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CIPROFLOXACIN 400MG/200ML SOLUTION FOR INFUSION

Active substance(s): CIPROFLOXACIN

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Ciprofloxacin 400 mg/200 ml, solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution for infusion contains 2 mg ciprofloxacin (as hydrogen sulphate)
200 ml solution contains 400 mg ciprofloxacin.
Excipient with known effect: Sodium
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for infusion
Clear, colourless solution
pH of the solution: 4.0 to 4.9

4
4.1

CLINICAL PARTICULARS
Therapeutic indications
Ciprofloxacin 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 Gramnegative bacteria



Urinary tract infections



Epididymo-orchitis including cases due to Neisseria gonorrhoeae



Pelvic inflammatory disease including cases due to Neisseria gonorrhoeae

In the above genital tract infections when thought or known to be due to Neisseria
gonorrhoeae it is particularly important to obtain local information on the prevalence
of resistance to ciprofloxacin and to confirm susceptibility based on laboratory
testing.


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



Treatment of infections in neutropenic patients



Prophylaxis of infections in neutropenic patients



Inhalation anthrax (post-exposure prophylaxis and curative treatment)

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

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 coadministration with other appropriate antibacterial agents depending on the pathogens
involved.

Adults

Indications

Daily dose in mg

Infections of the lower respiratory tract

Infections of the
upper respiratory
tract

Urinary tract
infections

Genital tract
infections

Acute exacerbation
of chronic sinusitis

400 mg twice daily to
400 mg three times a
day
400 mg twice daily to
400 mg three times a
day

Total duration of treatment
(including switch to oral therapy
as soon as possible)
7 to 14 days

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
Complicated and
uncomplicated
pyelonephritis

400 mg three times a
day
400 mg twice daily to
400 mg three times a
day

28 days up to 3 months

Prostatitis

400 mg twice daily to
400 mg three times a
day

2 to 4 weeks (acute)

Epididymo-orchitis
and pelvic
inflammatory
diseases

400 mg twice daily to
400 mg three times a
day

at least 14 days

7 to 21 days, it can be continued
for longer than 21 days in some
specific circumstances (such as
abscesses)

Indications

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

Total duration of treatment
(including switch to oral therapy
as soon as possible)
1 day

Diarrhoea caused by
Shigella dysenteriae
type 1
Diarrhoea caused by
Vibrio cholerae
Typhoid fever
Intra-abdominal
infections due to
Gram-negative
bacteria

400 mg twice daily

5 days

400 mg twice daily

3 days

400 mg twice daily
400 mg twice daily to
400 mg three times a
day

7 days
5 to 14 days

Infections of the skin and soft tissue

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

Treatment of infections or prophylaxis of
infections in neutropenic patients
Ciprofloxacin should be co-administered
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 post-exposure
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

Infections of the
gastro-intestinal
tract and intraabdominal
infections

Daily dose in mg

Paediatric population
Indication

Cystic fibrosis

Daily dose in mg

10 mg/kg body weight three times a day with a
maximum of 400 mg per dose.

Total duration of
treatment (including
switch to oral therapy
as soon as possible)
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
post-exposure
curative treatment
for persons
requiring parenteral
treatment
Drug administration
should begin as
soon as possible
after suspected or
confirmed
exposure.
Other severe
infections

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

10 mg/kg body weight three times a day with a
maximum of 400 mg per dose.

According to the type of
infections

Older people
Older people 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]
> 60
30-60
< 30
Patients on haemodialysis
Patients on peritoneal dialysis

Serum Creatinine
[µmol/L]
< 124
124 to 168
> 169
> 169
> 169

Intravenous Dose
[mg]
See Usual Dosage.
200-400 mg every 12h
200-400 mg every 24h
200-400 mg every 24h (after
dialysis)
200-400 mg every 24h

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 Kabi 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 Ciprofloxacin Kabi and 30 minutes
for 200 mg Ciprofloxacin Kabi. 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).

