Document: spc-doc_PL 36780-0002 change

• spc-doc_PL 17277-0009
• spc-doc_PL 20568-0003
• spc-doc_PL 20568-0005
• spc-doc_PL 24780-0001
• spc-doc_PL 36780-0002

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ciprofloxacin 2 mg/ml Solution for Infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each bag contains 2 mg/ml ciprofloxacin (as lactate).

Each bag filled with 100 ml of the Solution for Infusion contains 200 mg ciprofloxacin (as lactate).

Each bag filled with 200 ml of the Solution for Infusion contains 400 mg ciprofloxacin (as lactate).

Excipient with known effect:

• Glucose (see section 4.4).

o For 100 ml bag: Contains 5 g glucose per bag (see section 4.4) o For 200 ml bag: Contains 10 g glucose per bag (see section 4.4)

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for infusion.

Clear, nearly colourless to slightly yellowish solution.

The pH value of the solution for infusion ranges from 3.5 to 4.6 and the solution has an osmolality of approximately 310 mOsm/Kg.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ciprofloxacin 2 mg/ml solution for infusion is indicated for the treatment of the following infections (see sections 4.4 and 5.1).

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.

•    Lower respiratory tract infections due to Gram-negative bacteria

o exacerbations of chronic obstructive pulmonary disease o broncho-pulmonary infections in cystic fibrosis or in bronchiectasis o 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

o Epididymo-orchitis including cases due to susceptible Neisseria gonorrhoeae

o 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

•    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).

4.2 Posology and method of administration

The dosage is determined by the indication, the severity and the site of the infection, the susceptibility to ciprofloxacin of the causative organism(s), the renal function of the patient and, in children and adolescents the body weight.

The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course.

After intravenous initiation of treatment, the treatment can be switched to oral treatment with tablet or suspension if clinically indicated at the discretion of the physician. IV treatment should be followed by oral route as soon as possible.

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 co-administration with other appropriate antibacterial agents.

Treatment of some infections (e.g. pelvic inflammatory disease, intraabdominal 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

Indications		Daily dose in mg	Total duration of treatment (including switch to oral therapy as soon as possible)
Infections of the lower respiratory tract		400 mg twice daily to 400 mg three times a day	7 to 14 days
Infections of the upper respiratory tract	Acute exacerbation of chronic sinusitis	400 mg twice daily to 400 mg three times a day	7 to 14 days
	Chronic suppurative otitis media	400 mg twice daily to 400 mg three times a day	7 to 14 days
	Malignant external otitis	400 mg three times a day	28 days up to 3 months

Indications		Daily dose in mg	Total duration of treatment (including switch to oral therapy as soon as possible)
Urinary tract infections (see section 4.4)	Complicated and uncomplicated pyelonephritis	400 mg twice daily to 400 mg three times a day	7 to 21 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses)
	Prostatitis	400 mg twice daily to 400 mg three times a day	2 to 4 weeks (acute)
Genital tract infections	Epididymo-orchitis and pelvic inflammatory diseases	400 mg twice daily to 400 mg three times a day	at least 14 days
Infections of the gastrointestinal 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	400 mg twice daily	1 day
	Diarrhoea caused by Shigella dysenteriae type 1	400 mg twice daily	5 days
	Diarrhoea caused by Vibrio cholerae	400 mg twice daily	3 days
	Typhoid fever	400 mg twice daily	7 days

Indications		Daily dose in mg	Total duration of treatment (including switch to oral therapy as soon as possible)
	Intraabdominal infections due to Gramnegative bacteria	400 mg twice daily to 400 mg three times a day	5 to 14 days
Infections o soft tissue	f the skin and	400 mg twice daily to 400 mg three times a day	7 to 14 days
Bone and joint infections		400 mg twice daily to 400 mg three times a day	max. of 3 months
Neutropenic patients with fever that is suspected to be due to a bacterial infection Ciprofloxacin should be coadministered with appropriate antibacterial agent(s) in accordance to official guidance.		400 mg twice daily to 400 mg three times a day	Therapy should be continued over the entire period of neutropenia
Inhalation anthrax postexposure prophylaxis and curative treatment for persons requiring parenteral treatment Drug administration should begin as soon as possible after suspected or confirmed exposure.		400 mg twice daily	60 days from the confirmation of Bacillus anthracis exposure

