Ciprobay Tablet 250 mg. 500 mg. 750 mg FC Tablets

CIPROBAY is indicated for the treatment of severe and/or complicated infections caused by ciprofloxacin-sensitive bacteria where other antimicrobials, approved for a similar indication and to which the causative bacteria are sensitive, were considered not to be an appropriate treatment option, have failed, are contraindicated, or not tolerated. CIPROBAY in not indicated/approved for the initiation of treatment (first-line treatment) of infections described as mild/moderate/acute and uncomplicated, caused by bacteria sensitive to ciprofloxacin, unless treatment with other appropriate antimicrobials, approved for a similar indication and to which the causative bacteria are sensitive, have failed, are contraindicated, or not tolerated. CIPROBAY is indicated for the treatment of the following bacterial infections where these infections are compliant with the indication context.

• Severe and/or complicated lower respiratory tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenza, and Haemophilus para-influenzae.
• Severe and/or complicated urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus epidermidis and Streptococcus faecalis.
• Severe and/or complicated skin and soft tissue infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus epidermidis and Streptococcus pyogenes.
• Severe and/or complicated gastro-intestinal infections: Infective diarrhoea caused by Escherichia coli, Campylobacter jejuni, Shigella flexneri and Shigella sonnei.
• Severe and/or complicated bone infections: Osteomyelitis due to susceptible Gram-negative organisms.
• Prophylaxis of invasive infections due to Neisseria meningitidis in patients over 18 years of age.

In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside must be administered concomitantly. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to CIPROBAY. Therapy with CIPROBAY may be initiated in severe and/or complicated infections before results of these tests are known; once results become available, appropriate therapy should be continued.

CIPROBAY tablets and CIPROBAY SUSPENSION 5% The dosage range is 250 - 750 mg twice daily. The duration of treatment to contain and eradicate an infection depends upon the type and severity of the infection, immunological status, clinical response and bacteriological findings. Use the lowest effective dose for the shortest time to contain and eradicate infection. For infections of the kidneys, urinary tract and abdominal cavity the treatment period is up to 7 days. In all other infections the treatment period is 7 - 14 days. In streptococcal infections, the treatment must last at least 10 days because of the risk of late complications. Severe and/or complicated infections of the lower respiratory tract: 750 mg twice daily. In cystic fibrosis patients the dose is 750 mg twice daily. The low body mass of these patients should, however, be taken into consideration when determining dosage (7.5 to 15 mg/kg/day). Severe and/or complicated infections of the urinary tract: 500 mg twice daily. Severe and/or complicated infections of the skin: 750 mg twice daily. Severe and/or complicated infectious diarrhoea: 500 mg twice daily. Severe and/or complicated bone infections: 750 mg twice daily. Treatment may be required for 4 - 6 weeks or longer. Prophylaxis of invasive infections due to Neisseria meningitides: 500 mg single dose tablet or oral suspension. In cases of a mild/moderate/acute and uncomplicated infection, where all other appropriate antimicrobials approved for a similar indication have failed, are contraindicated, or are not well tolerated, the following dosage instruction are advised: Infections of the lower respiratory tract: 250 mg twice daily Infections of the urinary tract: 250 mg twice daily Infections of the skin: 500 mg twice daily Infectious diarrhoea: 500 mg twice daily Bone infections: 500 mg twice daily If the patient is unable to take CIPROBAY film-coated tablets or suspension, because of the severity of the illness or for other reasons (e.g. patients on parenteral nutrition), therapy should be commenced with intravenous CIPROBAY. After intravenous administration treatment may be continued orally. CIPROBAY IV The dosage of CIPROBAY IV is determined by the severity and type of infection, the sensitivity of the causative organism(s) and the age, mass and renal function of the patient. The usual dose is 100 mg - 200 mg IV every 12 hours. For severe and/or complicated infections 400 mg may be administered every 12 hours (i.e. bd). Intravenous therapy should be discontinued as soon as oral CIPROBAY therapy can be substituted. The usual duration of intravenous therapy is up to 7 days. Cystic fibrosis In cystic fibrosis patients the usual dose is 200 mg IV twice daily. The often low body mass of these patients should, however, be taken into consideration when determining dosage (5 - 10 mg/kg/day). Missed dose If a dose is missed, it should be taken anytime but not later than 6 hours prior to the next scheduled dose. If less than 6 hours remains before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