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3

Contraindications



Hypersensitivity to the active substance, to other quinolones or to any of the
excipients listed in 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 coadministered with other appropriate antibacterial
agents.
Streptococcal Infections (including Streptococcus pneumoniae)
Ciprofloxacin is not recommended for the treatment of streptococcal infections due to
inadequate efficacy.
Genital tract infections
Epididymo-orchitis and pelvic inflammatory diseases may be caused by
fluoroquinolone-resistant Neisseria gonorrhoeae. Ciprofloxacin should be coadministered with another appropriate antibacterial agent unless ciprofloxacinresistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not
achieved after 3 days of treatment, the therapy should be reconsidered.
Intra-abdominal infections
There are limited data on the efficacy of ciprofloxacin in the treatment of postsurgical intra-abdominal infections.
Travellers’ diarrhoea
The choice of ciprofloxacin should take into account information on resistance to
ciprofloxacin in relevant pathogens in the countries visited.
Infections of the bones and joints
Ciprofloxacin should be used in combination with other antimicrobial agents
depending on the results of the microbiological documentation.
Inhalational anthrax
Use in humans is based on in-vitro susceptibility data and on animal experimental
data together with limited human data. Treating physicians should refer to national
and /or international consensus documents regarding the treatment of anthrax.
Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye
specialist should be consulted immediately.
Paediatric 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 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 (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 benefitrisk 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 lifethreatening. If such reaction occurs, ciprofloxacin should be discontinued and an
adequate medical treatment is required.
Musculoskeletal System
Ciprofloxacin should generally not be used in patients with a history of tendon
disease/disorder related to quinolone treatment. Nevertheless, in very rare instances,
after microbiological documentation of the causative organism and evaluation of the

risk/benefit balance, ciprofloxacin may be prescribed to these patients for the
treatment of certain severe infections, particularly in the event of failure of the
standard therapy or bacterial resistance, where the microbiological data may justify
the use of ciprofloxacin.
Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may
occur with ciprofloxacin, as soon as the first 48 hours of treatment. Inflammation and
ruptures of tendon may occur even up to several months after discontinuation of
ciprofloxacin therapy. The risk of tendinopathy may be increased in elderly patients or
in patients concomitantly treated with corticosteroids (see section 4.8).
At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment
should be discontinued. Care should be taken to keep the affected limb at rest.
Ciprofloxacin should be used with caution in patients with myasthenia gravis (see
section 4.8).
Photosensitivity
Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking
ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight
or UV irradiation during treatment (see section 4.8).
Central Nervous System
Ciprofloxacin like other quinolones are known to trigger seizures or lower the seizure
threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be
used with caution in patients with CNS disorders which may be predisposed to
seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8).
Psychiatric reactions may occur even after the first administration of ciprofloxacin. In
rare cases, depression or psychosis can progress to 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)
Older people 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 Older people, section 4.5, section 4.8, section 4.9).

Gastrointestinal System
The occurrence of severe and persistent diarrhoea during or after treatment (including
several weeks after treatment) may indicate an antibiotic-associated colitis (lifethreatening with possible fatal outcome), requiring immediate treatment (see section
4.8). In such cases, ciprofloxacin should immediately be discontinued, and an
appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this
situation.
Renal and urinary System
Crystalluria related to the use of ciprofloxacin has been reported (see section 4.8).
Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of
the urine should be avoided.
Impaired renal function
Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment
is needed in patients with impaired renal function as described in section 4.2 to avoid
an increase in adverse drug reactions due to accumulation of ciprofloxacin.
Hepatobiliary System
Cases of hepatic necrosis and life-threatening hepatic failure have been reported with
ciprofloxacin (see section 4.8). In the event of any signs and symptoms of hepatic
disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen),
treatment should be discontinued.
Glucose-6-phosphate dehydrogenase deficiency
Haemolytic reactions have been reported with ciprofloxacin in patients with glucose6-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, agomelatine). 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.
NaCl Load
Ciprofloxacin Kabi contains 15.1 mmol (347 mg) sodium per 100 ml solution for
infusion.
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.

4.5

Interaction with other medicinal products and other forms of interaction

Effects of other medicinal 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 antiarrhythmics, 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.
Metoclopramide
Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a
shorter time to reach maximum plasma concentrations. No effect was seen on the
bioavailability of ciprofloxacin.
Omeprazole
Concomitant administration of ciprofloxacin and omeprazole containing medicinal
products results in a slight reduction of Cmax and AUC of ciprofloxacin.
Effects of ciprofloxacin on other medicinal products:
Tizanidine
Tizanidine must not be administered together with ciprofloxacin (see section 4.3). In a
clinical study with healthy subjects, there was an increase in serum tizanidine
concentration (Cmax increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold,

