Document: spc-doc_PL 00289-1433 change

• spc-doc_PL 00289-1433
• spc-doc_PL 04569-0511
• spc-doc_PL 08553-0172
• spc-doc_PL 11311-0411
• spc-doc_PL 20532-0010
• spc-doc_PL 40378-0161

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ciprofloxacin 100 mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg ciprofloxacin as ciprofloxacin hydrochloride. For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

White, biconvex, round film-coated tablets, debossed “CIP 100” on one side and plain on the other.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Ciprofloxacin Film-Coated tablets are indicated for the treatment of the following infections (see sections 4.4 and 5.1). Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Adults

• Lower respiratory tract infections due to Gram-negative bacteria

-    exacerbations of chronic obstructive pulmonary disease

-    broncho-pulmonary infections in cystic fibrosis or in bronchiectasis

- pneumonia

•    Chronic suppurative otitis media

•    Acute exacerbation of chronic sinusitis especially if these are caused by Gramnegative bacteria

•    Urinary tract infections

•    Gonococcal urethritis and cervicitis

•    Epididymo-orchitis including cases due to Neisseria gonorrhoeae

•    Pelvic inflammatory disease including cases due to Neisseria gonorrhoeae

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

•    Infections of the gastro-intestinal tract (e.g. travellers’ diarrhoea)

•    Intra-abdominal infections

•    Infections of the skin and soft tissue caused by Gram-negative bacteria

•    Malignant external otitis

•    Infections of the bones and joints

•    Treatment of infections in neutropenic patients

•    Prophylaxis of infections in neutropenic patients

•    Prophylaxis of invasive infections due to Neisseria meningitidis

•    Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Children and adolescents

•    Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa

•    Complicated urinary tract infections and pyelonephritis

•    Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.

Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Posology

The dosage is determined by the indication, the severity and the site of the infection, the susceptibility to ciprofloxacin of the causative organism(s), the renal function of the patient and, in children and adolescents the body weight.

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

Treatment of infections due to certain bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter or Staphylococci) may require higher ciprofloxacin doses and coadministration 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 (potentially including initial parenteral treatment with ciprofloxacin)
Infections of the lower respiratory tract		500 mg twice daily to 750 mg twice daily	7 to 14 days
Infections of the upper respiratory tract	Acute exacerbation of chronic sinusitis	500 mg twice daily to 750 mg twice daily	7 to 14 days
	Chronic suppurative otitis media	500 mg twice daily to 750 mg twice daily	7 to 14 days
	Malignant external otitis	750 mg twice daily	28 days up to 3 months
Urinary tract infections	Uncomplicated cystitis	250 mg twice daily to 500 mg twice daily	3 days
		In pre-menopausal women, 500 mg single dose may be used
	Complicated cystitis, Uncomplicated pyelonephritis	500 mg twice daily	7 days
	Complicated pyelonephritis	500 mg twice daily to 750 mg twice daily	at least 10 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses)
	Prostatitis	500 mg twice daily to 750 mg twice daily	2 to 4 weeks (acute) to 4 to 6 weeks (chronic)
Genital tract infections	Gonococcal urethritis and cervicitis	500 mg as a single dose	1 day (single dose)
	Epididymo-orchitis and pelvic inflammatory diseases	500 mg twice daily to 750 mg twice daily	at least 14 days
Infections of the gastro-intestinal tract and intraabdominal infections	Diarhoea caused by bacterial pathogens including Shigella spp. other than Shigella dysenteriae type 1 and empirical treatment of severe travellers' diarrhoea	500 mg twice daily	1 day
	Diarrhoea caused by Shigella dysenteriae type 1	500 mg twice daily	5 days
	Diarrhoea caused by Vibrio cholerae	500 mg twice daily	3 days
	Typhoid fever	500 mg twice daily	7 days

Special propulations

Paediatric population

Indications	Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Cystic fibrosis	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	10 to 14 days
Complicated urinary tract infections and pyelonephritis	10 mg/kg body weight twice daily to 20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	10 to 21 days
Inhalation anthrax postexposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. 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 500 mg per dose.	60 days from the confirmation of Bacillus anthracis exposure
Other severe infections	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	According to the type of infections

Geriatric patients

Geriatric patients should receive a dose selected according to the severity of the infection and the patient’s creatinine clearance.