CIPROBAY is contraindicated in:

• patients who have shown hypersensitivity to ciprofloxacin or any other quinolones or to any of the excipients listed in section 6.1.
• concomitant use of ciprofloxacin with other medicines known to prolong the QT interval, or in patients with disorders that prolong the QT interval to such an extent that it leads to prolonged QTcF interval known to associated with serious and potentially fatal dysrhythmias or if symptomatic dysrhythmias occur with concomitant use at time intervals shorter than QT intervals usually associated with dysrhythmias.
• pregnancy and lactation (see section 4.6)
• myasthenia gravis where alternative appropriate antibiotic choices are available to treat these patients.
• concurrent administration of CIPROBAY and tizanidine (see section 4.5).
• a history of tendon, muscle, joint, central nervous system, epilepsy or psychotic disorders especially those related to previous quinolone/fluoroquinolone use where alternative, appropriate antibiotic choices are available for treatment.
• aortic aneurysm and/or dissection or in patients with risk factors or conditions predisposing for aortic aneurysm and/or dissection if alternative appropriate antibiotic choices are available.
• Patients with confirmed mitral valve and/or aortic valve regurgitation unless no safer appropriate alternative antibiotic is available, has failed, or is not well tolerated.
• concomitant use of fluoroquinolones with ACE inhibitors/angiotensin-receptor blockers in patients with moderate to severe renal impairment (creatinine clearance u2264 30 mL/min) and in the elderly.
• CIPROBAY is contraindicated in children under 18 years. There is evidence of damage to the cartilage of weight bearing joints in immature animals.