range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Increased serum
tizanidine concentration is associated with a potentiated hypotensive and sedative
effect.
Methotrexate
Renal tubular transport of methotrexate may be inhibited by concomitant
administration of ciprofloxacin, potentially leading to increased plasma levels of
methotrexate and increased risk of
methotrexate-associated toxic reactions. The concomitant use is not recommended
(see section 4.4).
Theophylline
Concurrent administration of ciprofloxacin and theophylline can cause an undesirable
increase in serum theophylline concentration. This can lead to theophylline-induced
side effects that may rarely be life threatening or fatal. During the combination, serum
theophylline concentrations should be checked and the theophylline dose reduced as
necessary (see section 4.4).
Other xanthine derivatives
On concurrent administration of ciprofloxacin and caffeine or pentoxifylline
(oxpentifylline), raised serum concentrations of these xanthine derivatives were
reported.
Phenytoin
Simultaneous administration of ciprofloxacin and phenytoin may result in increased
or reduced serum levels of phenytoin such that monitoring of drug levels is
recommended.
Cyclosporin
A transient rise in the concentration of serum creatinine was observed when
ciprofloxacin and cyclosporin containing medicinal products were administered
simultaneously. Therefore, it is frequently (twice a week) necessary to control the
serum creatinine concentrations in these patients.
Vitamin K antagonists
Simultaneous administration of ciprofloxacin with a vitamin K antagonist may
augment its anti-coagulant effects.
The risk may vary with the underlying infection, age and general status of the patient
so that the contribution of the fluoroquinolone to the increase in INR (international
normalised ratio) is difficult to assess. The INR should be monitored frequently
during and shortly after co-administration of ciprofloxacin with a vitamin K
antagonist (e.g. warfarin, acenocoumarol, phenprocoumon, or fluindione).
Glibenclamide
In particular cases, concurrent administration of ciprofloxacin and glibenclamide
containing medicinal products can intensify the action of glibenclamide
(hypoglycaemia).
Duloxetine

In clinical studies, it was demonstrated that concomitant use of duloxetine with strong
inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase
of AUC and Cmax of duloxetine. Although no clinical data are available on a possible
interaction with ciprofloxacin, similar effects can be expected upon concomitant
administration (see section 4.4).
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 Cmax and
AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related
side effects and dose adjustment as appropriate is recommended during and shortly
after co-administration with ciprofloxacin (see section 4.4).
Lidocaine
It was demonstrated in healthy subjects that concomitant use of lidocaine containing
medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme,
reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was
well tolerated, a possible interaction with ciprofloxacin associated with side effects
may occur upon concomitant administration.
Clozapine
Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7
days, serum concentrations of clozapine and N-desmethylclozapine were increased by
29% and 31%, respectively.
Clinical surveillance and appropriate adjustment of clozapine dosage during and
shortly after co-administration with ciprofloxacin are advised (see section 4.4).
Sildenafil
Cmax and AUC of sildenafil were increased approximately twofold in healthy
subjects after an oral dose of 50 mg given concomitantly with 500 mg ciprofloxacin.
Therefore, caution should be used prescribing ciprofloxacin concomitantly with
sildenafil taking into consideration the risks and the benefits.
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 ciprofloxacin may increase blood levels of zolpidem, concurrent
use is not recommended.
4.6

Fertility, pregnancy and lactation

Pregnancy

The data that are available on administration of ciprofloxacin to pregnant women indicates no
malformative or feto/neonatal toxicity of ciprofloxacin. Animal studies do not indicate direct
or indirect harmful effects with respect to reproductive toxicity. In juvenile and prenatal
animals exposed to quinolones, effects on immature cartilage have been observed, thus, it
cannot be excluded that the drug could cause damage to articular cartilage in the human
immature organism / foetus (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during
pregnancy.
Breast-feeding
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.
ADRs derived from clinical studies and post-marketing surveillance with
Ciprofloxacin (oral, intravenous and sequential therapy) sorted by categories of
frequency are listed below. The frequency analysis takes into account data from both
oral and intravenous administration of ciprofloxacin.
System Organ
Class

Common

Uncommon

≥ 1/100 to

≥ 1/1 000 to

< 1/10

< 1/100

Infections and
Infestations

Mycotic
superinfections

Blood and
Lymphatic
System Disorders

Eosinophilia

Immune System
Disorders

Rare
≥ 1/10 000 to
< 1/1 000

Very Rare
< 1/10 000

Leukopenia,
Anaemia,
Neutropenia,
Leukocytosis
Thrombocytopenia
, Thrombocytosis

Haemolytic
anaemia,
Agranulocytosis
(life-threatening),
Pancytopenia (lifethreatening), Bone
marrow depression
(lifethreatening)

Allergic reaction,
Allergic oedema /
Angiooedema

Anaphylactic
reaction,
Anaphylactic
shock (lifethreatening) (see
section 4.4),
Serum sicknesslike reaction

Frequency not
known (cannot be
estimated from
available data)

≥ 1/100 to

≥ 1/1 000 to

< 1/10

< 1/100

Rare
≥ 1/10 000 to
< 1/1 000

Very Rare
< 1/10 000

Frequency not
known (cannot be
estimated from
available data)

