Document: spc-doc_PL 20532-0012 change

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ciprofloxacin 500 mg film-coated tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500mg of ciprofloxacin as ciprofloxacin hydrochloride.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets.

White or yellowish, 8.2 x 17 mm oval, biconvex, film-coated tablets. Scored on one side and side-wall scored, marked C500 on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

Treatment of infections caused by ciprofloxacin-sensitive pathogens, such as:

Infections of:

-    The respiratory tract. Ciprofloxacin may be indicated for treating pneumonia due to gram-negative pathogens. In pneumococcal pneumonia treated in an outpatient setting, Ciprofloxacin is not the drug of first choice.

-    The urinary tract: acute uncomplicated cystitis, complicated infections and pyelonephritis.

-    the genital organs, including acute, uncomplicated gonorrhoea, prostatitis severe gastro-enteritis

-    the skin and soft tissue

-    the bones and joints

-    Severe systemic infections: e.g. septicaemia, peritonitis (in case of peritonitis, the anaerobic compartment should be covered by another antibacterial agent (metronidazole like), infections in immuno-suppressed patients.

Children and adolescents:

Acute pulmonary exacerbation of cystic fibrosis in children and adolescents

(5-17 years) caused by Pseudomonas aeruginosa.

Ciprofloxacin is not recommended for other indications in this age group.

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

4.2 Posology and method of administration

The dose 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. Treatment may be initiated with tablets or intravenous injection according to the condition of the patient. The duration of treatment depends on the severity of the disorder and on the clinical and bacteriological course. In principle, treatment should be maintained for at least 3 days after body temperature has returned to normal, or clinical symptoms have resolved.

The following dose recommendations are provided as a guideline and refer to oral dosing only (Note that different dose recommendations apply to intravenous administration of ciprofloxacin).

Adults: The dosage range for adults is 100-750mg twice daily.

Clinical Indication	Posology	Usual duration of treatment
Respiratory tract infections:	250-500 mg twice daily	7 - 14 days
Urinary tract infections: - acute, uncomplicated cystitis in women	100-250mg twice daily	3 days
Urinary tract infections: -complicated infections and pyelonephritis	250-500 mg twice daily.	7 - 14 days
Prostatitis:	500 mg twice	Up to 28 days

	daily
Gonorrhoea: -acute, uncomplicated:	250-500mg	Single dose
Severe gastroenteritis:	500 mg twice daily	• 3-7 days
Skin and soft tissue infections:	500 mg twice daily	5-10 days
Bone and joint infections:	500-750 mg twice daily	4 to 6 weeks or longer
Severe systemic infections:	500-750 mg twice daily

In particularly severe, life-threatening infections - especially those involving Pseudomonas, staphylococci or streptococci, e.g. osteomyelitis, septicaemia, streptococcal pneumonia, recurrent bouts of infection in mucoviscidosis patients, bone and joint infections or peritonitis - the recommended dose is 750 mg ciprofloxacin twice daily.

Elderly patients:

Elderly patients should receive a dose depending on the severity of the disorder and on creatinine clearance.

Children and adolescents (5-17 years):

Clinical Indication	Posology	Usual duration of treatment
Acute pulmonary exacerbation of cystic fibrosis caused by Pseudomonas aeruginosa:	40 mg/kg/24h divided in two doses i.e. 20mg/kg twice daily (maximum 1500 mg daily).	10 - 14 days
Other indications	Not recommended	N/A

Impaired renal or hepatic function

Adults:

1. Impaired renal function:

clearance:	creatinine level:
31 to 60 ml/min/1.73m2	120-170 pmol/l (1.4 -1.9 mg/dl)	Maximum dose 1000mg per day.
< 30 ml/min/1.73m2	> 175 gmol/l (> 2.0 mg/dl)	Maximum dose 500mg per day*.

* In patients with severe infections and severe renal impairment a unit dose of 750mg can be given. However patients should be carefully monitored.

Monitoring of drug levels in blood provides the most reliable basis for dose adjustment. Dosage intervals should remain the same as in patients with normal renal function.

2. Impaired renal function + haemodialysis

Recommended dose: 500 mg per day administered as a single dose following haemodialysis. Monitoring of drug levels in blood provides the most reliable basis for dose adjustment.

3. Impaired renal function + continuous ambulatory peritoneal dialysis (CAPD)

Recommended dose: 500mg per day administered as a single dose following CAPD.

Monitoring of drug levels in blood provides the most reliable basis for dose adjustment.

