APPROVED BY

Order of the Ministry

of Ukraine

11.01.2016 №  6_

Registration certificate

№ UA/10746/01/01

 

 

INSTRUCTION

for medical use of the preparation

СІРROFLOXACIN

 

Composition:

Active substance: 100 ml of solution contain 200 mg of ciprofloxacin;

Exipients: lactic acid, sodium chloride, disodium edetate, concentrated hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for infusion.

Basic physical and chemical properties: Clear, colourless solution.

Pharmaceutical group. Antibacterial agents for systemic use. Pharmacotherapeutic group: Fluoroquinolones. Ciprofloxacin. ATC code: J01M A02.

Pharmacological properties.

Pharmacodynamics.

Ciprofloxacin inhibits DNA gyrase enzyme which plays an important role in the process of segment despiralization and spiralization of chromosomes during the phase of bacterial growth and prevents transcription of chromosomal information required for normal metabolism of the bacterial cell, which leads to inhibition of the ability of pathogen reproduction.

The drug provides rapid and pronounced bactericidal effect on microorganisms that are both in the phase of reproduction, and in the stable phase. Shows high effectiveness in relation to almost all gram-positive and gram-negative pathogens. Escherichia coli, Shigella spp., Salmonella spp., Citrobacter spp., Klebsiella spp., Enterobacter spp., Serratia spp., Hafnia spp., Edwardsiella spp., Proteus (both indole positive and indole negative strains), Morganella spp., Providencia spp., Yersinia, Vibrio spp., Aeromonas spp., Plesiomonas, Pasteurella, Haemophilus, Campylobacter spp., Pseudomonas spp. (including Pseudomonas aeruginosa), Legionella, Neisseria spp., Moraxella spp., Branhamella spp., Acinetobacter spp., Brucella spp., Staphylococcus spp., Listeria spp., Corynebacterium, Chlamydia, and bacterial plasmid forms are sensitive to ciprofloxacin. Gardnerella spp., Flavobacterium spp., Alcaligenes spp., Streptococcus agalactiae, Streptococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridans, Mycoplasma hominis, Mycobacterium tuberculosis, Mycobacterium fortuitum demonstrate different sensitivity. Anaerobic cocci (Peptococcus, Peptostreptococcus) are moderately sensitive to ciprofloxacin and Bacteroides - stable. Ciprofloxacin is effective against the bacteria that produce beta-lactamase. It is active against microorganisms resistant to almost all antibiotics, sulfanilamide and nitrofurane drugs. In some cases, ciprofloxacin is active against strains resistant to other drugs of fluoroquinolones. However, you should keep in mind that there is a cross resistance between different fluoroquinolones. As a rule, Streptococcus faecium, Ureaplasma urealyticum, Nocardia asteroides, Treponema pallidum are resistant to the drug. Resistance to ciprofloxacin is developed slowly and gradually ( " multi-stage" type).

Pharmacokinetics.

Ciprofloxacin is quickly and well absorbed by all tissues of the body. After intravenous introduction the maximum plasma concentrations are achieved in 60-90 minutes. At steady state of balance the volume of distribution makes 2.3 l/kg. Since ciprofloxacin binding with proteins is mild (20-30%), and the substance is in plasma mainly in the un-ionized form, almost all amount of the introducted drug can freely diffuse into extravasal space. In this regard, in certain body fluids and tissues the ciprofloxacin concentrations are significantly able to exceed the level of the drug in serum (in particular, there is a high concentration of ciprofloxacin in bile). Ciprofloxacin is excreted mainly by the kidneys (almost 45% - unchanged, about 11% - as metabolites). The rest of the dose is excreted through the intestine (approximately 20% - unchanged, about 5.6% - as metabolites). Renal clearance is 5.3 ml/min/kg and total clearance - 8.10 ml/min/kg. The half-life is 3-5 hours. Due to the fact that the drug is excreted in different ways, the increase of half-life is observed only in significantly impaired renal function (the increase of this index may occur to 12 hours).

Clinical particulars.

Indications.

Ciproxin solution for infusion is indicated for the treatment of the following infections (see section «Precautions and use » and «Pharmaceutical properties»). 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. 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 byPseudomonas 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 section «Precautions for use» and «Pharmaceutical properties»).

Contraindications.

Hypersensitivity to the active substance, to other quinolones or to any of the excipients.

Concomitant administration of ciprofloxacin and tizanidine (see section «Interaction with other medicinal products and other forms of interaction»).

Interaction with other medicinal products and other forms of interaction. 