Children and adolescents

Indication	Daily dose in mg	Total duration treatment	of
		(including switch	to
		oral therapy as soon
		as possible)

Indication	Daily dose in mg	Total duration of treatment (including switch to oral therapy as soon as possible)
Cystic fibrosis	10 mg/kg body weight three times a day with a maximum of 400 mg per dose.	10 to 14 days
Complicated urinary tract infections and pyelonephritis	6 mg/kg body weight three times a day to 10 mg/kg body weight three times a day with a maximum of 400 mg per dose.	10 to 21 days
Inhalation anthrax postexposure curative treatment for persons requiring parenteral treatment 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 400 mg per dose.	60 days from the confirmation of Bacillus anthracis exposure
Other severe infections	10 mg/kg body weight three times a day with a maximum of 400 mg per dose.	According to the type of infections

Geriatric patients

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

Renal and hepatic impairment

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

Creatinine Clearance [ml/min/1.73 m2]	Serum Creatinine [^mol/l]	Intravenous Dose [mg]
> 60	< 124	See Usual Dosage.
30-60	124 to 168	200-400 mg every 12 h
< 30	> 169	200-400 mg every 24 h

Patients on > 169 haemodialysis	200-400 mg every 24 h (after dialysis)
Patients on > 169 peritoneal dialysis	200-400 mg every 24 h

In patients with impaired liver function no dose adjustment is required.

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

Method of administration

Ciprofloxacin 2 mg/ml solution for infusion should be checked visually prior to use. It must not be used if cloudy.

Ciprofloxacin should be administered by intravenous infusion. For children, the infusion duration is 60 minutes.

In adult patients, infusion time is 60 minutes for 400 mg of Ciprofloxacin 2 mg/ml solution for infusion and 30 minutes for 200 mg of Ciprofloxacin 2 mg/ml solution for infusion. Slow infusion into a large vein will minimise patient discomfort and reduce the risk of venous irritation.

The infusion solution can be infused either directly or after mixing with other compatible infusion solutions (see section 6.2).

4.3 Contraindications

•    Hypersensitivity to the active substance, to other quinolones or to any of the excipients (see section 6.1).

•    Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).

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 isolates.

For epididymo-orchitis and pelvic inflammatory diseases, empirical ciprofloxacin should only be considered in combination with another appropriate antibacterial agent (e.g. a cephalosporin) 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.

Intra-abdominal infections

There are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical 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 5-17 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 1-17 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, even within the first 48 hours of treatment. Inflammation and tendon rupture 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).

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.

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 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

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 woman 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 Geriatric Patients, section 4.5, section 4.8, section 4.9).

Hypoglycaemia

As with other quinolones, hypoglycaemia has been reported most often in diabetic patients, predominantly in the elderly population. In all diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).

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 the 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). Coadministration 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.

Injection Site Reaction

Local intravenous site reactions have been reported with the intravenous administration of ciprofloxacin. These reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.

Glucose Load

Ciprofloxacin 2 mg/ml solution for infusion contains 5 g glucose in 100 ml solution for infusion and 10 g glucose in 200 ml of solution for infusion. This should be taken into account in patients with diabetes mellitus.

Patients with rare glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products 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 the QT interval (e.g. Class IA and

III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).

Probenecid

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

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.

Ciclosporin

A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and ciclosporin 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 is 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, phenprocoumin, or fluinidione).

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).

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 determined in healthy subjects that concomitant use of lidocaine containing medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2, 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 coadministration with ciprofloxacin are advised (see section 4.4).

