CYPROBAX

APPROVED

by Order of the Ministry of Health

of Ukraine

as of 01.09.10 No. 750

Registration Certificate

No. UA/11001/01/01

 

INSTRUCTION

For medical application of drug

CYPROBAX

 

Drug Formulation:

active substance: ciprofloxacin; 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-(1-piperazinyl)-3-quinolinecarboxylic acid;

1 tablet contains ciprofloxacin hydrochloride in terms of ciprofloxacin 500 mg;

adjuvants: lactose monohydrate, microcrystalline cellulose, sodium lauryl sulphate, gelatinized starch, povidone, magnesium stearate, talc, sodium crosscarmellose, hypromellose, titanium dioxide (E 171), polyethylene glycol 6000.

Dosage Form. Tablets coated with membrane.

Pharmacotherapeutic Group.

Antibacterial drugs for systemic application. Fluoroquinolones.

ATC Code J01M A02.

Clinical Characteristics.

Indications.

Uncomplicated and complicated infections caused by agents susceptible to ciprofloxacin.

  • Respiratory infections: ciprofloxacin may be recommended for treatment of pneumonia caused by Klebsiella spp., Enterobacter spp., Proteus spp., Escherichia coli, Pseudomonas aeruginosa, Haemophilus spp., Moraxella catarrhalis, Legionella, and staphylococci.
  • Infections of middle ear (otitis media) and paranasal sinuses (sinusitis), especially infections caused by gram-negative microorganisms, particularly by Pseudomonas aeruginosa or staphylococci.
  • Eye infections.
  • Renal infections and infections of urinary tracts.
  • Genital infections, including adnexitis, gonorrhoea, and prostatitis.
  • Infections of abdominal cavity organs (infections of gastrointestinal tract, biliary tracts, and peritonitis).
  • Infections of skin and soft tissues.
  • Infections of bones and joints.
  • Sepsis.
  • Infections or high risk of infections (prevention) in patients with depressed immune system (including in course of treatment with immunosuppressive agents, and in case of neutropenia).
  • Selective intestine decontamination in course of treatment with immunosuppressive agents.
  • Prevention of invasive infections caused by Neisseria meningitides.

When prescribing it is necessary to take into account the current instruction for medical application for the purpose of proper application of antibacterial drug.

Children.

Ciprofloxacin may be applied in children as a second and third line drug for treatment of complicated infections of urinary tracts and pyelonephritis caused by Escherichia coli (age of children receiving the treatment was between 1 and 17 years old), as well as for treatment of pulmonary exacerbations caused by Pseudomonas aeruginosa in children with pulmonary mucoviscidosis (age of children receiving treatment was between 5 and 17 years old).

Treatment with ciprofloxacin may be prescribed only after the thorough estimation of risk/usefulness ratio due to probable development of side effects on joints and/or surrounding tissues.

Adults and children.

Reduction of risk of anthrax development or progression after aerogenic contact with Bacillus anthracis.

Contraindications.

Ciprofloxacin should not be applied in case of hypersensitivity to the active substance of the drug or other drugs of fluoroquinolones group, or any of the adjuvants of the drug.

Simultaneous application of ciprofloxacin and tizanidine is contraindicated due to clinically significant side effects (arterial hypotension, drowsiness) connected with the increase in tizanidine concentration in blood plasma.

Method of Application and Dosage.

Dosage regime

Unless otherwise indicated, the following daily doses are recommended:

For adults

  Tablets coated with membrane

(milligram of ciprofloxacin)

Respiratory infections (depending on seriousness of the disease and causative agent) 2 x 500 mg to 2 x 750 mg
Infections of urinary tracts:

-     acute, uncomplicated;

-     cystitis in women (before menopause);

-     complicated.

 

 

 

2 x 250 mg to 2 x 500 mg

single-time dose – 500 mg

2 x 500 mg to 2 x 750 mg

Gonorrhoea:

-     extragenital;

-     acute, uncomplicated.