4.    Impaired hepatic function Dose adjustment not necessary.

5.    Impaired renal and hepatic function

Dose adjustment as under 1, with monitoring of serum ciprofloxacin concentrations.

Children and adolescents (5-17years):

Dosage in children with reduced renal and liver function has not been investigated.

Method of administration:

The tablets are to be swallowed whole with liquid. They can be taken at any time regardless of meals. Ingestion on an empty stomach accelerates the absorption of active substance. Dairy products with a high calcium content (milk, yoghurt) may reduce ciprofloxacin absorption (refer to section 4.5).

4.3 Contraindications

-    Ciprofloxacin must not be used in cases of hypersensitivity to ciprofloxacin or any of the excipients or other chemotherapeutic agents of the quinolone type.

-    Pregnancy, Lactation (refer to section 4.6).

-    In patients with a history of tendon disorders related to fluoroquinolone administration (refer to section 4.4)

-    Children and growing adolescents (5 - 17 years), contraindicated except for the treatment of acute pulmonary exacerbation of cystic fibrosis (refer to sections 4.1, 4.2 and 4.4).

-    Children under 5 years.

4.4 Special warnings and precautions for use

Use in patients with epilepsy and other central nervous system (CNS) disorders:

In patients with epilepsy or other lesions of the central nervous system (e.g. reduced convulsion threshold, a history of seizures, diminished cerebral bloodflow, changes in brain structure or stroke), ciprofloxacin is only to be used after carefully weighing the benefits against the risk, because the possibility of central nervous side effects puts these patients at increased risk.

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.

Pseudomembranous colitis is a particular form of enterocolitis that can occur with antibiotics (in most cases due to Clostridium difficile). If severe and persistent diarrhoea occurs during or after treatment, the doctor should be consulted, even if Clostridium difficile is only suspected, administration of ciprofloxacin should be discontinued immediately and appropriate treatment given.

Patients with a family history of or actual defects in glucose-6-phosphate dehydrogenase activity are prone to haemolytic reactions with quinolones, and so ciprofloxacin should be used with caution in these patients.

Ciprofloxacin use has rarely been associated with photosensitivity. However, patients should be recommended to avoid prolonged exposure to sunlight or UV radiation during treatment with ciprofloxacin. If this is not possible appropriate precautions should be taken.

Tendonitis and/or rupture of tendons (which mainly affects the Achilles tendon) are observed during treatment with quinolone antibiotics. These reactions are especially observed in elderly patients and patients treated with corticosteroids. After the first signs of pain or inflammation, the treatment should be discontinued and the affected extremity should be made non-weight bearing. If the symptoms originate from the Achilles tendon, care should be taken to avoid rupture of both tendons (i.e. by use of splints to both Achilles tendons or support of both heels) (refer to section 4.3).

Because ciprofloxacin has some activity against Mycobacterium tuberculosis, falsenegative cultures may occur when specimens are obtained during ciprofloxacin treatment.

Ciprofloxacin should be used with caution in patients with myasthenia gravis.

Studies in immature animals showed ciprofloxacin may cause arthropathy in weightbearing joints. However, review of safety data in patients younger than 18 years (mainly cystic fibrosis patients) revealed no signs of drug related damages to cartilage or joints.

If failure of therapy is suspected in treatment of Pseudomonas aeruginosa or Staphylococcus, microbiological studies to identify resistant pathogens should be considered.

Cardiac disorders

Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as, 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, in these populations.

(See section 4.2 Elderly, section 4.5, section 4.8, section 4.9).

4.5 Interaction with other medicinal products and other forms of interaction

Antacids, iron, zinc, sucralfate, calcium, didanosine, oral nutritional solutions, dairy products

Absorption of ciprofloxacin is reduced when iron, zinc, sucralfate or antacids and highly buffered pharmaceuticals, containing magnesium, aluminium or calcium, are administered simultaneously. This also applies to sucralfate, antiviral drugs containing buffered didanosine formulations, oral nutritional solutions and large quantities of dairy products (milk or liquid milk products such as yoghurt). Therefore Ciprofloxacin should be administered either 1 to 2 hours before or at least 4 hours after the above mentioned products. This restriction does not apply to the group of H₂ receptor-blocking antacids.

Xanthine derivatives

Concurrent administration of ciprofloxacin and theophylline may cause increased plasma concentrations of theophylline. This may lead to theophylline induced undesirable effects, which in very rare cases are life threatening. During concurrent administration of theophylline, the plasma concentrations should be monitored, and the theophylline dose should be adjusted adequately. On concurrent administration of ciprofloxacin and caffeine or pentoxifylline, raised serum concentrations of these xanthine derivatives were reported.