Crystalluria related to the use of ciprofloxacin has been observed. Patients receiving CIPROBAY should be well hydrated and excessive alkalinity of the urine should be avoided. Side effects that may be potentially life-threatening are pancytopenia and marrow depression. (See section 4.8). Concurrent administration with methotrexate may increase the concentration of methotrexate to toxic levels. Tendinitis may occur. It most frequently involves the Achilles tendon and may lead to tendon rupture. The risk of tendinitis and tendon rupture is increased in the elderly and in patients using corticosteroids and in patients with a kidney or lung transplant. Close monitoring of these patients is therefore necessary if CIPROBAY is prescribed. All patients should consult their medical practitioner if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with CIPROBAY must be discontinued immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon. Tendinitis and/or tendon rupture may still occur for several months after completion of treatment. The recovery process may be prolonged (weeks to months) and full recovery to the pre-treatment status may not occur. Streptococcus pneumoniae infections CIPROBAY should not be used for treatment of pneumococcal infections due to limited efficacy against Streptococcus pneumoniae. Severe infections and/or infections due to Gram-positive or anaerobic bacteria For the treatment of severe infections, CIPROBAY should be used in combination with another appropriate antibacterial medicine. CIPROBAY should not be used in staphylococcal infections and infections involving anaerobic bacteria. Cardiac disorders CIPROBAY has been associated with QT prolongation (See sections 4.3 and 4.8). Women tend to have a longer baseline QTc interval compared with men, and may be more sensitive to medicines prolonging the QTC interval, such as CIPROBAY. Elderly patients may be more susceptible to effects of CIPROBAY on the QT interval. Concomitant use of CIPROBAY with medicines or in patients with disorders that can result in prolongation of the QT interval is contraindicated if concomitant use leads to prolongation of QTc interval associated with serious or potentially fatal dysrhythmias or symptomatic dysrhythmias occur at QTc intervals less than usually associated with dysrhythmias e.g. class IA or III antidysrhythmics, tricyclic antidepressants, macrolides, antipsychotics, (see section 4.5) or congenital long QT syndrome, risk of Torsades de Pointes, uncorrected electrolyte imbalance such as hypokalaemia or hypomagnesaemia and cardiac disease such as heart failure, myocardial infarction, or bradycardia. A pre-treatment ECG and frequent follow up ECG monitoring is mandatory with concomitant use to determine whether concomitant use is contraindicated. There is some evidence of an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the elderly population. Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysmal disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissections, or in the presence of other risk factors or conditions predisposing aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcetu2019s disease, hypertension, known arthrosclerosis) (see section 4.3). In case of sudden abdominal, chest, or back pain, patients should be advised to immediately consult a medical practitioner in an emergency department of a hospital. Concomitant use of fluoroquinolones and ACE inhibitors/angiotensin-receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment, and monitored during treatment, with fluoroquinolone and ACE inhibitors/angiotensin receptor blockers. There is some evidence, although inconclusive, of a possible association between fluoroquinolone use and mitral valve and/or aortic valve regurgitation. A thorough cardiovascular examination including an echocardiogram should be performed before oral fluoroquinolones are prescribed. Fluoroquinolones should not be prescribed to patients with mitral valve and/or aortic valve regurgitation (see section 4.3). Children and adolescents CIPROBAY is contraindicated in children below the age of 18 years (see section 4.3). In children, arthropathy is reported to occur commonly (see additional information on special populations in section 4.2). Hypersensitivity Hypersensitivity and allergic reactions, including life-threatening anaphylactic/anaphylactoid shock may occur with the first exposure to CIPROBAY. In these cases, CIPROBAY must be discontinued, and appropriate medical treatment be instituted. Gastrointestinal System Pseudomembranous colitis which may be fatal if not treated should be considered if severe and persistent diarrhoea develop during and after treatment with CIPROBAY. In such cases CIPROBAY must be discontinued and appropriate antimicrobial and supportive therapy should be initiated. Medicines that inhibit peristalsis are contraindicated in this situation. Hepatobilliary system Cases of hepatic necrosis and life-threatening hepatic failure have been reported with CIPROBAY. 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 (see section 4.8). There may be a temporary increase in transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with previous liver damage (see section 4.8). Myasthenia gravis The use of CIPROBAY in patients with myasthenia gravis is contraindicated if alternative appropriate antibiotic choices are available (see section 4.3). CIPROBAY may exacerbate the symptoms of myasthenia gravis. Tendinitis and tendon rupture Tendinitis and tendon rupture (predominantly Achilles tendon), sometimes bilateral, may occur with CIPROBAY, even within the first 48 hours of treatment. Cases occurring up to several months after completion of therapy have been reported (see sections 4.3 and 4.8). The risk of tendinopathy may be increased in elderly patients during strenuous physical activity, in patients treated concomitantly with corticosteroids, in patients with renal impairment and patients with solid organ transplants. At any sign of tendinitis (e.g. painful swelling, inflammation) the administration of CIPROBAY should be discontinued and physical exercise be avoided. At any sign of tendinitis (e.g. painful swelling, inflammation) the affected extremity should be kept at rest, any inappropriate physical exercise should be avoided, a physician should be consulted and the antibiotic treatment should be discontinued. CIPROBAY should not be used in patients with a history of tendon disorders, especially those related to previous exposure to quinolone or fluoroquinolone use (see section 4.3). CIPROBAY should only be used in these patients if appropriate alternative antibiotic choices are not available, have failed, are contraindicated, or not tolerated. Seizures CIPROBAY is known to trigger seizures or lower the seizure threshold. In patients with epilepsy and in patients who have suffered from previous central nervous system (CNS) disorders (e.g. lowered convulsion threshold, previous history of convulsions, reduced cerebral blood flow, altered brain structure or stroke). CIPROBAY should only be used where alternative appropriate therapies have failed, are contraindicated, or not tolerated, since these patients are endangered due to possible central nervous system side effects. Cases of status epilepticus have been reported (see sections 4.3 and 4.8). If seizures occur, CIPROBAY should be discontinued. Peripheral neuropathy Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaesthesias, or weakness have been reported in patients receiving fluoroquinolones including CIPROBAY. Patients on treatment with CIPROBAY should be advised to inform their medical practitioner prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop (see section 4.8). The recovery process of neuropathy may be prolonged (weeks or months) and full recovery to the pre-treatment status may not occur. Psychiatric reactions Psychiatric reactions may occur after the first administration of fluoroquinolones, including CIPROBAY. Cases of depression or psychotic reactions may progress to suicidal ideations/thoughts and self-injury, such as attempted or completed suicide (see sections 4.3 and 4.8). In the event that a patient develops any of these reactions, CIPROBAY should be discontinued and appropriate measures instituted. Skin and Appendages CIPROBAY has been shown to produce photosensitivity reactions. Patients taking CIPROBAY should avoid direct exposure to excessive sunlight or UV-light. Therapy should be discontinued if photosensitisation (i.e. sunburn-like skin reactions) occurs (see section 4.8). Cytochrome P450 Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 enzymes. Care should be taken when other medicines which are metabolised via the same enzymatic pathway (e.g. theophylline, methylxanthines, caffeine, duloxetine, ropinirole, clozapine, olanzapine, agomelatine) are administered concomitantly. Increased plasma concentrations associated with specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin (see section 4.5). Dysglycaemia As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported with CIPROBAY. In CIPROBAY-treated patients, dysglycaemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. sulfonylurea) or with insulin. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).