 

2 x 250 mg

single-time dose – 500 mg

Genital infections:

-     uncomplicated gonorrhoea (including extragenital nidi of infection);

-     adnexitis, prostatitis, orchiepididymitis.

 

1 x 500 mg

 

2 x 500 mg to 2 x 750 mg

Diarrhoea 2 x 500 mg
Other  infections

(See Section “Indications”).

2 x 500 mg
-     in case of especially serious, life-threatening infections, for example, in case of recurrent infections in patients with mucoviscidosis;

-     in case of infections of bones and joints, septicaemia, peritonitis, particularly in case of presence of Pseudomonas, Staphylococcus or Streptococcus.

 

 

 

2 x 750 mg

 

Prevention of invasive infections caused by Neisseria meningitides. 1 x 500 mg

 

Additional information concerning certain groups of patients

Children

Mucoviscidosis complications

Present clinical and pharmacokinetic data testifies to the benefit of application of ciprofloxacin for treatment of pulmonary exacerbations caused by Pseudomonas aeruginosa, in children with pulmonary mucoviscidosis (aged from 5 to 17 years old), for treatment of pulmonary mucoviscidosis complications caused by Pseudomonas aeruginosa (experience of application only inn children aged from 5 to 17 years old), in dose of 20 mg of ciprofloxacin per kg of body weight taken orally twice a day (maximum daily dose of ciprofloxacin is 1500 mg) or 10 mg of ciprofloxacin/kg of body weight introduced intravenously 3 times a day (maximum daily dose of ciprofloxacin is 1200 mg).

  • complicated infections of urinary tracts and pyelonephritis

In case of complicated infections of urinary tracts and pyelonephritis the dose is 6-10 mg of ciprofloxacin per kg of body weight introduced intravenously every eight hours, but not more than maximum dose of 400 mg, or 10-20 mg of ciprofloxacin per kg of body weight taken orally every 12 hours, but not more than maximum dose of 750 mg.

 

Dosage regime for elderly patients (> 65 years old)

In course of treatment of elderly patients as low doses of ciprofloxacin as possible should be applied, depending on the seriousness of disease and creatinine clearance.

 

Dosage regime in case of impaired renal or liver function

In adults

  • Impaired renal function:

-     In case of creatinine clearance from 30 to 60 ml/min/1.73 m2 (moderate renal impairment) or its concentration in blood plasma from 1.4 to 1.9 mg/100 ml, the maximum daily dose of ciprofloxacin should be 1000 mg for oral application.

-     In case of creatinine clearance less than 30 ml/min/1.73 m2 (severe renal impairment) or its concentration in blood plasma equivalent to or more than 2 mg/100 ml, the maximum daily dose of ciprofloxacin should be 500 mg per day for oral application.

  • Impaired renal function and haemodialysis:

-     In case of creatinine clearance from 30 to 60 ml/min/1.73 m2 (moderate renal impairment) or its concentration in blood plasma from 1.4 to 1.9 mg/100 ml, the maximum daily dose of ciprofloxacin should be 1000 mg per day for oral application.

-     In case of creatinine clearance less than 30 ml/min/1.73 m2 (severe renal impairment) or its concentration in blood plasma equivalent to or more than 2 mg/100 ml, the maximum daily dose of ciprofloxacin should be 500 mg per day for oral application.

  • Impaired renal function and chronic peritoneal dialysis in the outpatient setting:

-     Oral application of ciprofloxacin in the form of tablets coated with membrane in dosage of 1 tablet of ciprofloxacin 500 mg.

  • Impaired liver function:

-     There is no need in dose adjustment.

  • Impaired renal and liver function:

-     In case of creatinine clearance from 30 to 60 ml/min/1.73 m2 (moderate renal impairment) or its concentration in blood plasma from 1.4 to 1.9 mg/100 ml, the maximum daily dose of ciprofloxacin should be 1000 mg per day for oral application.

-     In case of creatinine clearance less than 30 ml/min/1.73 m2 (severe renal impairment) or its concentration in blood plasma equivalent to or more than 2 mg/100 ml, the maximum daily dose of ciprofloxacin should be 500 mg per day for oral application.