Renal and hepatic impairment

Recommended starting and maintenance doses for patients with impaired renal function:

Serum Creatinine    Oral Dose

[pmol/l]    [mg]

< 124    See Usual Dosage.

124 to 168_ 250-500 mg every 12 h

< 30	> 169	250-500 mg every 24 h
Patients on haemodialysis	> 169	250-500 mg every 24 h
		(after dialysis)
Patients on peritoneal dialysis	> 169	250-500 mg every 24 h

In patients with impaired liver function no dose adjustment is required.

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

Method of administration

Tablets are to be swallowed unchewed with fluid. They can be taken independent of mealtimes. If taken on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets should not be taken with dairy products (e.g. milk, yoghurt) or mineral-fortified fruit-juice (e.g. calcium-fortified orange juice) (see section 4.5).

In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous ciprofloxacin until a switch to oral administration is possible.

4.3 Contraindications

•    Hypersensitivity to the active substance, to other quinolones or to any of the excipients listed in section 6.1.

•    Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).

4.4 Special warnings and precautions for use

Severe infections and mixed infections with Gram-positive and anaerobic pathogens Ciprofloxacin monotherapy is not suited for treatment of severe infections and infections that might be due to Gram-positive or anaerobic pathogens. In such infections ciprofloxacin must be 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 gonorrhoeae. Ciprofloxacin should be coadministered with another appropriate antibacterial agent unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Intra-abdominal infections

There are limited data on the efficacy of ciprofloxacin in the treatment of 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.

Paediatric _ pupulation

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.

Broncho-pulmonary infections in cystic _fibrosis

Clinical trials have included children and adolescents aged 5-17 years. More limited experience is available in treating children between 1 and 5 years of age.

Complicated urinary tract infections and pyelonephritis

Ciprofloxacin treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation. Clinical trials have included children and adolescents aged 1-17 years.

Other specific severe infections

Other severe infections in accordance with official guidance, or after careful 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

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.

Vision disorder

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see section 4.8).

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 older people or in patients concomitantly treated with corticosteroids (see section 4.8).

At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest. Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).

Photosensitivity

Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment (see section 4.8).

Central Nervous System

Ciprofloxacin like other quinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to suicidal ideations/thoughts culminating in attempted suicide or completed suicide. In the occurence of such cases, ciprofloxacin should be discontinued.

Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).

Cardiac disorders

Caution should be taken when using fluoroquinolones, including Ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:

-    congenital long QT syndrome

-    concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

-    uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia) cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)

Older people and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations.

(see sections 4.2 Geriatric patinets, 4.5, 4.8 and 4.9).

Gastrointestinal System

The occurrence of severe and persistent diarrhoea during or after treatment (including several weeks after treatment) may indicate an antibiotic-associated colitis (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.

Renal and urinary system

Crystalluria related to the use of ciprofloxacin has been reported (see section 4.8). Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.

Impaired renal _ function

Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment is needed in patients with impaired renal function as described in section 4.2 to avoid an increase in adverse drug reactions due to accumulation of ciprofloxacin.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (see section 4.8). In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Haemolytic reactions have been reported with ciprofloxacin in patients with 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. Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary (see section 4.5).

Methotrexate

The concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).

Interaction with tests

The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other _ products on ciprofloxacin:

Drugs known to prolong QT interval

Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4.).

Chelation Complex Formation

The simultaneous administration of ciprofloxacin (oral) and multivalent cation-containing drugs and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer), sucralfate or antacids, and highly buffered drugs (e.g. didanosine tablets) containing magnesium, aluminium, or calcium reduces the absorption of ciprofloxacin. Consequently, ciprofloxacin 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

Dietary calcium as part of a meal does not significantly affect absorption. However, the concurrent administration of dairy products or mineral-fortified drinks alone (e.g. milk, yoghurt, calcium-fortified orange juice) with ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced.

Probenecid

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

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.

Omeprazole

Concomitant administration of ciprofloxacin and omeprazole containing medicinal products results in a slight reduction of Cmax and AUC of ciprofloxacin.

Effects of ciprofloxacin on other medicinal products:

Tizanidine

Tizanidine must not be administered together with ciprofloxacin (see section 4.3). In a clinical study with healthy subjects, there was an increase in serum tizanidine concentration (Cmax increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Increased serum tizanidine concentration is associated with a potentiated hypotensive and sedative effect.

