Cifogru 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.

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

- 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. travelers’ diarrhea)

• 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 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).

Posology

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, 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.

Adult

((Table))

pediatric population 

((Table))

Elderly patients

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

Patients with renal and hepatic impairment

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

((Table))

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

Cifogru 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 Cifogru solution for infusion and 30 minutes for 200 mg Cifogru solution for infusion. Slow infusion into a large vein will minimize 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 6.6).

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 pneumonia)

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) 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.

Intra‐abdominal infections

There are limited data on the efficacy of ciprofloxacin in the treatment of post‐surgical intra‐abdominal infections.

Travellers' diarrhea

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.

Pediatric population

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 randomized 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 (see section 4.8).

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 anaphylactic 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 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, because symptoms can be exacerbated (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 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 antiarrhythmic, tricyclic antidepressants, macrolides, antipsychotics)

‐ Uncorrected electrolyte imbalance (e.g. hypokalemia, 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 patients, section 4.5, section 4.8, section 4.9).

Hypoglycemia

As with other quinolones, hypoglycemia 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 diarrhea 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

Crystal Luria 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

Hemolytic 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 hemolysis 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 metabolized by this enzyme (e.g. theophylline, clozapine,olanzapine ropinirole, tizanidine, duloxetine, agomelatine). 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). Co‐administration of ciprofloxacin and tizanidine is contra‐indicated.

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.

NaCl Load

In patients for whom sodium intake is of medical concern (patients with congestive heart failure, renal failure, nephrotic syndrome, etc.), the additional sodium load should be taken into account (for sodium chloride content, see section 2).

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).

Probenecid

Probenecid interferes with renal secretion of ciprofloxacin. Co‐administration of probenecid and

ciprofloxacin increases ciprofloxacin serum concentrations.

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.

Cyclosporine

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 anticoagulant

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 normalized 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).

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 C max 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 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 coadministration

with ciprofloxacin are advised (see section 4.4).

Sildenafil

C max 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.

Agomelatine

In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2

isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60‐fold increase of

agomelatine exposure. Although no clinical data are available for a possible interaction with

ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant

administration (see 'Cytochrome P450' in section 4.4).

Zolpidem

Co‐administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not

recommended.

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 / fetus (see section 5.3).

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

Breast-feeding

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

Due to its neurological effects, ciprofloxacin may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.

Like all drug products, CIFOGRU ® can have side effects which need not affect everybody. However, the following incidence rating is used to evaluate the frequency of side effects:

• Frequent: fewer than 1 in 10 but more than 1 in 100 treated patients

• Uncommon: fewer than 1 in 100 but more than 1 in 1,000 treated patients

• Rare: fewer than 1 in 1,000 but more than 1 in 10,000 treated patients

• Very rare: fewer than 1 in 10,000 treated patients, including isolated cases

Infections and infestations

Uncommon: Mycotic super infections

Blood and lymphatic system disorder:

Uncommon: Increased numbers of certain white blood cells (eosinophilia).

Rare: Leukopenia, Anemia, Neutropenia, Leukocytosis, thrombocythemia and Thrombocytopenia

Very rare: Hemolytic anemia Agranulocytosis, Pancytopenia (life-threatening), and Bone marrow depression (life threatening).

Immune system disorders

Rare: Allergic reaction, swelling as a result of an allergic reaction (allergic Edema / angioedema)

Very rare: Hypersensitivity reaction (anaphylactic reaction), difficult breathing ranging up to lifethreatening shock (anaphylactic shock) (see section 4.4), and serum disease‐like reaction.

Metabolism and nutrition disorders

Uncommon: Anorexia.

Rare: Increased blood glucose (hyperglycemia) and Hypoglycemia.

Psychiatric Disorders:

Uncommon: Psychomotor hyperactivity/ agitation

Rare: Confusion and disorientation, anxiety reaction, abnormal dreams, depression, hallucinations.

Very rare: Psychotic reactions (potentially culminating in suicidal ideations/ thoughts or suicide attempts and completed suicide) (see section 4.4)

Frequency not known: Mania, incl. hypomania

Nervous system disorders

Uncommon: Headache, dizziness, sleep disorders, taste disorders.

Rare: Par‐ and Dysesthesia, Hypoesthesia, Tremor, Seizures (including status epilepticus see section 4.4) and Vertigo

Very rare: Migraine, Disturbed coordination, Gait disturbance, Olfactory nerve disorders

Intracranial hypertension and pseudotumor cerebri.