There is no experience of drug application in children with impaired renal or liver function.

Method of Application

Ciprofloxacin tablets coated with membrane should be swallowed, not, chewed, with small amount of liquid.

Ciprofloxacin tablets coated with membrane may be taken irrespective of meals.

Drug taking on an empty stomach accelerates uptake of active substance. In such a case the ciprofloxacin tablets coated with membrane should not be taken with dairy products or drinks rich in minerals (such as milk, yoghurt, or orange juice rich in calcium). However, calcium contained in food does not significantly influence the ciprofloxacin absorption.

Duration of Treatment

Period of treatment depends on the seriousness of disease, its clinical course and bacteriological profile. It is necessary to continue treatment within at least 3 days after disappearing of fever or clinical symptoms. The average duration of treatment:

  • 1 day in case of acute uncomplicated gonorrhoea and cystitis;
  • up to 7 days in case of infections of kidneys, urinary tracts and abdominal cavity organs;
  • in patients with depressed immunity the treatment is performed during the whole period of neutropenia;
  • in case of osteomyelitis the course of treatment may last for up to 2 months;
  • 7-14 days in case of all other infections.

In case of infections caused by streptococci the treatment should be prolonged to at least 10 days in order to avoid risk of development of complications in a remote period.

In case of infections caused by Chlamydia the course of treatment should also last for at least 10 days.

Children

Mucoviscidosis complications

In case of pulmonary mucoviscidosis complications caused by Pseudomonas aeruginosa in children (aged from 5 to 17 years old) the duration of treatment is 10-14 days.

Complicated infections of urinary tracts and pyelonephritis

In case of complicated infections of urinary tracts and pyelonephritis caused by Escherichia coli the course of treatment is 10-21 days.

Side Reactions.

The frequency of undesirable side reactions reported in respect of ciprofloxacin has been generalised in the table below. The unwanted side effects within each occurrence group are given in order of seriousness reduction.

Very often (≥ 1/10); often (≥ 1/100 to < 1/10); not often (≥ 1/1000 to ≤1/100);

rare (≥ 1/10000 to ≤ 1/1000); very rare (≤ 1/10000); unknown (cannot be evaluated on the basis of present data).

Undesirable side reaction the frequency of which is impossible to determine are given under “unknown” group.

 

System or organs Often Not often Rare Very rare Unknown
Infections and invasions   Mycotic superinfections Antibiotics-associated colitis (very rarely – with probable fatal outcome)    
Blood formation and lymphatic systems   Eosinophilia Leukopenia, anaemia, neutropenia, leucocytosis,

thrombocytopenia, thrombocytosis

Haemolytic anaemia, agranulocytosis, pancytopenia (such that is dangerous for life), inhibition of bone marrow (such that is dangerous for life)  
Immune system     Allergic reactions, allergic/ angioneurotic oedema Anaphylactic reactions, anaphylactic shock (such that is dangerous for life), and reactions similar to serum disease  
Nutrition and metabolism disorders   Anorexia Hyperglycaemia    
Mental disorders   Psychomotor excitability / anxiety Mental confusion and disorientation, anxiety, hyper drowsiness, depression, hallucinations Psychosis  
Nervous system   Headache, dizziness, sleep disorders, taste disorders Paresthesia, dysesthesia, hypoesthesia, tremor, cramps, vertigo Migraine, coordination disorders, flair disorder, hyperesthesia, and intracranial hypertension Peripheral neuropathy and polyneuropathy
Organs of vision     Visual impairment Impaired colour perception  
Organs of hearing and equilibrium     Ringing in ears, deafness Impaired hearing  
Heart     Tachycardia   Prolongation of Q-T interval, ventricular arrhythmia, bidirectional ventricular tachycardia*
Vascular system     Vasodilation, decrease in arterial pressure, loss of consciousness Vasculitis  
Respiratory organs; thoracic and mediastinal disorders     Dyspnoea (including asthmatic conditions)    
Gastrointestinal tracts Nausea, diarrhoea Vomiting, pain in gastrointestinal area, dyspeptic disorders, meteorism   Pancreatitis  
Liver and biliary tracts   Increase if level of transaminases, hyperbilirubinemia Impaired liver function, jaundice, hepatitis (non-infectious) Liver necrosis (very rarely progressing to liver impairment threatening the life)  
Skin and subcutaneous tissues   Rash, itching, urticaria Photosensitization reactions, nonspecific blisters Petechia, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (with potential danger to life), and toxic epidermal necrolysis (with potential danger to life)  
Skeletomuscular system and connective tissue   Arthralgia Myalgia, arthritis, increase in muscular tonus, and muscular convulsions Muscular weakness, tendinitis, tendon rapture (mainly Achilles tendon), exacerbation of myasthenia symptoms  
Kidneys and urinary system   Renal function disturbances Renal impairment, haematuria, crystalluria, tubulointerstitial nephritis    
Body in general; reaction at point of introduction   Nonspecific pain syndrome, malaise, fever Oedemas, hyperhidrosis Walking disorders  
Deviations from laboratory indices   Increase in level of alkaline phosphatase in blood Deviations from normal level of prothrombin, increase in amylase level    

