SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

TARIVID IV Infusion Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Ofloxacin, 2 mg/ml

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for Infusion

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ofloxacin is indicated for the treatment of the following bacterial infections in adults when caused by sensitive organisms (see sections 4.4 and 5.1):

-    Upper and Lower Urinary Tract: Acute and chronic lower urinary tract infections; acute and chronic upper urinary tract infections (pyelonephritis),

For the below-mentioned infections ofloxacin should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections:

-    Complicated skin and soft-tissue infections

-    Acute exacerbation of chronic bronchitis

-    Community acquired pneumonia

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

4.2 Posology and method of administration

General dosage recommendations: The dose of ofloxacin is determined by the type and severity of the infection. A daily dose of up to 400 mg ofloxacin may be given as a single dose. In this case, it is preferable to administer ofloxacin in the morning.

Daily doses of more than 400 mg must be divided into two separate doses and be given at approximately equal intervals

Adults: The usual intravenous dosages in adults are:

Complicated urinary tract infection: 200 mg daily.

Acute exacerbation of chronic bronchitis, community acquired pneumonia:

200 mg twice daily.

Complicated skin and soft tissue infections: 400 mg twice daily.

Ofloxacin solution is only intended for SLOW intravenous infusion; it is administered once or twice daily. The infusion time for Tarivid IV should not be less than 30 minutes for 200 mg. This is of particular importance when ofloxacin is administered concomitantly with drugs that can lead to a reduction in blood pressure or with barbiturate-containing anaesthetics. Generally, individual doses are to be given at approximately equal intervals.

The dose may be increased to 400 mg twice daily in severe or complicated infections.

Posology in patients with renal insufficiency

In patients with impaired renal function, the following oral or I.V. dosages are recommended:

CREATININE	UNIT DOSE	NUMBER / 24	INTERVALS
CLEARANCE	mg*	h	h
50 - 20 ml/min	100 - 200	1	24
< 20 ml/min**	100	1	24
or haemodialysis	or
or peritoneal dialysis	200	1	48

* According to indication or dose interval.

** The serum concentration of ofloxacin should be monitored in patients with severe renal impairment and dialysis patients.

When creatinine clearance cannot be measured, it can be estimated with reference to the serum creatinine level using the following Cockcroft's formula for adults:

Posology in hepatic insufficiency (e g. cirrhosis with ascites)

It is recommended that a maximum daily dose of 400 mg of ofloxacin be not exceeded, because of possible reduction of excretion.

Children: Ofloxacin is not indicated for use in children or growing adolescents.

Elderly

Age in itself does not impose to adapt the dosage of ofloxacin. However, special attention to renal function should be paid in elderly patients, and the dosage should be adapted accordingly. (See section 4.4 QT interval prolongation)

Duration of treatment: The duration of treatment is determined according to the response of the causative organisms and the clinical picture. As with all antibacterial agents, treatment with Tarivid should be continued for at least 3 days after the body temperature has returned to normal and the symptoms have subsided.

In most cases of acute infection, a course of treatment lasting 7 to 10 days is sufficient. Once the patient's condition has improved, the mode of administration should be changed from parenteral to oral, normally at the same total daily dose.

Treatment should not exceed 2 months duration.

4.3 Contraindications

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

•    Ofloxacin should not be used in patients with a past history of tendinitis related to fluoroquinolone administration.

•    Ofloxacin, like other 4-quinolones, is contra-indicated in patients with a history of epilepsy or with a lowered seizure threshold.

•    Ofloxacin is contra-indicated in children or growing adolescents, and in pregnant or breast-feeding women, since animal experiments do not entirely exclude the risk of damage to the cartilage of joints in the growing subject.

•    Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions when treated with quinolone antibacterial agents.

4.4 Special warnings and precautions for use

Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including ofloxacin. Therefore ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to ofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).

Ofloxacin is not the drug of first choice for pneumonia caused by Pneumococci or Mycoplama or infection caused by P-haemolytic Streptococci.

Resistance to fluoroquinolones of E. 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 E. coli to fluoroquinolones.