Sildenafil

Cmax and AUC of sildenafil were increased approximately two fold 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 indicate 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 / fetus (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.

Thus, the ability to drive or to operate machinery may be impaired.

4.8 Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are nausea, diarrhoea, vomiting, transient increase in transaminases, rash, and injection and infusion site reactions.

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.

Note: The frequency of occurrence of adverse events is classified as follows:

Very common (> 1/10)

Common (> 1/100 to < 1/10)

Uncommon (> 1/1000 to < 1/100)

Rare (> 1/10 000 to < 1/1 000)

Very rare (<1/10000)

Not known (Cannot be estimated from the available data)

System Organ Class	Very Common (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1000 to < 1/100	Rare (> 1/10 000 to < 1/1 000	Very Rare (<1/10000)	Not known Cannot be estimated from the available data
Infections and Infestations			Mycotic superinfections	Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4)
Blood and Lymphatic System Disorders			Eosinophilia	Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopenia Thrombocytaemia	Haemolytic anaemia Agranulocytosis Pancytopenia (life-threatening) Bone marrow depression (life-threatening)
Immune System Disorders				Allergic reaction Allergic oedema / angio-oedema	Anaphylactic reaction Anaphylactic shock (life-threatening) (see section 4.4) Serum sickness-like reaction
Metabolism and Nutrition Disorders			Anorexia Decreased appetite	Hyperglycaemia Hypoglycaemia
Psychiatric Disorders			Psychomotor hyperactivity / agitation	Confusion and disorientation Anxiety reaction Abnormal dreams Depression (potentially culminating in suicidal ideations / thoughts, or suicide attempts and completed suicide (see section 4.4) Hallucinations	Psychotic reactions (potentially culminating in suicidal ideations / thoughts or suicide attempts and completed suicide (see section 4.4)

System Organ Class	Very Common (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1000 to < 1/100	Rare (> 1/10 000 to < 1/1 000	Very Rare (<1/10000)	Not known Cannot be estimated from the available data
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 and pseudotumor cerebri	Peripheral neuropathy and polyneuropathy (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		Ventricular arrhythmia and torsades de pointes * (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolongation (see section 4.4 and 4.9).

System Organ Class	Very Common (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1000 to < 1/100	Rare (> 1/10 000 to < 1/1 000	Very Rare (<1/10000)	Not known Cannot be estimated from the available data
Vascular Disorders				Vasodilatation Hypotension Syncope	Vasculitis
Respiratory, Thoracic and Mediastinal Disorders				Dyspnoea (including asthmatic condition)
Gastrointestinal Disorders		Nausea Diarrhoea	Vomiting Gastrointestinal 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 necrolysis (potentially life-threatening)	Acute generalised exanthematous pustulosis (AGEP)

System Organ Class	Very Common (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1000 to < 1/100	Rare (> 1/10 000 to < 1/1 000	Very Rare (<1/10000)	Not known Cannot be estimated from the available data
Musculoskeletal, Connective Tissue and Bone Disorders			Musculoskeletal 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 Administration Site Conditions		Injection and infusion site reactions (only intravenous administration)	Asthenia Fever	Oedema Sweating (hyperhidrosis)
Investigations			Increase in blood alkaline phosphatase	Increased amylase		International normalized ratio increased (in patients treated with Vitamin K antagonists)

The following undesirable effects have a higher frequency category in the subgroups of patients receiving intravenous or sequential (intravenous to oral) treatment:

Common	Vomiting, Transient increase in transaminases, Rash
Uncommon	Thrombocytopenia, Thrombocytaemia, Confusion and disorientation, Hallucinations, Par- and dysaesthesia, Seizures, Vertigo, Visual disturbances, Hearing loss, Tachycardia, Vasodilatation, Hypotension, Transient hepatic impairment, Cholestatic icterus, Renal failure, Oedema
Rare	Pancytopenia, Bone marrow depression, Anaphylactic shock, Psychotic reactions, Migraine, Olfactory nerve disorders, Hearing impaired, Vasculitis, Pancreatitis, Liver necrosis, Petechiae, Tendon rupture

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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, e.g. ventricular emptying followed by medical carbon, it is recommended to monitor renal function, including urinary pH and acidity, 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

Pharmacotherapeutic group: Fluoroquinolones, ATC code: J01MA02 Mechanism of action:

As a fluoroquinolone antibacterial agent, the bactericidal action of ciprofloxacin results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.