 

The following undesirable side effects belong to the high frequency category in subgroups of patients that receive the drug intravenously or in series (intravenous introduction followed by oral taking):

 

Often Vomiting, transient increase in activity of transaminases, rash
Not often Thrombocytopenia, thrombocytosis, mental confusion and disorientation, hallucinations, paresthesia, dysesthesia, cramps, vertigo, dizziness, visual disorders, impaired hearing, tachycardia, vasodilation, decrease in arterial pressure, transient liver impairment, jaundice, renal impairment, oedema.
Rare Pancytopenia, inhibition of bone marrow, anaphylactic shock, psychotic reactions, migraine, flair disorders, impaired hearing, vasculitis, pancreatitis, liver necrosis, petechia, tendon rapture.

Application in children

Frequency of arthropathy cases mentioned above is based on data received in course of adult studies. Arthropathy is frequently observed in children (See Section “Peculiarities of Application”).

Overdosage.

Due to serious overdosage in course of oral taking the reversible toxic action on renal parenchyma was observed in some cases.

Therefore, in case of overdosage it is recommended that ordinary measures were accompanied with control of renal function and application of antacids containing magnesium and calcium which reduce ciprofloxacin absorption.

Only small amount of ciprofloxacin (< 10%) is excreted by means of haemodialysis or peritoneal dialysis.

 

 

Application during Pregnancy and Breast-Feeding Periods.

Pregnancy

Since safety of ciprofloxacin application in pregnant women has not been established and it is impossible to completely exclude the probability of damage to articular cartilages in newly-born ciprofloxacin shall not be applied in pregnant.

Breast-feeding period

Ciprofloxacin penetrates in breast milk. Due to potential risk of damage to articular cartilages in newly-born, ciprofloxacin should not be applied during breast-feeding period.

Children

Ciprofloxacin may be applied in children as a second and third line drug for treatment of complicated infections of urinary tracts and pyelonephritis caused by Escherichia coli (age of children receiving the treatment was between 1 and 17 years old), as well as for treatment of pulmonary exacerbations caused by Pseudomonas aeruginosa in children with pulmonary mucoviscidosis (age of children receiving treatment was between 5 and 17 years old).

Treatment with ciprofloxacin may be prescribed only after the thorough estimation of risk/usefulness ratio due to probable development of side effects on joints and/or surrounding tissues. Experience in children treatment with other indications is limited.

Peculiarities of Application.

Serious infections and/or infections caused by gram-positive or anaerobic bacteria

For the purpose of treatment of serious infections and infections caused by staphylococci or anaerobic bacteria Ciprobax shall be applied in combination with relevant antibacterial agents.

Pneumococci

Ciprofloxacin is not recommended for treatment of pneumococcal infections due to insufficient efficiency in respect of bacteria of Streptococcus pneumoniae group.