Hypersensitivity and allergic reactions

Hypersensitivity and allergic reactions have been reported for fluoroquinolones after first administration. Anaphylactic and anaphylactoid reactions can progress to life-threatening shock, even after the first administration. In these cases ofloxacin should be discontinued and suitable treatment (e.g treatment for shock) should be initiated.

Severe bullous reactions

Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with ofloxacin (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Clostridium difficile-associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with ofloxacin (including several weeks after treatment), may be symptomatic of pseudo-membranous colitis (CDAD). CDAD may range in severity from mild to life threatening, the most severe form which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with ofloxacin .If pseudo-membranous colitis is suspected, ofloxacin must be stopped immediately.

Appropriate specific antibiotic therapy must be started without delay (e.g. oral vancomycin, oral teicoplanin or metronidazole). Products inhibiting the peristalsis are contraindicated in this clinical situation

Patients predisposed to seizures

Quinolones may lower the seizure threshold and may trigger seizures. Ofloxacin is contraindicated in patients with a history of epilepsy (see section 4.3) and, as with other quinolones, ofloxacin should be used with extreme caution in patients predisposed to seizures.

Such patients may be patients with pre-existing central nervous system lesions, concomitant treatment with fenbufen and similar non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such as theophylline (see section 4.5: Interactions).

In case of convulsive seizures, treatment with ofloxacin should be discontinued Tendonitis

Tendonitis, rarely observed with quinolones, may occasionally lead to rupture involving Achilles tendon in particular. Tendinitis and tendon rupture, sometimes bilateral, may occur within 48 hours of starting treatment with ofloxacin and have been reported up to several months after discontinuation of. The risk of tendinitis and tendon rupture is increased in patients aged over 60 years and in patients using corticosteroids. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section 4.2). Close monitoring of these patients is therefore necessary if they are prescribed ofloxacin. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with ofloxacin must be halted immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon (see sections 4.3 and 4.8).

Patients with renal impairment

Since ofloxacin is mainly excreted by the kidneys, the dose of ofloxacin should be adjusted in patients with renal impairment (see section 4.2).

QT interval prolongation

Very rare cases of QT interval prolongation have been reported in patients taking fluoroquinolones. Caution should be taken when using fluoroquinolones, including ofloxacin, 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)

•    Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including Ofloxacin, in these populations.

(See section 4.2 Elderly, section 4.5, section 4.8 section 4.9).

Patients with history of psychotic disorder

Psychotic reactions have been reported in patients receiving fluoroquinolones. In some cases these have progressed to suicidal thoughts or self-endangering behaviour including suicide attempt, sometimes after a single dose (see section 4.8). In the event that a patient develops these reactions, ofloxacin should be discontinued and appropriate measures instituted.

Ofloxacin should be used with caution in patients with a history of psychotic disorder or in patients with psychiatric disease.

Patients with impaired liver function

Ofloxacin should be used with caution in patients with impaired liver function, as liver damage may occur. Cases of fulminant hepatitis potentially leading to liver failure (including fatal cases) have been reported with fluoroquinolones. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritis or tender abdomen. (See section 4.8: Undesirable effects)

Patients treated with vitamin K antagonists

Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with fluoroquinolones, including ofloxacin, in combination with a vitamin K antagonist (e.g.warfarin), coagulation tests should be monitored when these drugs are given concomitantly (see section 4.5)

Myasthenia gravis

Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Ofloxacin is not recommended in patients with a known history of myasthenia gravis

Prevention of photosensitisation

Photosensitisation has been reported with ofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium), during treatment and for 48 hours following treatment discontinuation in order to prevent photosensitisation

Superinfection

As with other antibiotics, the use of ofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If secondary infection occurs during therapy, appropriate measures should be taken.

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including ofloxacin, which can be rapid in its onset. Ofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition (see section 4.8).

Dysglycaemia

As with all quinolones, disturbances in blood glucose, including both hyperglycaemia and hypoglycaemia have been reported, 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 these diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).

Patients with glucose-6-phosphate-dehydrogenase deficiency

Patients with latent or diagnosed glucose-6-phosphate-dehydrogenase deficiency may be predisposed to haemolytic reactions if they are treated with quinolones. Therefore, if ofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).

Interference with laboratory tests

In patients treated with ofloxacin, determination of opiates in urine may give falsepositive results. It may be necessary to confirm positive opiate screens by more specific method.