Metabolism and
Nutrition
Disorders

Anorexia

Hyperglycaemia

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
Par- and
Dysaesthesia,
Hypoaesthesia,
Tremor, Seizures
(incl. status
epilepticus, see
section 4.4),
Vertigo

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

Mania, hypomania

Nervous System
Disorders

Headache,
Dizziness, Sleep
disorders, Taste
disorders

Migraine,
Disturbed
coordination, Gait
disturbance,
Olfactory nerve
disorders,
Intracranial
hypertension

Peripheral
neuropathy (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

Vascular
Disorders

Vasodilatation,
Hypotension,
Syncope

Respiratory,
Thoracic and
Mediastinal
Disorders

Dyspnoea
(including
asthmatic
condition)

System Organ
Class

Common

Uncommon

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).
Vasculitis

Rare
≥ 1/10 000 to
< 1/1 000

Very Rare
< 1/10 000

Vomiting,
Gastrointestinal,
and abdominal
pains, Dyspepsia,
Flatulence

Antibiotic
associated diarrhea
incl
pseudomembraneo
us colitis (very
rarely with
possible fatal
outcome) (see
section 4.4)

Pancreatitis

Hepatobiliary
Disorders

Increase in
transaminases,
Increased bilirubin

Hepatic
impairment,
Cholestatic
icterus, Hepatitis

Liver necrosis
(very rarely
progressing to lifethreatening 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, StevensJohnson
Syndrome
(potentially lifethreatening),
Toxic epidermal
necrolysis
(potentially lifethreatening)

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

Asthenia Fever

Oedema Sweating
(hyperhidrosis)

System Organ
Class

Gastrointestinal
Disorders

General
Disorders and
Administration
Site Conditions

Common

Uncommon

≥ 1/100 to

≥ 1/1 000 to

< 1/10

< 1/100

Nausea Diarrhoea

Injection and
infusion site
reactions (only
intravenous
administration)

Frequency not
known (cannot be
estimated from
available data)

Acute generalised
exanthemato us
pustulosis
(AGEP), DRESS

Common

System Organ
Class

Uncommon

≥ 1/100 to

≥ 1/1 000 to

< 1/10

< 1/100
Increase in blood
alkaline
phosphatase

Investigations

Rare
≥ 1/10 000 to
< 1/1 000

Very Rare
< 1/10 000

Increased amylase

Frequency not
known (cannot be
estimated from
available data)
International
normalised 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
Uncommon

Vomiting, Transient increase in transaminases, Rash
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 population
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 national reporting system.
For the UK:
You can report side effects directly via the Yellow Card Scheme:
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
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.
Management
Apart from routine emergency measures, it is recommended to monitor renal function,
including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept
well hydrated.
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.

5.1

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.
Pharmacodynamic effects:
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 crossresistance 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
Microorganisms
Susceptible
Resistant
Enterobacteria
S ≤ 0.5 mg/L
R > 1 mg/L
Pseudomonas
S ≤ 0.5 mg/L
R > 1 mg/L
Acinetobacter
S ≤ 1 mg/L
R > 1 mg/L
Staphylococcus spp.1
S ≤ 1 mg/L
R > 1 mg/L
Haemophilus influenzae and
S ≤ 0.5 mg/L
R > 0.5 mg/L
Moraxella catarrhalis
Neisseria gonorrhoeae
S ≤ 0.03 mg/L
R > 0.03 mg/L
Neisseria meningitidis
S ≤ 0.03 mg/L
R > 0.03 mg/L
Non-species-related
S ≤ 0.5 mg/L
R > 1 mg/L
breakpoints*
1 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).
COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive micro-organisms
Bacillus anthracis (1)
Aerobic Gram-negative micro-organisms
Aeromonas spp.
Brucella spp.
Citrobacter koseri
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae*
Legionella spp.
Moraxella catarrhalis*
Neisseria meningitidis
Pasteurella spp.
Salmonella spp.*
Shigella spp. *
Vibrio spp.
Yersinia pestis

