Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Villerton Invest SA, Rue Edward Steichen 14, 2540 Luxembourg
Hypersensitivity to the active substance, to other quinolones or to any of the excipients (see section 6.1).
Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).
Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older 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 aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
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.
Ciprofloxacin is not recommended for the treatment of streptococcal infections due to inadequate efficacy.
Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. 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.
There are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical intra-abdominal infections.
The choice of ciprofloxacin should take into account information on resistance to ciprofloxacin in relevant pathogens in the countries visited.
Ciprofloxacin should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.
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.
The use of ciprofloxacin in children and adolescents should follow available official guidance. Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.
Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. Safety data from a randomised double-blind study on ciprofloxacin use in children (ciprofloxacin: n=335, mean age = 6.3 years; comparators: n=349, mean age = 6.2 years; age range = 1 to 17 years) revealed an incidence of suspected drug-related arthropathy (discerned from joint-related clinical signs and symptoms) by Day +42 of 7.2% and 4.6%. Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug-related arthropathy cases over time was not statistically significant between groups. Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue (see section 4.8).
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.
Ciprofloxacin treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation.
Clinical trials have included children and adolescents aged 1-17 years.
Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify a ciprofloxacin use.
The use of ciprofloxacin for specific severe infections other than those mentioned above has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.
Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose (see section 4.8) and may be life-threatening. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required.
Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.
Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, even within the first 48 hours of treatment. Inflammation and ruptures of tendon may occur even up to several months after discontinuation of ciprofloxacin therapy The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).
At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest.
Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).
Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment (see section 4.8).
Ciprofloxacin like other quinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to suicidal ideations/thoughts culminating in attempted suicide or completed suicide. In the occurrence of such cases, ciprofloxacin should be discontinued.
Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).
Caution should be taken when using fluoroquinolones, including ciprofloxacin in patients with known risk factors for prolongation of the QT interval such as, for example:
Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations.
(See section 4.2 Elderly, section 4.5, section 4.8, section 4.9).
The occurrence of severe and persistent diarrhoea during or after treatment (including several weeks after treatment) may indicate an antibiotic-associated colitis (life-threatening with possible fatal outcome), requiring immediate treatment (see section 4.8). In such cases, ciprofloxacin should immediately be discontinued, and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this situation.
Crystalluria related to the use of ciprofloxacin has been reported (see section 4.8). Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.
Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment is needed in patients with impaired renal function as described in section 4.2 to avoid an increase in adverse drug reactions due to accumulation of ciprofloxacin.
Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (see section 4.8). In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued.
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.
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.
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.
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, aglomelatine). Co-administration of ciprofloxacin and tizanidine is contra-indicated. Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary (see section 4.5).
The concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).
The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.
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.
As with other quinolones, hypoglycaemia has been reported most often in diabetic patients, predominantly in the elderly population. In all diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).
As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported (see section 4.8), usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.
This medicinal product contains 354.1 mg sodium per 100 ml, equivalent to 18 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).
Probenecid
h4.
Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.
Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.
Concomitant administration of ciprofloxacin and omeprazole containing medicinal products results in a slight reduction of C~max~ and AUC of ciprofloxacin.
Tizanidine must not be administered together with ciprofloxacin (see section 4.3). In a clinical study with healthy subjects, there was an increase in serum tizanidine concentration (C~max~ increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Increased serum tizanidine concentration is associated with a potentiated hypotensive and sedative effect.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and increased risk of methotrexate-associated toxic reactions. The concomitant use is not recommended (see section 4.4).
Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration. This can lead to theophylline-induced side effects that may rarely be life threatening or fatal. During the combination, serum theophylline concentrations should be checked and the theophylline dose reduced as necessary (see section 4.4).
On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.
Simultaneous administration of ciprofloxacin and phenytoin may result in increased or reduced serum levels of phenytoin such that monitoring of drug levels is recommended.
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.
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).
In particular cases, concurrent administration of ciprofloxacin and glibenclamide containing medicinal products can intensify the action of glibenclamide (hypoglycaemia).
In clinical studies, it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and C~max~ of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration (see section 4.4).
It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of C~max~ and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related side effects and dose adjustment as appropriate is recommended during and shortly after co-administration with ciprofloxacin (see section 4.4).
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.
Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised (see section 4.4).
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.
In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of agomelatine exposure. Although no clinical data are available for a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant administration (‘Cytochrome P450’ in section 'Special warnings and precautions for use).
Co-administration ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.