Effects of other products on ciprofloxacin:

Probenecid.

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

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 «Precautions for use»).

Effects of ciprofloxacin on other medicinal products:

Tizanidine.

Tizanidine must not be administered together with ciprofloxacin (see section «Contraindications»). 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 «Precautions for use»).

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 «Precautions for use»).

Other xanthine derivatives.

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

Phenytoin.

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

Cyclosporin.

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

Vitamin K antagonists.

Simultaneous administration of ciprofloxacin with a vitamin K antagonist may augment its anti-coagulant effects. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalised ratio) is difficult to assess. The INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with a vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).

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 «Precautions for use»).

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 «Precautions for use»).

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 «Precautions for use»).

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.

Precautions for use.

For patients with epilepsy, seizures in history, disease and organic brain damage, ciprofloxacin should be used only if necessary because of the risk of adverse reactions in the central nervous system.

When severe and prolonged diarrhea has occurred during or after treatment with ciprofloxacin, the diagnosis of pseudomembranous colitis, which requires immediate discontinuation of the drug and the indication of appropriate therapy, should be excluded.

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 gonorrhoeaeisolates. 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.

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.

Considered, that single-dose of ciprofloxacin, which can be used for uncomplicated cystitis in women before menopause, is less effective than long-term drug therapy. This fact should be considered, regading that the level of resistance of Escherichia coli to quinolones is increased.

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.

Antibiotic diarrhea caused by Clostridium difficile.

There are some cases of antibiotic diarrhea caused by Clostridium difficile, which can vary in severity from mild diarrhea to fatal colitis when using almost all antibiotics, including when Ciprofloxacin is used. Treatment with antibacterial agents causes the change of normal flora of the colon, that leads to excessive growth of Clostridium difficile.

Clostridium difficile produces toxins A and B which promote the development of antibiotic diarrhea. Clostridium difficile produces a large amount of toxin, causes the increase of morbidity and mortality because of possible pathogen resistance to antimicrobial therapy and the necessity of colectomy. You should remember about the potential of antibiotic diarrhea caused by Clostridium difficile in all patients with diarrhea after antibiotic use. Thorough collection of medical history is required, since the possible development of antibiotic diarrhea caused by Clostridium difficile, within two months after administration of antibacterial agents may occur. If the diagnosis of antibiotic diarrhea caused by Clostridium difficile, is considered or confirmed, antibiotics that have no effect on Clostridium difficile, should be discontinued. Depending on the clinical data, it is necessary to carry out the correction of water-electrolytic balance and to consider the necessity of additional administration of protein drugs and to use antibiotics to which Clostridium difficile is sensitive. The surgery may be needed.

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. he increase of suspected drug-related arthropathy cases over time was not statistically significant. However, the 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 trial.

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 trial 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.

In some cases, hypersensitivity and allergic reactions may occur after the first ciprofloxacin administration (see section «Adverse Reactions»). At first sings of reactions you should immediately inform your doctor.

In rare cases, anaphylactic / anaphylactoid reactions can progress to a state of shock that may be life-threatening for patients. In some cases they are observed after the first ciprofloxacin administration. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required. (treatment of anaphylactic shock).

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 «Adverse Reactions»). 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 «Adverse Reactions»).

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 «Adverse Reactions»).

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 «Adverse Reactions»). 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 «Adverse Reactions»).

Cardiac disorders.

The use of ciprofloxacin is associated with the cases of QT prolongation (see section «Adverse Reactions»).

Since women have more prolonged QT interval than men, they could be more sensitive to drugs that lead to a prolongation of QT interval. Elderly patients also could be more sensitive to the effects of drugs on the prolongation of QT interval. You should be careful with the concomitant prescription of ciprofloxacin and drugs that may cause the prolongation of QT interval (such as IA class and III antiarrhythmics, tricyclic antidepressants, macrolides and antipsychotics) (see section «Interaction with other medicinal products and other forms of interaction»), and in case when patients have risk factors for QT prolongation or development of bidirectional ventricular spindle tachycardia (e.g. congenital syndrome of QT prolongation, uncorrelated electrolyte disorders such as hypokalemia or hypomagnesaemia and heart disease, including heart failure, myocardial infarction or bradycardia) .

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.

Gastrointestinal tract.