NSAID’s

Animal trials have shown that concurrent administration of very high doses of a quinolone and certain non steroid anti-inflammatory drugs (NSAID) (but not acetylsalicylic acid) may provoke convulsions.

Ciclosporin

A transient increase in the concentration of plasma creatinine is seen, when ciprofloxacin and ciclosporin are administered simultaneously. Plasma creatinine concentrations should be checked regularly in these patients

Warfarin

Simultaneous administration of ciprofloxacin and warfarin may increase the effect of warfarin.

Glibenclamide

Simultaneous administration of ciprofloxacin and glibenclamide may increase the effect of glibenclamide.

Probenecid

Probenecid inhibits the renal excretion of ciprofloxacin resulting in an increase of the plasma concentration of ciprofloxacin.

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin. The maximum plasma concentration is therefore achieved more rapidly. The bioavailability of ciprofloxacin is not affected.

Mexiletine

Simultaneous administration of ciprofloxacin and mexiletine can lead to increased concentrations of mexiletine.

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.

Premedicants

It is recommended that opiate premedicants, (e.g. papaveretum) or opiate premedicants used with anticholinergic premedicants, (e.g. atropine or hyoscine) are not used concomitantly with ciprofloxacin, as the serum levels of ciprofloxacin are reduced.

Co-administration of ciprofloxacin and benzodiazepine premedicants has been shown not to affect ciprofloxacin plasma levels. However, since decreased clearance of diazepam, with a prolonged half-life have been reported during co-administration of ciprofloxacin and diazepam, and in an isolated case with midazolam, careful monitoring of benzodiazepine therapy is recommended.

Ropinirole

A potential for increased plasma levels of ropinirole with possible increase in adverse effects exists. In case of combined use, increased clinical monitoring and dosage adjustment of ropinirole may be required.

Buffered Didanosine formulations

Clinically important interactions have been reported with buffered didanosine formulations (please refer to the first paragraph of this section).

Drugs known to prolong QT interval

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

4.6 Pregnancy and lactation

Use during pregnancy is contraindicated. As with other quinolones, ciprofloxacin has been shown to cause arthropathy in immature animals, and therefore its use during pregnancy is contraindicated.

Administration to nursing mothers is contraindicated since quinolones administered at therapeutic doses are excreted in breast milk in quantities that can be expected to affect the infant.

4.7 Effects on ability to drive and use machines

Even when used as prescribed, this medicinal product can alter the capacity for reactions to an extent that impairs the ability to drive a vehicle, to operate machinery or to work safely. This applies to a greater degree at the start of treatment, when the dose is increased, and when switching medication, as well as in conjunction with alcohol.

4.8 Undesirable effects

Adverse effects have been reported in 5-14% of patients receiving ciprofloxacin. Most frequent adverse effects of the drug involve the gastro-intestinal tract and the central nervous system.

The following undesirable effects have been observed:

Effects on the gastrointestinal tract

Common (> 1/100, < 1/10): Nausea, diarrhoea, vomiting, digestive disorders, abdominal pain, flatulence, loss of appetite.

Rare (> 1/10,000, < 1/1,000): Pseudomembranous colitis.

Effects on the nervous system

Common (> 1/100, < 1/10): Dizziness, headache, tiredness, agitation, tremor, confusion;

Very rare (< 1/10,000): insomnia, paraesthesias, sweating, ataxia, convulsive seizures (the spasmodic threshold in epilepsy may be reduced), increased intracranial pressure, anxiety states, nightmares, distress, depression, hallucinations;

In isolated cases: psychotic reactions (involving in some cases a risk of self-injury).

These reactions occurred in some cases with the first dose of the medicinal product. If such reactions occur, Ciprofloxacin is to be discontinued immediately and the treating physician informed.

Effects on sensory organs

Very rare (< 1/10,000): dysgeusia and dysosmia as well as a possible loss of the sense of smell, which normally resolves after the end of the therapy, disturbed vision (e.g. diplopia, chromatopsia), tinnitus, transient (especially high-frequency) hearing loss.

Hypersensitivity reactions

The following reactions occurred in some cases with the first dose of the medicinal product. If such reactions occur, Ciprofloxacin is to be discontinued immediately and the treating physician informed.

Common (> 1/100, < 1/10): Skin reactions such as rash, pruritis, drug fever.

