofloxacin and glibenclamide containing medicinal products can intensify the action of glibenclamide (hypoglycaemia).

Duloxetine

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 (see section 4.4).

Oral anticoagulants

Simultaneous administration of ciprofloxacin with warfarin may augment its anticoagulant effects. There have been many reports of increases in oral anticoagulant activity in patients receiving antibacterial agents, including fluoroquinolones. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the fluoroquinolone to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant agent.

Ropinirole

It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of C_max and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related side effects and dose adjustment as appropriate is recommended during and shortly after co-administration with ciprofloxacin (see section 4.4).

Lidocaine

It was demonstrated in healthy subjects that concomitant use of lidocaine containing medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.

Clozapine

Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised (see section 4.4).

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. Therefore, caution should be used prescribing ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.

4.6 Fertility, pregnancy and lactation

Pregnancy

The data that are available on administration of ciprofloxacin to pregnant women indicates no malformative or feto/neonatal toxicity of ciprofloxacin. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed, thus, it cannot be excluded

that the drug could cause damage to articular cartilage in the human immature organism / foetus (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during pregnancy.Lactation

Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.

4.7    Effects on ability to drive and use machines

Due to its neurological effects, ciprofloxacin may affect reaction time. Ciprofloxacin could result in impairment of the patient's ability to drive or operate machinery, particularly in conjunction with alcohol.

4.8    Undesirable Effects

The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.

ADRs derived from clinical studies and post-marketing surveillance with Ciprofloxacin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.

System Organ Class	Commo n >1/100 to < 1/10	Uncommon >1/1 000 to < 1/100	Rare >1/10 000 to < 1/1 000	Very Rare < 1/10 000	Freque ncy not known (cannot be estimate d from availabl e data)
Infections and Infestations		Mycotic superinfection s	Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4)
Blood and Lymphatic System Disorders		Eosinophilia	Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopen ia Thrombocytaemi	Haemolytic anaemia Agranulocytosis Pancytopenia (life-threatening) Bone marrow depression (life-

			a	threatening)
Immune System Disorders			Allergic reaction Allergic oedema / angiooedema	Anaphylactic reaction Anaphylactic shock (life-threatening) (see section 4.4) Serum sicknesslike reaction
Metabolism and Nutrition Disorders		Anorexia	Hyperglycaemia
Psychiatric Disorders		Psychomotor hyperactivity / agitation	Confusion and disorientation Anxiety reaction Abnormal dreams Depression (potentially culminating in suicidal ideations/thought s or suicide attempts and completed suicide) Hallucinations	Psychotic reactions (potentially culminating in suicidal ideations/thought s or suicide attempts and completed suicide) (see section 4.4)
Nervous System Disorders		Headache Dizziness Sleep disorders Taste disorders	Par- and Dysaesthesia Hypoaesthesia Tremor Seizures (including status epilepticus see section 4.4) Vertigo	Migraine Disturbed coordination Gait disturbance Olfactory nerve disorders Intracranial hypertension	Periphe ral neuropa thy (see section 4.4)
Eye Disorders			Visual disturbances (e.g. diplopia)	Visual colour distortions
Ear and Labyrinth Disorders			Tinnitus Hearing loss / Hearing impaired
Cardiac Disorders			Tachycardia		Ventric ular arrhyth mia, QT prolong ation, torsades de

					pointes (reporte d predomi nantly in patients with risk factors for QT prolong ation), ECG QT prolong ed (see section 4.4 and 4.9)*
Vascular Disorders			Vasodilatation Hypotension Syncope	Vasculitis
Respiratory, Thoracic and Mediastinal Disorders			Dyspnoea (including asthmatic condition)
Gastrointestin al Disorders	Nausea Diarrhoe a	Vomiting Gastrointestin al and abdominal pains Dyspepsia Flatulence		Pancreatitis
Hepatobiliary Disorders		Increase in transaminases Increased bilirubin	Hepatic impairment Cholestatic icterus Hepatitis	Liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section 4.4)
Skin and Subcutaneous Tissue Disorders		Rash Pruritus Urticaria	Photosensitivity reactions (see section 4.4)	Petechiae Erythema multiforme Erythema nodosum Stevens-Johnson syndrome (potentially life- threatening) Toxic epidermal	Acute generali sed exanthe matous pustulos is (AGEP)