Anaerobic micro-organisms
Mobiluncus
Other micro-organisms
Chlamydia trachomatis ($)
Chlamydia pneumoniae ($)
Mycoplasma hominis ($)
Mycoplasma pneumoniae ($)
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive micro-organisms
Enterococcus faecalis ($)
Staphylococcus spp. *(2)
Aerobic Gram-negative micro-organisms
Acinetobacter baumannii+
Burkholderia cepacia +*
Campylobacter spp.+*
Citrobacter freundii*
Enterobacter aerogenes
Enterobacter cloacae *
Escherichia coli*
Klebsiella oxytoca
Klebsiella pneumoniae*
Morganella morganii*
Neisseria gonorrhoeae*
Proteus mirabilis*
Proteus vulgaris*
Providencia spp.
Pseudomonas aeruginosa*
Pseudomonas fluorescens
Serratia marcescens*
Anaerobic micro-organisms
Peptostreptococcus spp.
Propionibacterium acnes
INHERENTLY RESISTANT ORGANISMS
Aerobic Gram-positive micro-organisms
Actinomyces
Enteroccus faecium
Listeria monocytogenes
Aerobic Gram-negative micro-organisms
Stenotrophomonas maltophilia
Anaerobic micro-organisms
Excepted as listed above
Other micro-organisms
Mycoplasma genitalium
Ureaplasma urealitycum

*

Clinical efficacy has been demonstrated for susceptible isolates in approved
clinical indications
($): Resistance rate ≥ 50% in one or more EU countries
(1): Natural intermediate susceptibility in the absence of acquired mechanism of
resistance
Studies have been conducted in experimental animal infections due to
inhalations of Bacillus anthracis spores; these studies reveal that antibiotics
starting early after exposition avoid the occurrence of the disease if the
treatment is made up to the decrease of the number of spores in the organism
under the infective dose. The recommended use in human subjects is based
primarily on in-vitro susceptibility and on animal experimental data together
with limited human data. Two-month treatment duration in adults with oral
(2): ciprofloxacin given at the following dose, 500 mg bid, is considered as
effective to prevent anthrax infection in humans. The treating physician should
refer to national and /or international consensus documents regarding treatment
of anthrax.
Methicillin-resistant S. aureus very commonly express co-resistance to
fluoroquinolones. The rate of resistance to methicillin is around 20 to 50%
among all staphylococcal species and is usually higher in nosocomial isolates.
+

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 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 non-ionised 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-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 iso-enzymes.
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 population
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 Cmax 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 phototumorigenic 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
Sodium chloride
Sulphuric acid
Sodium hydroxide for pH adjustment
Water for injections

6.2

Incompatibilities
Ciprofloxacin cannot be mixed with solutions that are not stable at a pH of
approximately 4.
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6

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

Do not refrigerate or freeze.
Keep infusion bag in the overpouch until ready to use in order to protect from light.

Keep the infusion bottle in the outer carton until ready to use in order to protect from light.
For storage conditions of the medicinal product see section 6.3.

6.5

Nature and contents of container
Clear flexible polyolefine bag with aluminium overpouch or polyethylene bottles
(KabiPac).
Ciprofloxacin 100 mg/50 ml solution for infusion:
pack sizes:
1, 5, 10, 12, 20, 30 or 40 bags
1, 5, 10, 12, 20, 25, 30 or 40 bottles.
Ciprofloxacin 200 mg/100 ml solution for infusion:
pack sizes:
1, 5, 10, 12, 20, 30 or 40 bags.
1, 5, 10, 12, 20, 25, 30 or 40 bottles.
Ciprofloxacin 400 mg/200 ml solution for infusion:
pack sizes:
1, 5, 10, 12, 20, 30 or 40 bags.
1, 5, 10, 12, 20, 30 or 40 bottles.
Not all pack sizes may be marketed.

6.6.

Special precautions for disposal
Any unused product or waste material should be disposed of in accordance
with local requirements.
Use only clear solutions and undamaged containers.
For single use only.
Any unused medical product or waste material should be disposed of in
accordance with local requirements.
To be used immediately after the bag/bottle is opened.
Do not prepare admixtures in glass bottles.
Ciprofloxacin Kabi is compatible with isotonic sodium chloride solution,
Ringer’s solution, Ringer’s lactate solution, 50 mg/ml (5 %) or 100 mg/ml
(10 %) glucose solution and 50 mg/ml (5 %) glucose solution with 2.25 mg/ml
(0.225 %) or 4.5 mg/ml (0.45 %) sodium chloride solution. Compatibility with
these solutions has been proven in the dilution range of 1+1 and 1+4,
corresponding to ciprofloxacin concentrations of 0.4 to 1 mg/ml. Unless
compatibility is proven, the solution for infusion should always be
administered separately (see also section 6.2).
The reconstituted solution should be inspected visually for particulate matter
and discoloration prior to administration. The reconstituted solution is clear
and colourless.

7

MARKETING AUTHORISATION HOLDER
Fresenius Kabi Limited
Cestrian Court
Eastgate Way
Manor Park
Runcorn
Cheshire
WA7 1NT
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 08828/0172

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/09/2010

10

DATE OF REVISION OF THE TEXT
26/09/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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