Frequency not known: Peripheral neuropathy and polyneur-opathy (see section 4.4)

Eye disorder:

Rare: Visual disturbances (including blurred and double vision)

Very rare: Visual color distortions

Ear Labyrinth Disorders:

Rare: Tinnitus, transient hearing disorders (e.g. ranging from difficulty hearing to loss of hearing)

Cardiac Disorders:

Rare: Tachycardia

Frequency not known: Ventricular arrhythmia, torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see sections 4.4 and 4.9)

Vascular disorders:

Rare: Vasodilatation, low blood pressure, Syncope.

Very rare: Inflammatory changes to the blood vessels, associated with skin symptoms (vasculitis).

Respiratory Thoracic and Mediastinal Disorders:

Rare: Difficult breathing (dyspnoea), including asthmatic conditions.

Gastrointestinal disorders

Frequent: Nausea, diarrhea

Uncommon: Vomiting, impaired digestion, stomach and abdominal pain, flatulence

Rare: Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4)

Very rare: Pancreatitis.

Hepatobiliary disorders

Uncommon: Increased level of certain liver enzymes in blood (transaminase), increased blood level of the bile pigment bilirubin (including hyperbilirubinemia),

Rare: Hepatic impairment, jaundice, hepatitis (non‐infective).

Very rare: Liver necrosis (ranging up to life‐threatening hepatic failure).

Skin and subcutaneous tissue disorders

Uncommon: Rash, pruritus, nettle rash (urticaria)

Rare: Light sensitivity with reddening of the skin (photosensitivity reactions) (see section 2)

Very rare: Punctate skin hemorrhaging (petechiae), erythema nodosum, Disc‐shaped skin reddening (erythema multifome minor) ranging up to severe skin rash taking a feverish course (Stevens Johnson syndrome), blistering, detachment of the epidermis, oral and nasal rnucosa (toxic epidermal necrolysis)

Frequency not known: Acute Generalised Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Musculoskeletal, connective tissue and bone disorders

Uncommon: Musculoskeletal pain (e.g. extremity pain, back pain, chest pain) , Arthralgia.

Rare: Myalgia, arthritis, increased muscle tone and cramping.

Vent rare: Muscular weakness, inflammation of the tendons (tendinitis) , Torn tendons, especially the Achilles tendon, exacerbation of symptoms of myasthenia gravis (see section 4.4)

Renal and urinary disorders

Uncommon: Renal impairment .

Rare: Renal failure ,Haematuria ,Crystalluria (see section 4.4) ,Tubulointerstitial nephritis

General disorders and administration site conditions

Frequent: Local reactions at the injection site.

Uncommon: Asthenia, Fever.

Rare: Sweating (hyperhidrosis), edema.

Investigations

Uncommon: Increase in blood alkaline phosphatase.

Rare: Increased levels of certain enzymes (amylase).

Frequency not known: 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, Parand 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

To reports any side effect(s):

·       Saudi Arabia:

·       Other GCC States:

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 crystal Luria and hematuria. 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 acidify, if required, to prevent crystal Luria. 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 hemodialysis 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

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.

Pharmacokinetic/pharm acodynamics relationship

Efficacy mainly depends on the relation between the maximum concentration in serum (Cmax) 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:

E UCAST Recommendations

((Table))

Staphylococcus spp. ‐ breakpoints for ciprofloxacin relate to high dose therapy.

* Non‐species‐related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species‐specific breakpoint and not for those species where susceptibility testing is not recommended.

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).

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 Cmax 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 nonionised

form and has a large steady state distribution volume of 2‐3 L/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.

Biotransformation

Low concentrations of four metabolites have been reported, which were identified as:

desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and

formylciprofloxacin (M 4). The metabolites display in‐vitroantimicrobial activity but to a lower degree

than the parent compound.

Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 iso‐enzymes.

Elimination

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

((Table))

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 C max and AUC were not age‐dependent (above one year of age). No notable increase in C max 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%.

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 orPhototumorigenic effect of ciprofloxacin in‐vitroand 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.

Sodium Chloride, Hydrochloric Acid, Lactic acid 88%, Sodium Hydroxide and Water for injection.

Ciprofloxacin solution for infusion should be administered without mixing with any other substances or infusion fluids.

Do not store above 30°C, protect from light.

Polyolefin Bags 300ml with Plug for bag

The ciprofloxacin infusion solution is compatible with Ringer solution, Ringer lactate solution, 5 % and 10 % glucose solutions, when ciprofloxacin infusion solutions are mixed with compatible infusion solutions, for microbial reasons and light sensitivity these solutions must be administered shortly after admixture.

As the infusion solution is sensitive to light, only remove the bottles from the folding box for use. In daylight, the full efficacy of the solution is guaranteed over a period of 3 days.

For single use only.

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

The solution should be visually inspected for particulate matter and discoloration prior to administration. Only clear and colourless or slightly yellow solution should be used.

Any unused solution and the bags should be adequately disposed of, in accordance with local requirements.