				necrolysis (potentially life-threatening)
Musculoskelet al, Connective Tissue and Bone Disorders		Musculoskelet al pain (e.g. extremity pain, back pain, chest pain) Arthralgia	Myalgia Arthritis Increased muscle tone and cramping	Muscular weakness Tendinitis Tendon rupture (predominantly Achilles tendon) (see section 4.4) Exacerbation of symptoms of myasthenia gravis (see section 4.4)
Renal and Urinary Disorders		Renal impairment	Renal failure Haematuria Crystalluria (see section 4.4) Tubulointerstitial nephritis
General Disorders and Administratio n Site Conditions		Asthenia Fever	Oedema Sweating (hyperhidrosis)
Investigations		Increase in blood alkaline phosphatase	Prothrombin level abnormal Increased amylase		Internati onal normali sed ratio increase d (in patients treated with Vitamin K antagon ists)

Paediatric _ patients

The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).

4.9 Overdose

An overdose of 12 g has been reported to lead to mild symptoms of toxicity. An acute overdose of 16 g has been reported to cause acute renal failure.

Symptoms in overdose consist of dizziness, tremor, headache, tiredness, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic impairment as well as crystalluria and haematuria. Reversible renal toxicity has been reported.

Apart from routine emergency measures, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids may theoretically reduce the absorption of ciprofloxacin in overdoses.

Only a small quantity of ciprofloxacin (<10%) is eliminated by haemodialysis or peritoneal dialysis.

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Ciprofloxacin is a synthetic 4-quinolone derivative, with bactericidal activity. It acts via inhibition of bacterial DNA gyrase, ultimately resulting in interference with DNA function. Ciprofloxacin is highly active against a wide range of Gram-positive and Gram-negative organisms and has shown activity against some anaerobes, Chlamydia spp. and Mycoplasma spp.. Killing curves demonstrate the rapid bactericidal effect against sensitive organisms and it is often found that minimum bactericidal concentrations are in the range of minimum inhibitory concentrations.

Breakpoints

S 1 pg/ml, R 4 pg/ml

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local area information on resistance is desirable, particularly when treating severe infections. This information gives only an approximate guidance on probabilities whether micro-organisms will be susceptible to ciprofloxacin or not.

Sensitive:

Gram-positive bacteria

Corynebacterium diphtheriae 0% Corynebacterium spp. -Staphylococcus aureus (methicillin sensitive) Staphylococcus aureus (methicillin resistant) Streptococcus agalactiae    0 - 17%

Gram-negative bacteria

Acinetobacter baumanii 6 - 93% Acinetobacter spp.    14 - 70%

Aeromonas hydrophilia 0%

Aeromonas spp.-Bordetella pertussis    0%

Brucella melitensis    0%

Campylobacter jejuni/coli    0 - 82%

Campylobacter spp.    0%

Citrobacter freundii    0 - 4%

Citrobacter spp. 0%

Edwardsiella tarda    0%

Enterobacter aerogenes    0%

Enterobacter cloacae    0 - 3%

Enterobacter spp.    3 - 13%

Escherichia coli 2 -7%

Escherichia coli, EHEC and EPEC -Haemophilus influenzae0 - 1%

Haemophilus influenzae (B-lactam negative) Haemophilus influenzae (B-lactam positive) Haemophilus parainfluenzae    0%

Hafnia alvei 0%

Klebsiella oxytoca    0%

Klebsiella pneumoniae    2 - 5.8%

Klebsiella spp. 2 - 21%

Legionella pneumophila0%

Legionella spp 0%

Moraxella catarrhalis 0%

Morganella morganii    1 - 2%

Neisseria gonorrhoeae 0%

Neisseria gonorrhoeae, B-lactamase 0% Neisseria gonorrhoeae, B-lactamase positive Neisseria meningitidis 0%