Infections of genital tracts

Infections of genital tracts may be caused by fluoroquinolones-resistant isolates of Neisseria gonorrhoeae. If it is suspected or known that infections of genital tracts were caused by N. gonorrhoeae, it is especially important to receive information about the degree of ciprofloxacin resistance and confirm susceptibility to the drug on the basis of laboratory research results.

Cardiac activity disturbances

Ciprofloxacin is associated with prolongation of Q-T interval on ECG (See Section “Side Effects”). In general, elderly patients may be more susceptible to drug influence on Q-T interval. Ciprofloxacin should be carefully applied with accompanying drugs that may cause prolongation of Q-T interval (e.g., Ia or III class antiarrhythmic drugs), and in patients with risk factors in respect of mentioned conditions (e.g., prolongation of Q-T interval in history, unadjusted hypokaliemia).

Children

Similarly to other drugs of this group, it has been proved that ciprofloxacin may cause arthropathy of supporting joints in young animals. Analysis of data of safety of ciprofloxacin application in patients aged under 18 the majority of whom were suffering from mucoviscidosis has not given any proof of treatment-associated damaging of cartilaginous tissue or joints. Application of ciprofloxacin for other indications besides treatment of pulmonary exacerbations caused by Pseudomonas aeruginosa, in children with pulmonary mucoviscidosis (aged 5-17), treatment of complicated infections of urinary tracts and pyelonephritis caused by E. coli (aged 1-17), and anthrax after the contact has not been studied. Clinical experience of ciprofloxacin application in children with other indications is limited.

Hypersensitivity to the drug

In rare cases hypersensitivity and allergic reactions may be observed already after the first taking of ciprofloxacin, which the doctor should be immediately informed of.

In very rare cases anaphylactic/anaphylactoid reactions may progress to shock conditions, which is threatening the life of patient. In some cases they were observed already after the first taking of ciprofloxacin. In such cases application of ciprofloxacin should be immediately stopped and relevant treatment should be performed (treatment of anaphylactic shock).

Gastrointestinal tract

In case of serious and stable diarrhoea during or after the treatment inform the doctor, since this symptom may mask serious gastrointestinal disease (e.g., pseudomembranous colitis which may be life-threatening and lead to possible fatal outcome) requiring immediate treatment. In such cases ciprofloxacin taking should be stopped and relevant therapy applied (e.g., vancomycin taken orally, 4 x 250 mg/day). Drugs that inhibit peristalsis are contraindicated.

Possible are: temporary increase in activity of transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with former liver damage.

Musculoskeletal system

In case of any signs of tendinitis (e.g., painful swelling, inflammation) inform the doctor and stop antibiotic treatment. It is also necessary to keep the limb at rest and avoid inappropriate physical exercise (since it may lead to increase of risk of tendon rapture).

Tendon rapture (mainly of Achilles tendon) was observed mainly in course of drug application in elderly patients or in connection with treatment with glucocorticoids.

Ciprofloxacin should be carefully applied in patients with damaged tendons in past history associated with treatment with quinolones.

Nervous system

Patients with epilepsy and patients with disturbed function of central nervous system (e.g., reduction of spasmodic threshold, cramps in past history, decreased blood circulation in brain vessels, changes in brain structure or stroke) may take ciprofloxacin only in case when expected use exceeds the possible risk, since these patients belong to the risk group due to possible side reactions from CNS.

In some cases side reactions from CNS are observed already after the first taking of ciprofloxacin. In rare cases depression or psychosis may progress to life-threatening condition. In such cases stop ciprofloxacin taking and turn to the doctor.

Skin and subcutaneous tissue

It has been proved that ciprofloxacin causes photosensitization reactions; therefore, the patients taking ciprofloxacin must avoid intensive sunlight or ultraviolet radiation. In case of photosensitization reactions (e.g., similar to solar burns) the ciprofloxacin therapy should be stopped.

Cytochrome P450

Ciprofloxacin is known as a moderate inhibitor of 1A2 enzymes of cytochrome 450. It is necessary to take care in case of simultaneous application of ciprofloxacin and drugs that are metabolised in a similar enzymatic way (such as teofilin, methylxanthine, caffeine, duloxetine, clozapine). Increase in concentration of these drugs in blood serum is connected with inhibition of their metabolic clearance by ciprofloxacin, and may cause specific side effects.