Methotrexate

Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and increased risk of methotrexate-associated toxic reactions. The concomitant use is not recommended (see section 4.4).

Theophylline

Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration. This can lead to theophylline-induced side effects that may rarely be life threatening or fatal. During the combination, serum theophylline concentrations should be checked and the theophylline dose reduced as necessary (see section 4.4).

Other xanthine derivatives

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

Phenytoin

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

Ciclosporin

A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and ciclosporin 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 vitamin K antagonists may augment its anti-coagulant effects. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the 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).

Glibenclamide

In particular cases, concurrent administration of ciprofloxacin and glibenclamide containing medicinal products can intensify the action of glibenclamide (hypoglycaemia).

Duloxetine

In clinical studies, it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration (see section 4.4).

Ropinirole

It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of Cmax and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related side

effects and dose adjustment as appropriate is recommended during and shortly after coadministration with ciprofloxacin (see section 4.4).

Lidocaine

It was demonstrated in healthy subjects that concomitant use of lidocaine containing medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.

Clozapine

Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after co administration with ciprofloxacin are advised (see section 4.4).

Sildenafil

Cmax and AUC of sildenafil were increased approximately twofold in healthy subjects after an oral dose of 50 mg given concomitantly with 500 mg ciprofloxacin. Therefore, caution should be used prescribing ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.

4.6 Fertility, pregnancy and lactation

Pregnancy

The data that are available on administration of ciprofloxacin to pregnant women indicates no malformative or feto/neonatal toxicity of ciprofloxacin. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed, thus, it cannot be excluded that the drug could cause damage to articular cartilage in the human immature organism/foetus (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during pregnancy.

Breast-feeding

Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.

4.7 Effects on ability to drive and use machines

Due to its neurological effects, ciprofloxacin may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.

4.8 Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.

ADRs derived from clinical studies and post-marketing surveillance with ciprofloxacin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.

System	Common	Uncommon	Rare	Very Rare	Frequency
Organ Class	> 1/100 to	> 1/1000 to	> 1/10 000	< 1/10 000	not known
			to		(cannot be
	< 1/10	< 1/100	< 1/1000		estimated from available
					data)
Infections		Mycotic	Antibiotic
and		super-	associated
Infestations		infections	colitis (very rarely with possible fatal outcome) (see section 4.4)
Blood and		Eosinophilia	Leukopenia	Haemolytic
Lymphatic				anaemia
System Disorders			Anaemia	Agranulocytosi
			Neutropenia	s
			Leukocytosi	Pancytopenia
			s	(life- threatening)
			Thrombocyt o-penia	Bone marrow depression
			Thrombo-	(life-
			cytaemia	threatening)
Immune			Allergic	Anaphylactic
System			reaction	reaction
Disorders			Allergic	Anaphylactic
			oedema/	shock (life-
			angiooedem	threatening)
			a	(see section 4.4)
				Serum sickness-like reaction

Metabolism		Anorexia	Hyper-
and Nutrition Disorders			glycaemia
Psychiatric		Psychomoto	Confusion	Psychotic
Disorders		r	and	reactions
		hyperactivit	disorientatio	(potentially
		y/ agitation	n	culminating in suicidal
			Anxiety	ideations/thoug
			reaction	hts or suicide attempts and
			Abnormal dreams	completed suicide) (see section 4.4)
			Depression (potentially culminating in suicidal ideations/tho ughts or suicide attempts and completed suicide) (see section 4.4)
			Hallucinatio
			ns
Nervous		Headache	Par- and	Migraine	Peripheral
System			Dysaesthesia		neuropathy
Disorders		Dizziness		Disturbed	(see section
			Hypo-	coordination	4.4)
		Sleep disorders	aesthesia	Gait
			Tremor	disturbance
		Taste disorders	Seizures	Olfactory
			(incl. status epilepticus,	nerve disorders
			see section	Intracranial
			4.4)	hypertension
			Vertigo
Eye			Visual	Visual colour
Disorders			disturbances (e.g. diplopia)	distortions
Ear and			Tinnitus