Patients with rare hereditary disorders

Patients with rare hereditary disorders of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Drugs known to prolong QT interval

Ofloxacin, 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).

Prolongation of bleeding time has been reported during concomitant administration of Tarivid and anticoagulants.

Theophylline, fenbufen or similar non-steroidal antiinflammatory drugs

No pharmacokinetic interactions of ofloxacin were found with theophylline in a clinical study. However, a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, nonsteroidal anti-inflammatory drugs, or other agents, which lower the seizure threshold.

In case of convulsive seizures, treatment with ofloxacin should be discontinued.

Glibenclamide

Ofloxacin may cause a slight increase in serum concentrations of glibenclamide administered concurrently; patients treated with this combination should be closely monitored.

Probenecid, cimetidine, furosemide and methotrexate

Probenecid decreased the total clearance of ofloxacin by 24%, and increased AUC by 16%. The proposed mechanism is a competition or inhibition for active transport at the renal tubular excretion. Caution should be exercised when ofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid, cimetidine, furosemide and methotrexate.

Vitamin K antagonists

Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with ofloxacin in combination with a vitamin K antagonist (e.g. warfarin) .Coagulation tests should be monitored in patients treated with vitamin K antagonists (see section 4.4) because of a possible increase in the effect of coumarin derivatives.

4.6 Fertility, pregnancy and lactation

Pregnancy

Based on a limited amount of human data, the use of fluoroquinolones in the first trimester of pregnancy has not been associated with an increased risk of major malformations or other adverse effects on pregnancy outcome. Animal studies have shown damage to the joint cartilage in immature animals but no teratogenic effects. Therefore ofloxacin should not be used during pregnancy. (See section 4.3: Contraindications)

Breast-feeding

Ofloxacin is excreted into human breast milk in small amounts. Because of the potential for arthropathy and other serious toxicity in the nursing infant, breast feeding should be discontinued during treatment with ofloxacin. (See section 4.3: Contraindications)

4.7 Effects on ability to drive and use machines

Since there have been occasional reports of somnolence, impairment of skills, dizziness and visual disturbances, patients should know how they react to Tarivid before they drive or operate machinery. These effects may be enhanced by alcohol.

4.8 Undesirable effects

System organ class	Common ( 1/100 to <1/10 )	Uncommo n £1/1,000 to <1/100)	Rare £1/10,000 to <1/1,000)	Very rare (< 1/10,000)	Not known (cannot be estimated from available data)*
Infections and infestations		Fungal infection, Pathogen resistance
Blood and the lymphatic system disorders				Anaemia Haemolytic anaemia, Leukopenia, Eosinophilia, Thrombo cytopenia	Agranulocytosis Bone marrow failure
Immune system disorders			Anaphylactic reaction*, Anaphylactoi d reaction*, Angioedema*	Anaphylactic shock*, Anaphylactoid shock*
Metabolism and Nutrition disorders			Anorexia		Hypoglycaemia in diabetics treated with hypoglycaemic agents (see Section 4.4) Hyperglycaemia Hypoglycaemic coma
Psychiatric disorders		Agitation, Sleep disorder, Insomnia	Psychotic disorder (for eg. hallucination), Anxiety, Confusional state, Nightmares, Depression		Psychotic disorder and depression with self-endangering behaviour including suicidal ideation or suicide attempt (see Section 4.4) Nervousness
Nervous system disorders		Dizziness, Headache	Somnolence, Paraesthesia, Dysgeusia, Parosmia	Peripheral sensory neuropathy* Peripheral sensory motor neuropathy* Convulsion*, Extra-pyramidal symptoms or other disorders of muscular coordination	Tremor Dyskinesia Ageusia Syncope