Influence on the results of laboratory tests

Ciprofloxacin in vitro may influence the results of inoculation of Mycobacterium spp. flora by inhibiting the growth of mycobacteria culture and lead to false-negative results of inoculation test in patients taking ciprofloxacin.

Ability to Affect Rate of Reactions when Driving or Operating Other
Mechanisms.

Fluoroquinolones, the representative of which ciprofloxacin is, may influence the patient’s ability to drive the car and operate mechanisms due to CNS reactions (See Section “Side Reactions”).

 

Interaction with Other Drugs and Other Types of Interaction.

Antiarrhythmic drugs of Ia or III type

It is necessary to take care in case of simultaneous application of ciprofloxacin and antiarrhythmic drugs of Ia or III type, since ciprofloxacin may intensify the prolongation of Q-T interval (See Section “Peculiarities of Application”).

Formation of chelate complex

In case of simultaneous application of ciprofloxacin (orally) and drugs containing multivalent cations, mineral additives (e.g., calcium, magnesium, aluminium, iron), phosphate-binding polymers (e.g., sevelamer, lanthanum carbonate), sucralfates or antacids, as well as drugs with large buffer capacity (e.g., didanosine tablets) that contain magnesium, aluminium or calcium, the ciprofloxacin absorption is decreased. Due to this, ciprofloxacin should be taken 1-2 hours before or at least 4 hours after taking of these drugs.

This restriction does not concern antacids belonging to H2-receptor blocking agents.

Food and dairy products

It is necessary to avoid simultaneous taking of ciprofloxacin and dairy products or products rich in minerals (e.g., milk, yoghurt, orange juice with high calcium content). Other products containing calcium do not significantly affect the ciprofloxacin absorption.

Probenecid

Probenecid slows down the ciprofloxacin excretion with bile. Simultaneous application of drugs containing probenecid and ciprofloxacin leads to increase in level of ciprofloxacin concentration in blood plasma.

Metoclopramide

Metoclopramide accelerates ciprofloxacin absorption (in case of oral application) which leads to reduction of time required for achievement of maximum drug concentration in blood plasma. No influence on ciprofloxacin bioavailability has been observed.

Omeprazole

Simultaneous application of ciprofloxacin and drugs containing omeprazole leads to slight decrease in Cmax, and area under ciprofloxacin “concentration-time” curve (AUC).

Tizanidine

The clinical study of healthy volunteers simultaneously taking ciprofloxacin and tizanidine showed the increase in tizanidine concentration in blood plasma (increase in Cmax by 7 times, range – 4-21 times, increase in AUC value by 10 times, range – 6-24 times). Increase in tizanidine concentration in blood serum is associated with hypotensive and sedative side effects. Therefore the simultaneous application of ciprofloxacin and drugs containing tizanidine is contraindicated (See Section “Contraindications”).

Teofilin

Combined application of ciprofloxacin and drugs containing teofilin may lead to undesirable increase in teofilin concentration in blood plasma which, in its turn, may cause the development of side effects. In rare cases such side effects may be dangerous for life or lead to fatal outcome. If simultaneous application of these drugs is unavoidable, it is necessary to control teofilin concentration in blood serum and decrease its dose (See Section “Peculiarities Application”).

Other xanthine derivatives

There have been reports of increase in concentration of xanthines in blood serum after simultaneous application of ciprofloxacin and drugs containing caffeine or pentoxifylline (oxpentifylline).

Methotrexate

Simultaneous application of ciprofloxacin may slow down the tubular transportation (renal metabolism) of methotrexate which may lead to increase in methotrexate concentration in blood plasma. This may also be accompanied by increase in probability of toxic side reactions caused by methotrexate. Due to this, patients receiving combined therapy with methotrexate and ciprofloxacin should stay under careful observation.