Labyrinth Disorders			Hearing loss/ Hearing impaired
Cardiac Disorders			Tachycardia		Ventricular arrhythmia and torsades de pointes (reported predominant ly in patients with risk factors for QT prolongation ), ECG QT prolonged (see sections 4.4 and 4.9)
Vascular Disorders			Vasodilatatio n Hypotension Syncope	Vasculitis
Respiratory, Thoracic and Mediastinal Disorders			Dyspnoea (including asthmatic condition)
Gastro intestinal Disorders	Nausea Diarrhoea	Vomiting Gastro intestinal and abdominal pains Dyspepsia Flatulence		Pancreatitis
Hepatobiliary Disorders		Increase in transaminase s Increased bilirubin	Hepatic impairment Cholestatic icterus	Liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section

			Hepatitis	4.4)
Skin and		Rash	Photo-	Petechiae	Acute
Subcutaneou			sensitivity		generalised
s Tissue		Pruritus	reactions	Erythema	exanthemato
Disorders			(see section	multiforme	us pustulosis
		Urticaria	4.4)	Erythema nodosum	(AGEP)
				Stevens- Johnson syndrome (potentially life- threatening)
				Toxic epidermal necrolysis (potentially life- threatening)
Musculo-		Musculo-	Myalgia	Muscular
skeletal,		skeletal pain		weakness
Connective		(e.g. extremity	Arthritis	Tendinitis
Tissue and		pain, back	Increased
Bone		pain, chest	muscle tone	Tendon rupture
Disorders		pain)	and	(pre-
			cramping	dominantly
		Arthralgia		Achilles tendon) (see section 4.4)
				Exacerbation of symptoms of myasthenia gravis (see section 4.4)
Renal and		Renal	Renal failure
Urinary		impairment	Haematuria
Disorders			Crystalluria (see section 4.4)
			Tubulo interstitial nephritis

General Disorders and Administratio n Site Conditions		Asthenia Fever	Oedema Sweating (hyperhidrosi s)
Investigation s		Increase in blood alkaline phosphatase	Increased amylase		Internationa l normalised ratio increased (in patients treated with Vitamin K antagonists)

Paediatric population

The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

An overdose of 12 g has been reported to lead to mild symptoms of toxicity. An acute overdose of 16 g has been reported to cause acute renal failure.

Symptoms 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. Calcium or magnesium containing antacids may theoretically reduce the absorption of ciprofloxacin in overdoses. Patients should be kept well hydrated.

Only a small quantity of ciprofloxacin (<10%) is eliminated by haemodialysis or peritoneal dialysis.

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Fluoroquinolones ATC code: J01M A02

Mechanism of action

As a fluoroquinolone antibacterial agent, the bactericidal action of ciprofloxacin results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.

PK/PD relationship

Efficacy mainly depends on the relation between the maximum concentration in serum (Cmax) and the minimum inhibitory concentration (MIC) of ciprofloxacin for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.

Mechanism of resistance

In-vitro resistance to ciprofloxacin can be acquired through a stepwise process by target site mutations in both DNA gyrase and topoisomerase IV. The degree of crossresistance between ciprofloxacin and other fluoroquinolones that results is variable. Single mutations may not result in clinical resistance, but multiple mutations generally result in clinical resistance to many or all active substances within the class. Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physiochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. All in-vitro mechanisms of resistance are commonly observed in clinical isolates. Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to ciprofloxacin. Plasmid-mediated resistance encoded by qnr-genes has been reported.

Spectrum of antibacterial activity:

Breakpoints separate susceptible strains from strains with intermediate susceptibility and the latter from resistant strains:

EUCAST Recommendations

Microorganisms	Susceptible	Resistant
Enterobacteria	S < 0.5 mg/l	R > 1mg/l
Pseudomonas	S < 0.5 mg/l	R > 1mg/l
Acinetobacter	S < 1 mg/l	R > 1 mg/l
Staphylococcus spp.1	S < 1 mg/l	R > 1 mg/l
Haemophilus influenzae and Moraxella catarrhalis	S < 0.5 mg/l	R > 0.5 mg/l
Neisseria gonorrhoeae	S < 0.03 mg/l	R > 0.06 mg/l
Neisseria meningitidis	S < 0.03 mg/l	R > 0.06 mg/l
Non-species-related breakpoints*	S < 0.5 mg/l	R > 1 mg/l

¹ Staphylococcus spp. - breakpoints for ciprofloxacin relate to high dose therapy.