You should inform your doctor in case of occurrence of severe and persistent diarrhoea during or after treatment (even several weeks after treatment) because this symptom can mask a severe gastro-intestinal disease (e.g. Pseudomembranous colitis, which can be fatal), which requires immediate treatment (see section «Adverse Reactions»). 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 «Adverse Reactions»). 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 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 «Adverse Reactions»). 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. There may be a temporary increase of transaminase level, alkaline phosphatase, development of cholestatic jaundice, especially in patients with liver damage treated with ciprofloxacin (see section «Adverse Reactions»).

Glucose-6-phosphate dehydrogenase deficiency

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

Resistance

During or following a course of treatment with ciprofloxacin bacteria that demonstrate resistance to ciprofloxacin may be isolated, with or without a clinically apparent superinfection. There may be a particular risk of selecting for ciprofloxacin-resistant bacteria during extended durations of treatment and when treating nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450

Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine,olanzapine ropinirole, tizanidine, duloxetine). Co-administration of ciprofloxacin and tizanidine is contra-indicated. Increased concentration in plasma, which is associated with specific adverse reactions, is determined by inhibition of their metabolic clearance of ciprofloxacin. 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 (seesection «Interactionwithothermedicinalproductsandotherformsofinteraction»).

Methotrexate.

The concomitant use of ciprofloxacin with methotrexate is not recommended (see section «Interaction with other medicinal products and other forms of interaction»).

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.

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. 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.

Effects on ability to drive and use machines.

Due to its neurological effects, ciprofloxacin may affect reaction time (see section «Adverse Reactions»). Thus, the ability to drive or to operate machinery may be impaired.

Way of administration and dosage.

Doctor determines the dosage individually depending on the location and severity of the infection and the sensitivity of the pathogen, the patient's renal function, and for children and adolescents - according to body weight.

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

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.

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 to 3 months
Urinary tract infections	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 gastro-intestinal tract and intra-abdominal 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 byShigella 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
	Intra-abdominal infections due to Gram-negative bacteria	400 mg twice daily to 400 mg three times a day	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
Neutropenic patients with fever that is suspected to be due to a bacterial infection. 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 ofBacillus anthracis exposure

Children.

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 post-exposure 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

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.

Impaired renal function.

Creatinine Clearance [ml/min/1,73 m²]	Serum Creatinine [µmol/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 haemodialysis	> 169	200-400 mg every 24 h (after dialysis)
Patients on peritoneal dialysis	> 169	200-400 mg every 24 h

Impaired liver function.

No dose adjustment is required.

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

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 solution for infusion and 30 minutes for 200 mg Ciprofloxacin 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.

Compatibility with other solutions.

Ciprofloxacin infusion solution is compatible with Ringer's solution, 0.9% sodium chloride, 5% and 10% glucose, 10% fructose solution, 5% glucose solution of 0,225% NaCl or 0,45% NaCl. If compatibility with other infusion solutions is not confirmed, the infusion solution of ciprofloxacin should be administered separately. The visible signs of incompatibility are precipitate, turbidity or discoloration of the solution

Children.

Ciprofloxacin is not recommended for children to treat other infections other than those referred in the section «Indications».

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 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.

Adverses reactions.

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

Data derived from clinical studies and post-marketing surveillance with Ciprofloxacin (oral, intravenous and sequential therapy) are listed below.

The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.

The frequency of adverse reactions meets the following criteria: common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare ( <1/10000) not known (can not be determined from the available data).

Infections and Infestations: uncommon – mycotic super-infections; rare – Antibiotic associated colitis (very rarely with possible fatal outcome) (see section «Precautions for use»).

Blood and Lymphatic System Disorders: uncommon – Eosinophilia, rare – anemia, neutropenia, leukopenia (granulocytopenia), leukocytosis, changed values of prothrombin, thrombocytopenia, thrombocytaemia (thrombocytosis), very rare – hemolytic anemia, petechiae, agranulocytosis, pancytopenia (life-threatening), bone marrow suppression (life-threatening).

Metabolism and Nutrition Disorders: uncommon – anorexia (loss of appetite), increased serum creatinine, increased level of urea nitrogen, rare - edema (peripheral, vascular, facial), hyperglycemia, hypoglycemia, very rare - increased amylase, increased lipase activity.

Psychiatric Disorders: uncommon – agitation, psychomotor hyperactivity / anxiety; rare – Confusion and disorientation, anxiety reaction, sleep disturbance (bad dreams), abnormal dreams, depression with possible suicidal ideas / thoughts or attempts / commit suicide, hallucinations; very rare – psychosis, psychotic reactions with possible suicidal ideas / thoughts or attempts / commit suicide (see section «Precautions for use»).