Medicines known to prolong QT interval CIPROBAY should not be used in patients receiving medicines known to prolong the QT interval (e.g. Class IA and II antidysrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see sections 4.3 and 4.4). Chelation Complex Formation The simultaneous administration of CIPROBAY (oral) and multivalent cation-containing medicines and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer, lanthanum carbonate), sucralfate or antacids and highly buffered medicines (e.g. anti-retrovirals) containing magnesium, aluminium or calcium reduce the absorption of CIPROBAY. Consequently, CIPROBAY should be administered either 1 - 2 hours before, or at least 4 hours after these preparations. The restriction does not apply to antacids belonging to the class of H2 receptor blockers. Food and Dairy Products The concurrent administration of dairy products or mineral fortified drinks alone (e.g. milk, yoghurt, calcium fortified orange juice) and CIPROBAY should be avoided because the absorption of CIPROBAY is reduced. Dietary calcium as part of a meal, however, does not significantly affect absorption. Metoclopramide Metoclopramide accelerates the absorption of CIPROBAY, resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of CIPROBAY. Omeprazole Concomitant administration of CIPROBAY and omeprazole containing medicines results in a 20% reduction of the Cmax and AUC of CIPROBAY. Tizanidine In a clinical study in healthy subjects, there was an increase in tizanidine serum concentrations (Cmax increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect (see section 4.4). Tizanidine-containing medicines must not be administered together with CIPROBAY (see section 4.5). Theophylline Concurrent administration of CIPROBAY with theophylline-containing medicines may lead to elevated plasma concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related side effects. If concomitant use of the two medicines cannot be avoided, plasma levels of theophylline should be monitored and dosage adjustments made as appropriate (see Cytochrome P450 in section 4.4). Other xanthine derivatives Concurrent administration of CIPROBAY with caffeine or pentoxifylline (oxpentifylline) containing products, may lead to raised serum concentrations of these xanthine derivatives. Phenytoin Altered (decreased or increased) serum levels of phenytoin were observed in patients receiving CIPROBAY and phenytoin simultaneously. To avoid the loss of seizure control associated with decreased phenytoin levels, and to prevent phenytoin overdose-related side effects when CIPROBAY is discontinued in patients receiving both agents, monitoring of phenytoin therapy, including phenytoin serum-concentration measurements, is recommended during and shortly after co-administration of CIPROBAY with phenytoin. Methotrexate Renal tubular transport of methotrexate may be inhibited by concomitant administration of CIPROBAY potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate-associated toxic reactions. Therefore, patients on methotrexate therapy should be carefully monitored when concomitant CIPROBAY therapy is indicated. NSAID Concomitant administration of the nonsteroidal anti-inflammatory medicines with quinolones such as CIPROBAY increases the risk of central nervous system stimulation and seizures. Ciclosporin Monitoring of serum creatinine concentrations is advised in patients on concomitant ciclosporin therapy, as transient increases in serum creatinine concentrations have been observed. Vitamin K antagonists Simultaneous administration of CIPROBAY with a vitamin K antagonist may augment its anticoagulant effects. The risk may vary with the underlying infection, age and general status of the patient, so that the contribution of ciprofloxacin to the increase in INR (international normalised ratio) is difficult to assess. The INR should be monitored frequently during and shortly after co-administration of CIPROBAY with a vitamin K antagonist (e.g. warfarin). Duloxetine An increase of duloxetine in blood concentrations can be expected with concomitant administration with CIPROBAY (see Cytochrome P450 in section 4.4). Ropinirole Concomitant use of ropinirole with ciprofloxacin as in CIPROBAY, a moderate inhibitor of the CYP450 1A2 isozyme, resulted in an increase of Cmax and AUC of ropinirole by 60% and 84%, respectively. Monitoring ropinirole-related side effects and/or dose adjustment as appropriate is recommended during and shortly after co-administration with CIPROBAY (see Cytochrome P450 in section 4.4). Lidocaine (Lignocaine) Concomitant use of lidocaine-(lignocaine)-containing medicines with a moderate inhibitor of CYP450 1A2 isozyme such as CIPROBAY, reduces the clearance of intravenous lidocaine by 22% and may increase the risk for lidocaine side effects. Clozapine Following concomitant administration of 250 mg CIPROBAY 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 CIPROBAY are advised (see Cytochrome P450 in 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 CIPROBAY. Caution is advised when prescribing CIPROBAY concomitantly with sildenafil. ACE inhibitors and angiotensin-receptor blockers Concomitant use of fluoroquinolones and ACE inhibitors/angiotensin-receptor blockers may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Safety during pregnancy and lactation has not been established (see section 4.3). Pregnancy The safety of CIPROBAY in pregnant women has not been established (see section 4.3). CIPROBAY must not be prescribed to pregnant women. Animal studies have demonstrated that CIPROBAY may damage the articular cartilage in the foetus. Lactation Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, mothers on CIPROBAY should not breastfeed their infants.