The data that are available on administration of ciprofloxacin to pregnant women indicates no malformative or feto/neonatal toxicity of ciprofloxacin. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed, thus, it cannot be excluded that the drug could cause damage to articular cartilage in the human immature organism/foetus (see section 5.3). As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during pregnancy.
Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.
Due to its neurological effects, ciprofloxacin may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.
The most commonly reported adverse drug reactions (ADRs) are nausea, diarrhoea, vomiting, transient increase in transaminases, rash, and injection and infusion site reactions.
ADRs derived from clinical studies and post-marketing surveillance with Ciprofloxacin (oral, intravenous and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.
Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1,000, Very Rare <1/10,000, Frequency not known (cannot be estimated from available data)
Uncommon: Mycotic superinfections
Uncommon: Eosinophilia
Rare: Leukopenia, Anaemia, Neutropenia, Leukocytosis, Thrombocytopenia, Thrombocytaemia
Very Rare: Haemolytic anaemia, Agranulocytosis, Pancytopenia (life-threatening), Bone marrow depression (life-threatening)
Rare: Allergic reaction, Allergic oedema/angio-oedema
Very Rare: Anaphylactic reaction, Anaphylactic shock (life-threatening) (see section 4.4), Serum sickness-like reaction
Uncommon: Decreased appetite
Rare: Hyperglycaemia, Hypoglycaemia (see section 4.4)
Uncommon: Psychomotor hyperactivity/agitation
Rare: Confusion and disorientation, Anxiety reaction, Abnormal dreams, Depression (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4), Hallucinations
Very Rare: Psychotic reactions (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4)
Frequency not known: Mania, hypomania
Uncommon: Headache, Dizziness, Sleep disorders, Taste disorders
Rare: Par- and Dysaesthesia, Hypoaesthesia, Tremor, Seizures (incl. status epilepticus see section 4.4), Vertigo
Very Rare: Migraine, Disturbed coordination, Gait disturbance, Olfactory nerve disorders, Intracranial hypertension and pseudomotor cerebri
Frequency not known: Peripheral neuropathy and polyneuropathy (see section 4.4)
Rare: Visual disturbances e.g. diplopia
Very Rare: Visual colour distortions
Rare: Tinnitus, Hearing loss/Hearing impaired
Rare: Tachycardia
Frequency not known: Ventricular arrhythmia and torsades de pointes* (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolongation (see section 4.4 and 4.9).
Rare: Vasodilatation, Hypotension, Syncope
Very Rare: Vasculitis
Rare: Dyspnoea (including asthmatic condition)
Common: Nausea, Diarrhoea
Uncommon: Vomiting, Gastrointestinal and abdominal pains, Dyspepsia, Flatulence
Rare: Antibiotic associated diarrhoea including pseudomembraneous colitis
Very Rare: Pancreatitis
Increase in transaminases
Increased bilirubin
Rare: Hepatic impairment, Cholestatic icterus, Hepatitis
Very Rare: Liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section 4.4)
Uncommon: Rash, Pruritus, Urticaria
Rare: Photosensitivity reactions (see section 4.4)
Very Rare: Petechiae, Erythema multiforme, Erythema nodosum, Stevens-Johnson syndrome (potentially life-threatening), Toxic epidermal necrolysis (potentially life-threatening)
Frequency not known: Acute generalised exanthematous pustulosis (AGEP); Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)
Uncommon: Musculoskeletal pain (e.g. extremity pain, back pain, chest pain), Arthralgia
Rare: Myalgia, Arthritis, Increased muscle tone and cramping
Very Rare: Muscular weakness, Tendinitis, Tendon rupture (predominantly Achilles tendon) (see section 4.4), Exacerbation of symptoms of myasthenia gravis (see section 4.4)
Uncommon: Renal impairment
Rare: Renal failure Haematuria, Crystalluria (see section 4.4), Tubulointerstitial nephritis
Common: Injection and infusion site reactions (only intravenous administration)
Uncommon: Asthenia, Fever
Rare: Oedema, Sweating (hyperhidrosis)
Frequency not known: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Uncommon: Increase in blood alkaline phosphatase
Rare: Prothrombin level abnormal, Increased amylase
Frequency not known: International normalised ratio increased (in patients treated with Vitamin K antagonists)
* These events were reported during the postmarketing period and were observed predominantly among patients with further risk factors for QT prolongation (see section 4.4).
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
The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).
This medicinal product must not be mixed with other medicinal products.
Unless compatibility with other solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding, and discoloration.
Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solutions (e.g. penicillins, heparin solutions), especially in combination with solutions adjusted to an alkaline pH (pH of ciprofloxacin solutions: 3.9–4.5).
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