Nervous System Disorders: uncommon – headache, dizziness, sleep disturbance, dysgeusia, rare – paresthesia (peripheral paralheziya), dysesthesia, hyperesthesia, tremor, seizures, including epileptic state (see section «Precautions for use»), vertigo, very rare – migraine, disturbed coordination, gait disturbance, parosmia (smell disorder), anosmia (usually reversable when the drug is discontinued), intracranial hypertension, ataxia, hyperesthesia not known – peripheral neuropathy and polyneuropathy (see section «Precautions for use»).

Gastrointestinal Disorders: common – nausea, diarrhoea, uncommon – vomiting, gastrointestinal and abdominal pains, dyspepsia, flatulence, rare – candidiasis (oral), pseudomembranous colitis, very rare - candidiasis, pseudomembranous colitis life-threatening pancreatitis.

Hepatobiliary Disorders: uncommon – increase in transaminases: ALT, AST, bilirubinemia, abnormal values of liver function tests, rare abnormal liver function, jaundice, cholestatic jaundice, hepatitis, very rare - liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section «Precautions for use»),

Skin and Subcutaneous Tissue Disorders: uncommon –rash, itching, macula-papular rash, urticaria, rare – photosensitivity reactions (see section «Precautions for use»), very rare – petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (life-threatening), toxic epidermal necrolysis (Lyell's syndrome) (life-threatening), persistent rash, not known – acute generalized exanthemized pustulosis.

Musculo-skeletal and Connective Tissue Disorders: uncommon – musculo-skeletal pain (e.g. extremity pain, back pain, chest pain), arthralgia (pain in joints), rare – myalgia (pain in muscles), swelling of the joints, arthritis, increased muscle tone and muscle cramps, very rare – muscular weakness, tendonitis, tendon rupture  (predominantly Achilles tendon) (see section «Precautions for use»), exacerbation of symptoms of myasthenia gravis (see section «Precautions for use»).

Renal and Urinary Disorders: uncommon – renal failure, rare – acute renal failure, haematuria, crystalluria (see section «Precautions for use»), tubulointerstitial nephritis.

Reproduction System Disorders: rare – vaginal candidiasis.

Immune System Disorder: rare – allergic reactions, allergic edema / angioedema, very rare - anaphylactoid (anaphylactic) reaction, anaphylaxis (life-threatening) (see section «Precautions for use»), a reaction similar to serum disease.

Eye Disorders: rare – visual disturbances (visual abnormalities), diplopia, hromatopsiya, very rare - disturbance of color perception.

Ear Disorders: rare – tinnitus, hearing loss / hearing impairment, rare - temporary deafness (especially at high frequency sound).

Respiratory, Thoracic and Mediastinal Disorders: rare – dyspnoea (including asthmatic condition), laryngeal edema

Vascular Disorders: uncommon – thrombophlebitis (at the site of infusion), very rare – vasculitis.

Cardiac Disorders: rare – tachycardia, vasodilatation (flushes), hypotension, syncope (fainting), not known - ventricular arrhythmia, QT prolongation, piruetna tachycardia (torsades de pointes) *

* These reactions were recorded during the postmarketing period and observed predominantly in patients with additional risk factors for QT prolongation (see section «Precautions for use»).

General Disorders and Administration Site Conditions: uncommon – asthenia, fever; rare – oedema, sweating (hyperhidrosis).

Other: pseudo brain tumor.

Investigations: uncommon – increase in blood alkaline phosphatase; rare – abnormal prothrombin level, increased amylase, not known – 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	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 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 «Precaution for use»).

Shelf life. 3 years.

Storage conditions.

Keep out of the reach of children.

Store in the original package at temperature not exceeding 25 °С.

Unused drug should be removed.

Incompatibility.

This drug should not be mixed with other medicinal products except those listed in the «Way of administration and Dosage».

If compatibility with other infusion drug is not confirmed, the infusion solution of ciprofloxacin should be administered separately.

Incompatibility is showed in the use with all infusion solutions / drugs that are physically or chemically unstable (e.g., penicillins, heparin solutions), especially in combination with solutions whose pH was brought to alkaline.

Package.

In 100 ml in containers. Each container in PVC film along with the text instruction in a box.

Terms of dispensing. On prescription.

Manufacturer.

Eurolife Healthcare Pvt. Ltd.

Manufacturer’s registered address.

Khasra № 520, Bhagwanpur, Roorkee, Haridwar, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, SW6 2PY, London, United Kingdom.

Date of last update.

11.01.2016