Non-steroid anti-inflammatory drugs

Combined application of very high doses of quinolones (gyrase inhibitors) and some non-steroid anti-inflammatory drugs (except for acetylsalicylic acid) may provoke cramps.

Cyclosporine

In case of simultaneous application of ciprofloxacin and cyclosporine the transient increase in serum creatinine concentration has been observed. Therefore, such patients require frequent control of serum creatinine concentration values (twice a week).

Vitamin K antagonists

Simultaneous application of ciprofloxacin and vitamin K antagonists may intensify anticoagulant action of ciprofloxacin. Risk may vary depending on infection, age, and patient’s general condition; therefore, it is difficult to estimate the accurate ciprofloxacin influence on the increase in values of International normalized ratio (INR). It is necessary to perform frequent control of INR during and immediately after combined introduction of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).

Glibenclamid

In separate cases simultaneous application of ciprofloxacin and drugs containing glibenclamid may increase intensity of glibenclamid action (hypoglycaemia).

Duloxetine

Clinical studies have shown that simultaneous application of duloxetine and strong inhibitors of CYP450 1A2 isoenzyme (such as fluvoxamine) may result in increase in duloxetine AUC and Cmax. Although there is no clinical data concerning interaction with ciprofloxacin, it is possible to foresee the interaction in case of simultaneous application of ciprofloxacin and duloxetine (See Section “Peculiarities of Application”).

Ropinirole

Simultaneous application of ropinirole with ciprofloxacin, moderate inhibitor of CYP450 1A2 isoenzyme, leads to increase in ropinirole AUC and Cmax by 60% and 84%, respectively. Monitoring of ropinirole side effects and relevant dose adjustment are recommended during and immediately after the combined introduction with ciprofloxacin (See Section “Peculiarities of Application”).

Lidocaine

Simultaneous application of drugs containing lidocaine and ciprofloxacin, moderate inhibitor of CYP450 1A2 isoenzyme, decreases lidocaine clearance introduced intravenously by 22%. Although treatment with lidocaine has been well-tolerated, the single-time application with ciprofloxacin may be followed by certain interaction which may be accompanied by side reactions.

Clozapine

After the single-time application of 250 mg of ciprofloxacin with clozapine the serum concentrations of clozapine and N-desmethylclozapine have been increased by 29% and 31%, respectively, during 7 days. The clinical observation and relevant adjustment of clozapine dosage are recommended during and immediately after the combined introduction with ciprofloxacin (See Section “Peculiarities of Application”).

Sildenafil

Study of healthy volunteers have shown approximately double increase in sildenafil Cmax and AUC after the oral taking of 50 mg simultaneously with 500 mg of ciprofloxacin.

Therefore, it is necessary to carefully prescribe simultaneous application of ciprofloxacin with sildenafil thoroughly weighing its risks and benefits.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Ciprofloxacin in vitro demonstrates high efficiency in respect of wide range of gram-negative and gram-positive causative agents. The mechanism of antibacterial action is caused by the ability of ciprofloxacin to inhibit the type II topoisomerases (DNA-gyrase and topoisomerase IV) required in numerous processes connected with DNA, such as replication, transcription, reparation and recombination.

 

Mechanism of resistance

Ciprofloxacin resistance in vitro is usually connected with target-site mutations in bacterial topoisomerases and NA-gyrase by means of multi-step mutations. Single mutations may lead to decrease in sensitivity rather than to clinical resistance. However, multiple mutations usually cause clinical resistance to ciprofloxacin and cross-resistance to quinolones.

Such resistance mechanisms inactivated by other antibiotics as decrease in permeability of bacterium external wall (typical of Pseudomonas aeruginosa) and active drug excretion out of cell (efflux) may influence the susceptibility to ciprofloxacin. There have been reports of development of plasmid-mediated resistance encrypted by qnr gene of antibiotic resistance. Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines may not influence the antibacterial activity of ciprofloxacin. Organisms resistant to these drugs may be susceptible to ciprofloxacin.

Minimum bactericidal concentration (MBC), as a rule, does not exceed minimum inhibitory concentration (MIC) more than twice.