Neisseria meningitidis, B-lactamase negative Plesiomonas shigelloides    0%

Proteus mirabilis    0 - 10%

Proteus vulgaris 4%

Providencia rettgeri -Providencia spp.    4%

Providencia stuartii -Pseudomonas aeruginosa    1 - 28%

Salmonella spp. 0%

Salmonella typhi    0 - 2%

Serratia liquefaciens -Serratia marcescens 23%

Serratia spp.    0 - 21%

Shigella spp.    0%

Vibrio cholerae    0%

Vibrio parahaemolyticus    0%

Vibrio spp.    0%

Yersinia enterocolitica 0%

Anaerobes

Bacteroides ureolyticus 0%

Clostridium perfringens -Peptococcus spp    0%

Peptostreptococcus spp. -Peptostreptococcus magnus    0%

Veillonella parvula 0%

Other pathogens

Chlamydia spp. -Helicobacter pylori -Mycobacterium fortuitum    0%

Mycobacterium tuberculosis    0%

Mycoplasma hominis 16%

Intermediate

Gram-positive aerobes

Enterococci 5%

Enterococcus faecalis 9 - 34%

Staphylococcus epidermis, methicillin sensitive 10 - 16% Staphylococcus epidermis, methicillin resistant 26 - 56% Staphylococcus haemolyticus    -

Staphylococcus haemolyticus, methicillin sensitive    8%

Staphylococcus haemolyticus, methicillin resistant    73%

Streptococcus anginosus    9%

Streptococcus bovis    -

Streptococcus milleri    5%

Streptococcus mitis    -

Streptococcus pneumoniae, penicillin sensitive 0 - 1%

Streptococcus pneumoniae, penicillin intermediate    -

Streptococcus pneumoniae, penicillin intermediate and resistant 2.8% Streptococcus pneumoniae, penicillin resistant -Streptococcus pyogenes 0 - 28%

Streptococcus, viridans group    -

Streptococcus viridans, penicillin sensitive    -

Streptococcus viridans, penicillin resistant    -

Streptococcus, B-haemolytic groups A, C, and G 0%

Gram-negative aerobes

Alcaligenes spp.    -

Listeria monocytogenes 0%

Listeria spp. 0%

Anaerobes

Fusobacterium spp.    -

Gardnerella vaginalis 0% Prevotella spp. -

Other pathogens

Ureaplasma urealyticum 11%

Resistant

Gram-positive aerobes

Enterococcus faecium -Stenotrophomonas maltophilia 94% Streptococcus sanguis -

Gram-negative aerobes

Flavobacterium meningosepticum Nocardia asteroides    -

Anaerobes

Bacteroides fragilis    -

Bacteroides thetaiotaomicron -Clostridium difficile -

Plasmid-related transfer of resistance has not been observed with ciprofloxacin and the overall frequency of development of resistance is low (10-9 - 10-7). Crossresistance to penicillins, cephalosporins, aminoglycosides and tetracyclines has not been observed and organisms resistant to these antibiotics are generally sensitive to ciprofloxacin. Ciprofloxacin is also suitable for use in combination with these antibiotics, and additive behaviour is usually observed.

5.2 Pharmacokinetic properties

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. The absolute bioavailability is reported to be 52-83% and ciprofloxacin is subject to only slight first pass metabolism. The oral bioavailability is approximately 70-80%.

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 Cmax and AUC. No specific recommendations are necessary with regard to time of administration of oral ciprofloxacin relative to food intake.

Distribution of ciprofloxacin within tissues 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 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 halflife 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 <20ml/minute) 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.

Results of pharmacokinetic studies in paediatric cystic fibrosis patients have shown dosages of 20mg/kg orally twice daily or 10mg/kg iv three times daily are recommended to achieve plasma concentration/time profiles comparable to those achieved in the adult population at the currently recommended dosage regimen.

5.3 Preclinical safety data

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 a 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 a 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.

As with other quinolones, damage to the weight-bearing joints of only juvenile rats and dogs treated with ciprofloxacin was noted in repeat dose toxicity testing. This was more noticeable in the dog. Although analysis of available safety data from ciprofloxacin use in paediatric patients did not disclose any evidence of drug related cartilage or articular damage, the use of ciprofloxacin in children and growing adolescents is generally not recommended, unless the benefits are considered to outweigh the potential risks (with the exception of treatment of cystic fibrosis). Additionally, because of the potential of arthropathy, the use of ciprofloxacin during pregnancy and lactation is not recommended.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate,

Sodium starch glycollate,

Povidone

Sodium stearyl fumarate.

Methocel E5 premium Polyethylene glycol

Titanium dioxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Blister strips in cardboard outers comprising:

PVC/Aluminium blister strips Pack size: 10 and 20 tablets

6.6 Special precautions for disposal

Not applicable.

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