Very rare (< 1/10,000):

-    punctiform cutaneous bleeding (petechiae), vesicles with haemorrhage (haemorrhagic bullae) and small nodules (papules) with crust formation showing vascular involvement (vasculitis), urticaria, erythema nodosum, erythema multiforme (mild to very severe forms i.e. Stevens-Johnson syndrome), Lyell’s syndrome.

-    interstitial nephritis, hepatitis, and hepatic necrosis to life-threatening hepatic failure.

-    anaphylactic/anaphylactoid reactions (e.g. ranging from facial, vascular and laryngeal oedema, through dyspnoea to shock), in some cases with the first dose of the medicinal product. If such reactions occur, Ciprofloxacin is to be discontinued immediately, and medical treatment for shock should be given.

Effects on the cardiovascular system

Uncommon (> 1/1,000, < 1/100): Palpitation;

Very rare (< 1/10,000): peripheral oedema, hot flushes, migraine, fainting, tachycardia.

Not known: ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see section 4.4 and 4.9).

Effects on the locomotor apparatus

Uncommon (>1/1000, <1/100): Arthralgia and joint swelling;

Very rare (< 1/10,000): muscular pains, inflammation of tendon sheaths (tenosynovitis);

In isolated cases, tendonitis and torn tendons (e.g. of Achilles' tendon) may occur during treatment with fluoroquinolones. These events were observed predominantly among older patients who had been systemically treated beforehand with corticosteroids. If tendonitis is suspected, treatment with Ciprofloxacin must be discontinued immediately, physical effort avoided and, if necessary, medical treatment initiated.

In isolated cases: Aggravation of the symptoms of myasthenia.

Effects on blood and blood components

Uncommon (>1/1000, <1/100): Eosinophilia, leucocytopenia, granulocytopenia, anaemia, thrombocytopenia;

Very rare (< 1/10,000): leucocytosis, thrombocytosis, haemolytic anaemia, pancytopenia, agranulocytosis, altered prothrombin values.

Influence on laboratory values / urinary sediment

Patients with liver damage in particular may show a transient rise in transaminases and alkaline phosphatase or even cholestatic jaundice; a transient increase in serum urea, creatinine or bilirubin;

In isolated cases: hyperglycaemia, crystalluria or haematuria.

Others

Uncommon (>1,1000, <1/100): pulmonary embolism, dyspnoea, pulmonary oedema, epistaxis, hemoptysis and hiccough;

Very rare (< 1/10,000): asthenia, a transient impairment of kidney function to transient renal failure, photosensitivity. It is therefore recommended that these patients avoid long lasting exposure to sunlight or irradiation with UV-light (solarium) during treatment with Ciprofloxacin. Treatment should be discontinued in cases of photosensitivity reactions (e.g. skin reactions similar to sun burn).

Long-term and repeated use of Ciprofloxacin can lead to superinfections with resistant bacteria or fungi.

4.9 Overdose

In acute and extreme overdosage reversible kidney damage is seen. Gastric emptying by eliciting vomiting or gastric lavage is therefore recommended. Activated charcoal, Mg- or Ca-containing antacids are administered in order to reduce the absorption of ciprofloxacin. The patient should be kept under accurate observation receiving both symptomatic and supportive treatment. The renal function should be monitored. At haemodialysis or peritoneal dialysis only a modest amount of ciprofloxacin (<10%) is eliminated.

Adequate hydration must be maintained to minimise the risk of crystalluria.

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

Pharmacotherapeutic group: Fluoroquinolones,

ATC Code: J 01 MA 02

Activity:

Ciprofloxacin is a synthetic 4-quinolone derivative antibacterial agent of the fluoroquinolone class.

Mechanism of action:

As a fluoroquinolone antibacterial agent, ciprofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.

Spectrum of activity:

Breakpoints:

BSAC: S < 1 mg/L; R> 2 mg/L, except Pseudomonas R > 8 mg/L and UTI R < 8 mg/L.

NCCLS: S < 1 mg/L; I = 2 mg/L; R > 4 mg/L.

Susceptibility

The prevalence of the acquired resistances can vary for some species geographically and with time. Therefore, it is important to obtain information on local resistance patterns, particularly when treating more severe infections.

The information provided below gives only an approximate guidance on probabilities whether micro-organisms will be susceptible to ciprofloxacin or not.