Susceptibility to ciprofloxacin in vitro

Prevalence of acquired resistance of selected species may vary depending on location and time; therefore, it is desirable to obtain local data concerning resistance, especially in course of treatment of severe infections. In case of necessity it is required to seek advice of an expert, if the local occurrence of resistance is such that the efficiency of agent is doubtful at least with some types of infections.

In general, the following stems and species of bacteria are in vitro susceptible to ciprofloxacin:

Aerobic gram-positive microorganisms:

Bacillus anthracis

Staphylococcus aureus                  (methicillin-susceptible isolates)

Staphylococcus

saprophyticus

Streptococcus spp.

Aerobic gram-negative microorganisms:

Aeromonas spp. Moraxella catarrhalis
Brucella spp. Neisseria meningitides
Citrobacter koseri Pasteurella spp.
Francisella tularensis Salmonella spp.*
Haemophilus ducreyi Shigella spp.
Haemophilius influenzae Vibrio spp.
Legionella spp. Yersinia pestis

 

Anaerobic microorganisms:

Mobiluncus

Other microorganisms

Chlamydia trachomatis

Chlamydia pneumoniae

Mucoplasma hominis

Mycoplasma pneumoniae

Various susceptibility to ciprofloxacin is demonstrated by: Acinetobacter baumann, Burkholderia cepacia, Campylobacter spp., Citrobacter freudii, Enterococcus faecalis, Enterobacter aerogenes, Enterobacter clocae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Providencia spp., Pseudomonas aeruginosa, Pseudomonas fluorescens, Serratia marcescens, Streptococcus pneumoniae, Peptostreptococcus spp., Propionibacterium acnes.

It is considered that the following microorganisms demonstrate heritable resistance to ciprofloxacin:

Staphylococcus aureus (methicillin-resistant) and Stenotrophomonas maltophilia, Actinomyces, Enterococcus faecium, Listeria monocytogenes, Mycoplasma genitalium, Ureaplasma urealitycum, anaerobic microorganisms (except for Mobiluncus, Peptostreptococcus, Propionibacterium acnes).

Pharmacokinetics.

Absorption.

Tablets coated with membrane

After oral taking of 250 mg, 500 mg or 750 mg of ciprofloxacin tablets ciprofloxacin is rapidly and well absorbed mainly from the upper segment of small intestine.

Cmax in blood serum is reached in 1-2 hours.

Absolute bioavailability of the drug is about 70-80%. Cmax in blood serum and AUC are increased proportionately to the dose.

Distribution

Ciprofloxacin binding with proteins is insignificant (20-30%), and the substance remains in plasma mainly in unionized form. Ciprofloxacin may freely diffuse into extravascular space. Significant distribution volume at the state of stable balance which may be up to 2-3 l/kg of body weight proves that ciprofloxacin penetrates into tissues in concentrations which may significantly exceed the drug level in blood serum.

Metabolism

There have been records of small concentrations of the following four metabolites: diethylciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3) and formylciprofloxacin (M4). M1-M3 metabolites in vitro demonstrate antimicrobial activity similar to or lower than the activity of nalidixic acid. M4 in the least amount is an equivalent of norfloxacin in terms of antimicrobial activity in vitro.

Excretion.

Ciprofloxacin is excreted mainly unchanged both by kidneys and through intestine.

Children.

The age dependence of Cmax and AUC has not been observed. After repeated drug application (10 mg/kg/three times a day) there has been no significant increase in Cmzx or AUC. The average period of half-life in children is about 4-5 hours.

Pharmaceutical Characteristics.

Main Physicochemical Properties:

Tablets of white or nearly white colour, coated with membrane, round-shaped, with notch on one side.

Effective Period.

3 years.

Storage Conditions.

Store under the temperature below 25°C in place out of reach of children.

Packaging.

10 tablets in blister, 1 blister in carton box.

Category of Selling.

On prescription.

Manufacturer.

Bioveeta Laboratories Ltd.

Location.

B705, Vardhaman vatika, G.B. Road, Manpada, Thane (W), India.

Date of Last Revision.