PK/PD relationship:

Efficacy mainly depends on the relation between the maximum concentration in serum (C_max) and the minimum inhibitory concentration (MIC) of ciprofloxacin for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.

Mechanism of resistance:

In-vitro resistance to ciprofloxacin can be acquired through a stepwise process by target site mutations in both DNA gyrase and topoisomerase IV. The degree of cross-resistance between ciprofloxacin and other fluoroquinolones that results is variable. Single mutations may not result in clinical resistance, but multiple mutations generally result in clinical resistance to many or 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. All in-vitro mechanisms of resistance are commonly observed in clinical isolates. Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to ciprofloxacin.

Plasmid-mediated resistance encoded by qnr-genes has been reported.

Spectrum of antibacterial activity:

Breakpoints separate susceptible strains from strains with intermediate susceptibility and the latter from resistant strains:

EUCAST Recommendations

Microorganism	Clinical MIC Breakpoints (mg/l)
	S (<)	R (>)	ECOFF
Enterobacteriaceae	0.5	1	0.125
Pseudomonas	0.5	1	05
Acinetobacter	1	1	1
Staphylococcus	1	1	1

Microorganism	Clinical MIC
	Breakpoints (mg/l)
	S (<)	R (>)	ECOFF
Staphylococcus, coagulase negative			ND
Enterococcus			4
Streptococcus A, B, C and G			2
Streptococcus pneumoniae	0.12	2	2
Viridans Streptococci			ND
Haemophilus influenzae	0.5	05	0.064
Moraxella catarrhalis	0.5	05	0.125
Neisseria gonorrhea	0.03	0.06	0.016
Neisseria meningitides*	0.03	0.06	0.016
Gram-positive anaerobes except Clostridium difficile			ND
Gram-negative anaerobes			ND
* Breakpoint applies only to use in prophylaxis of meningococcal c			isease.
S: sensitive. R: Resistant
NR: Not determined.
ECOFF: Common epidemiological cut-off point for surveillance of resistance.
-: susceptibility testing is not recommended as the species is a poor target for
therapy with the drug.

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

Groupings of relevant species according to ciprofloxacin susceptibility (for Streptococcus species see section 4.4)

COMMONLY SUSCEPTIBLE SPECIES

Aerobic Gram-positive micro-organisms

Bacillus anthracis (1)

5.2 Pharmacokinetic properties

Absorption

Following an intravenous infusion of ciprofloxacin the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of ciprofloxacin were linear over the dose range up to 400 mg administered intravenously.

Comparison of the pharmacokinetic parameters for a twice a day and three times a day intravenous dose regimen indicated no evidence of drug accumulation for ciprofloxacin and its metabolites.

A 60-minute intravenous infusion of 200 mg ciprofloxacin or the oral administration of 250 mg ciprofloxacin, both given every 12 hours, produced an equivalent area under the serum concentration time curve (AUC).

A 60-minute intravenous infusion of 400 mg ciprofloxacin every 12 hours was bioequivalent to a 500 mg oral dose every 12 hours with regard to AUC.

The 400 mg intravenous dose administered over 60 minutes every 12 hours resulted in a C_max similar to that observed with a 750 mg oral dose.

A 60-minute infusion of 400 mg ciprofloxacin every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.

Distribution

Protein binding of ciprofloxacin is low (20-30%). Ciprofloxacin is present in plasma largely in a non-ionised form and has a large steady state distribution volume of 2-3 litres/kg body weight. Ciprofloxacin reaches high concentrations in a variety of tissues such as lung (epithelial fluid, alveolar macrophages, biopsy tissue), sinuses, inflamed lesions (cantharides blister

fluid), and the urogenital tract (urine, prostate, endometrium) where total concentrations exceeding those of plasma concentrations are reached.