* Non-species-related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been

5.2 Pharmacokinetic properties

Absorption

Following oral administration of single doses of 250 mg, 500 mg, and 750 mg of ciprofloxacin tablets, ciprofloxacin is absorbed rapidly and extensively, mainly from the small intestine, reaching maximum serum concentrations 1-2 hours later.

Single doses of 100-750 mg produced dose-dependent maximum serum concentrations (Cmax) between 0.56 and 3.7 mg/L. Serum concentrations increase proportionately with doses up to 1000 mg. The absolute bioavailability is approximately 70-80%.

A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration-time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours.

Distribution

Protein binding of ciprofloxacin is low (20-30%). Ciprofloxacin is present in plasma largely in a non-ionised form and has a large steady state distribution volume of 2-3 L/kg body weight. Ciprofloxacin reaches high concentrations in a variety of tissues such as lung (epithelial fluid, alveolar macrophages, biopsy tissue), sinuses, inflamed lesions (cantharides blister fluid), and the urogenital tract (urine, prostate, endometrium) where total concentrations exceeding those of plasma concentrations are reached.

Biotransformation

Low concentrations of four metabolites have been reported, which were identified as: desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.

Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 iso-enzymes.

Elimination

Ciprofloxacin is largely excreted unchanged both renally and, to a smaller extent, faecally. The serum elimination half-life in subjects with normal renal function is approximately 4-7 hours.

Excretion of ciprofloxacin (% of dose)
	Oral Administration
	Urine	Faeces
Ciprofloxacin	44.7	25.0
Metabolites (Mj-M4)	11.3	7.5

Renal clearance is between 180-300 mL/kg/h and the total body clearance is between 480-600 mL/kg/h. Ciprofloxacin undergoes both glomerular filtration and tubular secretion. Severely impaired renal function leads to increased half lives of ciprofloxacin of up to 12 h.

Non-renal clearance of ciprofloxacin is mainly due to active trans-intestinal secretion and metabolism. 1% of the dose is excreted via the biliary route. Ciprofloxacin is present in the bile in high concentrations.

Paediatric population

The pharmacokinetic data in paediatric population are limited.

In a study in children Cmax and AUC were not age-dependent (above one year of age). No notable increase in Cmax and AUC upon multiple dosing (10 mg/kg three times daily) was observed.

In 10 children with severe sepsis Cmax was 6.1 mg/L (range 4.6-8.3 mg/L) after a 1-hour intravenous infusion of 10 mg/kg in children aged less than 1 year compared to

7.2 mg/L (range 4.7-11.8 mg/L) for children between 1 and 5 years of age. The AUC values were 17.4 mg*h/L (range 11.8-32.0 mg*h/L) and 16.5 mg*h/L (range 11.0-23.8 mg*h/L) in the respective age groups.

These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of paediatric patients with various infections, the predicted mean half-life in children is approx. 4-5 hours and the bioavailability of the oral suspension ranges from 50 to 80%.

5.3 Preclinical safety data

Non-clinical data reveal no special hazards for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential, or toxicity to reproduction.

Like a number of other quinolones, ciprofloxacin is phototoxic in animals at clinically relevant exposure levels. Data on photomutagenicity/ photocarcinogenicity show a weak photomutagenic or phototumorigenic effect of ciprofloxacin in-vitro and in animal experiments. This effect was comparable to that of other gyrase inhibitors.

Articular tolerability

As reported for other gyrase inhibitors, ciprofloxacin causes damage to the large weight-bearing joints in immature animals. The extent of the cartilage damage varies according to age, species and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) revealed no evidence of cartilage lesions. In a study in young beagle dogs, ciprofloxacin caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Microcrystalline cellulose Povidone K-30 Croscarmellose sodium Colloidal anhydrous silica Magnesium stearate

Film-coating: Hypromellose Titanium dioxide (E171) Macrogol 400

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Transparent or white opaque PVC/PVdC/aluminium blister in cardboard boxes.

Pack sizes: 6, 8, 10, 16, 20 film-coated tablets.

Hospital packs of 160 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

TEVA UK LIMITED BRAMPTON ROAD HAMPDEN PARK EASTBOURNE EAST SUSSEX BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/1433

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25 August 2004

DATE OF REVISION OF THE TEXT

15/06/2015