Fluoroquinolones, including CIPROBAY may result in an impairment of the patient's ability to drive or operate machinery due to musculoskeletal and/or CNS reactions (see section 4.8).

The frequencies of side effects reported with CIPROBAY in all clinical studies are summarised in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: Very common (u22651/10); common (u22651/100 to <1/10); uncommon (u22651/1 000 to u22641/100); rare (u22651/10 000 to u22641/1 000); very rare (u22641/10 000).

The side effects identified only during post-marketing surveillance, and for which a frequency could not be estimated. Metabolism and nutrition disorders: Hyperglycaemia, hypoglycaemic coma Nervous system disorders: Peripheral neuropathy and polyneuropathy, Guillain-Barre syndrome Cardiac disorders: QT prolongation, ventricular dysrhythmia, Torsades de Pointes*, aortic aneurysm and dissection Skin and subcutaneous tissue disorders: Acute generalized exanthematous pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Fixed drug eruption (see section 4.4). Investigations: Increased International Normalised Ratio (INR) (in patients treated with Vitamin K antagonist) *These events were reported during the post-marketing period and were observed predominantly among patients with further risk factors for QT prolongation (see section 4.4). Cases of mitral valve and/or aortic valve regurgitation were reported in patients treated with oral fluoroquinolones. Due to insufficient post-marketing information in the reported cases, it is unknown whether fluoroquinolone use was the causative factor, or a contributory factor, or played no role in the reported cases where mitral valve and/or aortic valve regurgitation was diagnosed.

In overdose, side effects may be exaggerated or exacerbated (see section 4.8). In the event of acute, excessive oral overdosage, reversible renal toxicity has been reported. Apart from routine emergency measures, renal function, including urinary pH and acidity should be monitored, to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids may reduce the absorption of CIPROBAY in overdose. Only a small quantity of CIPROBAY (< 10%) is eliminated by haemodialysis or peritoneal dialysis. Treatment should be symptomatic and supportive.