Metabolism

Low concentrations of four metabolites have been reported, which were identified as: desethylene ciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.

Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 isoenzymes.

Elimination

Ciprofloxacin is largely excreted unchanged both renally and, to a smaller extent, faecally.

Excretion of ciprofloxacin (% of dose)
	Intravenous Administration
	Urine	Faeces
Ciprofloxacin	61.5	15.2
Metabolites (M1-M4)	9.5	2.6

Renal clearance is between 180-300 ml/kg/h and the total body clearance is between 480-600 ml/kg/h. Ciprofloxacin undergoes both glomerular filtration and tubular secretion. Severely impaired renal function leads to increased half lives of ciprofloxacin of up to 12 h.

Non-renal clearance of ciprofloxacin is mainly due to active trans-intestinal secretion and metabolism. 1% of the dose is excreted via the biliary route. Ciprofloxacin is present in the bile in high concentrations.

Paediatric patients

The pharmacokinetic data in paediatric patients 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 C_max was 6.1 mg/l (range 4.6-8.3 mg/l) after a 1-hour intravenous infusion of 10 mg/kg in children aged less than 1 year compared to 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%.

5.3 Preclinical safety data

Non-clinical data reveal no special hazards for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential, or toxicity to reproduction.

Like a number of other quinolones, ciprofloxacin is phototoxic in animals at clinically relevant exposure levels. Data on photomutagenicity/ photocarcinogenicity show a weak photomutagenic or phototumourigenic effect of ciprofloxacin in-vitro and in animal experiments. This effect was comparable to that of other gyrase inhibitors.

Articular tolerability:

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

(S)-Lactic Acid

Glucose Monohydrate

Hydrochloric Acid Concentrated for pH adjustment Water for Injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

Unless compatibility with other solutions / drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding and discolouration.

Incompatibility appears when all infusion solutions / drugs that are physically or chemically unstable at the pH of the solutions (e.g. penicillins, heparin solutions), especially in combination with solutions adjusted to an alkaline pH (pH of ciprofloxacin solutions: 3.5 to 4.6.

6.3    Shelf life

24 months

From a microbiological point of view, the product should be used immediately.

If not used immediately, in use storage times and conditions prior to use are the responsibility of the user.

6.4    Special precautions for storage

Store in the original package to protect from light.

Do not refrigerate or freeze.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5    Nature and contents of container

Ciprofloxacin 2 mg/ml Solution for Infusion is packaged in a plastic container-closure system (infusion bag) of 100 ml or 200 ml. The container consists of the following components:

•    Plastic bag

•    Two port tubes (one as a medication site and one as an administration site)

•    One bag stopper

•    One twist-off protector

Each single-dose infusion bag is sealed into a laminated foil overpouch, which provides a moisture and light barrier.

Pack sizes of 10 and 50 bags for Ciprofloxacin 2 mg/ml Solution for Infusion in 100 ml bags.

Pack sizes of 10 and 30 bags for Ciprofloxacin 2 mg/ml Solution for Infusion in 200 ml bags.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

As the infusion solution is sensitive to light, the infusion bags should be removed from the box only immediately before use. In daylight conditions the full efficacy of the solution is guaranteed for a period of three days.

For single use only.

At cool temperatures precipitation may occur, which will re-dissolve at room temperature (15°C to 25°C).

Any unused solution should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Infomed Fluids SRL

50 Theodor Pallady Blvd., District 3,

032266 Bucharest,

Romania

Tel: + 40 21 345 02 22 Fax: + 40 21 345 31 85 E-mail: office@infomedfluids.ro

8    MARKETING AUTHORISATION NUMBER(S)

PL 36780/0002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/05/2014

10 DATE OF REVISION OF THE TEXT

17/10/2016