Organism	Prevalenc e of Resistanc e
Sensitive:
Gram-positive bacteria
Staphylococcus aureus (methicillin sensitive)	0 - 14%
Streptococcus agalactiae	0 - 17%
Gram-negative bacteria
Acinetobacter baumanii	6 - 93%
Acinetobacter spp.	14 - 70%
Aeromonas hydrophila	0%
Campylobacter jejuni/coli	0 - 82%
Citrobacter freundii	0 - 4%
Enterobacter aerogenes	0%
Enterobacter cloacae	0 - 3%
Enterobacter spp.	3 - 13%
Escherichia coli	2 -7%
Haemophilus influenzae	0 - 1%
Klebsiella spp.	2 - 21%
Moraxella catarrhalis	0%
Morganella morganii	1 - 2%
Neisseria gonorrhoeae	5%
Plesiomonas shigelloides	0%
Proteus mirabilis	0 - 10%
Proteus vulgaris	4%
Providencia spp.	4%
Pseudomonas aeruginosa	1 - 28%
Salmonella spp.	0%
Salmonella typhi	0 - 2%
Serratia liquefaciens	-
Serratia marcescens	23%
Shigella spp	0%

Vibrio spp	0%
Yersinia enterocolitica	0%
Anaerobes*
Peptococcus spp.	-
Peptostreptococcus spp.	-
Veillonella parvula	-
Other pathogens
Legionella pneumophila	-
Intermediate
Viridans streptococci	5-9%
Streptococcus pneumoniae	2.8%
Streptococcus pyogenes	2.8%
Other pathogens
Chlamydia spp	-
Resistant
Gram-positive aerobes
Enterococcus spp	-
Staphylococcus aureus (methicillin resistant)	48 - 90%
Gram-negative aerobes
Stenotrophomonas maltophila	-
Flavobacterium meningosepticum	-
Nocardia asteroides	-
Anaerobes
Bacteroides fragilis	-
Bacteroides thetaiotaomicron	-
Clostridium difficile	-

* Ciprofloxacin is not considered the drug of first choice for treatment of infections with anaerobes.

In-vitro investigations have shown that resistance to ciprofloxacin most commonly involves 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 drugs within the class. Impermeability and/or drug efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physicochemical properties of the various drugs within the class and the affinity of transport systems for each drug.

5.2 Pharmacokinetic properties

Absorption

After oral administration, ciprofloxacin is predominantly absorbed from the duodenum and upper jejunum and reaches peak serum concentrations within 60-90 min. After single doses of 250 mg and 500 mg C_max values are about 0.8-2.0 mg/l and 1.5-2.9 mg/l respectively

The absolute bioavailability is approximately 70 to 80%. C_max- and AUC-values are proportionally increased with the dose.

Food intake has no effect on the plasma concentration profile of ciprofloxacin.

Distribution

The steady-state volume of distribution of ciprofloxacin is 2-3 l/kg. Since the protein binding of ciprofloxacin is low (20-30%) and the substance is predominantly present in the blood plasma in non-ionised form, almost the entire quantity of the administered dose can diffuse freely into the extravasal space. As a result, the concentrations in certain body fluids and tissues may be markedly higher than the corresponding serum concentrations.

Metabolism / Elimination

Ciprofloxacin is essentially excreted in unchanged form, mostly in the urine. Renal clearance lies between 3 and 5 ml/min/kg, and total clearance amounts to 8-10 ml/min/kg. Both glomerular filtration and tubular secretion play a part in the elimination of ciprofloxacin.

Small concentrations of 4 metabolites were found: desethylene ciprofloxacin (M1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). M 1 to M 3 show antibacterial activity comparable with or smaller than nalidixic acid. M 4 with the lowest quantity, has an antimicrobial activity very much corresponding to norfloxacin.

Excretion after oral administration (in % of the ciprofloxacin dose):

urine faeces

The half-life of ciprofloxacin lies between 3 and 5 hours, both after oral and after intravenous administration.

Since ciprofloxacin is excreted not only via the kidneys, but also to a major extent via the gut, renal function must be substantially impaired before increases in serum elimination half-life of up to 12 hours are observed.

5.3 Preclinical safety data

Like other gyrase inhibitors, ciprofloxacin may induce joint damage during the growth phase of juvenile animals. Other preclinical effects were observed only at exposures, sufficiently in excess of the maximum human exposure, that make concern for human safety negligible in respect of animal data.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Microcrystalline cellulose Crospovidone Colloidal anhydrous silica Magnesium stearate.

Film coating:

Hypromellose Macrogol 400 Titanium dioxide (E171).

6.2 Incompatibilities

Not Applicable

10 DATE OF REVISION OF THE TEXT

25/03/2013