System organ class	Common ( 1/100 to <1/10 )	Uncommo n £1/1,000 to <1/100)	Rare £1/10,000 to <1/1,000)	Very rare (< 1/10,000)	Not known (cannot be estimated from available data)*
Eye disorders		Eye irritation	Visual disturbance		Uveitis
Ear and labyrinth disorders		Vertigo		Tinnitus, Hearing loss	Hearing impaired
Cardiac disorders			Tachycardia		Ventricular arrhythmias, torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see section 4.4 and 4.9)
Vascular disorders	applies only to the solution for infusion: Phlebitis		Hypotension		applies only to the solution for infusion: During infusion of ofloxacin, tachycardia and hypotension may occur. Such a decrease in blood pressure may, in very rare cases, be severe.
Respiratory, thoracic and mediastinal disorders		Cough, Naso pharyngitis	Dyspnoea, Bronchospas m		Allergic pneumonitis, Severe dyspnoea
Gastro intestinal disorders		Abdominal pain, Diarrhoea, Nausea, Vomiting	Enterocolitis, sometimes haemorrhagic	Pseudo membranous colitis* Jaundice cholestatic	Dyspepsia Flatulence Constipation Pancreatitis

System organ class	Common ( 1/100 to <1/10 )	Uncommo n £1/1,000 to <1/100)	Rare £1/10,000 to <1/1,000)	Very rare (< 1/10,000)	Not known (cannot be estimated from available data)*
Hepato-bilary disorders			Hepatic enzymes increased (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase) Blood bilirubin increased		Hepatitis, which may be severe*; Severe liver injury, including cases with acute liver failure, sometimes fatal, have been reported with ofloxacin, primarily in patients with underlying liver disorders (see section 4.4)
Skin and subcutaneous tissue disorders		Pruritus, Rash	Urticaria, Hot flushes, Hyperhidrosis Pustular rash	Erythema multiforme, Toxic epidermal necrolysis, Photosensitivity reaction*, Drug eruption Vascular purpura, Vasculitis, which can lead in exceptional cases to skin necrosis	Stevens-Johnson syndrome; Acute generalized exanthemous pustulosis; drug rash Stomatitis; Exfoliative dermatitis
Musculoskelet al and Connective tissue disorders			Tendonitis	Arthralgia, Myalgia, Tendon rupture (e.g. Achilles tendon) which may occur within 48 hours of treatment start and may be bilateral.	Rhabdomyolysis and/or Myopathy, Muscular weakness Muscle tear, muscle rupture Ligament rupture Arthritis
Renal and Urinary disorders			Serum creatinine increased	Acute renal failure	Acute interstitial nephritis
Congenital and familial/geneti c disorders					Attacks of porphyria in patients with porphyria

System organ class	Common ( 1/100 to <1/10 )	Uncommo n £1/1,000 to <1/100)	Rare £1/10,000 to <1/1,000)	Very rare (< 1/10,000)	Not known (cannot be estimated from available data)*
General disorders and administration site conditions	applies only to the solution for infusion: Infusion site reaction (pain, reddening)				Asthenia Pyrexia Pain (including pain in back, chest, and extremities)

* postmarketing experience

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

The most important signs to be expected following acute overdosage are CNS symptoms such as confusion, dizziness, impairment of consciousness and seizures, increases QT interval as well as gastrointestinal reactions such as nausea and mucosal erosions.

CNS effects including confusional state, convulsion, hallucination, and tremor have been observed in post marketing experience.

Elimination of ofloxacin may be increased by forced diuresis.

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa.

A fraction of ofloxacin may be removed from the body with haemodialysis.

Peritoneal dialysis and CAPD are not effective in removing ofloxacin from the body. No specific antidote exists.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Quinolone antibacterials, Fluoroquinolones. ATC code J01M A01

Mechanism of action

Ofloxacin is a quinolone-carboxylic acid derivative with a wide range of antibacterial activity against both Gram-negative and Gram-positive organisms.

The primary mode of action of the quinolones is the specific inhibition of bacterial DNA gyrase. This enzyme is required for DNA replication, transcription, repair and recombination. Its inhibition leads to expansion and destabilisation of the bacterial DNA and hence to cell death.

It appears that certain quinolones, including ofloxacin, have a second non RNA dependent action on bacterial cells, which enhances bactericidal effectiveness. The nature of this second action has not yet been clarified.

PK/PD relationship

Fluoroquinolones have a concentration-dependent bactericidal activity, with a moderate post antibiotic effect. For this class of antimicrobials, the ratio between AUC and MIC or Cmax and MIC is predictive of clinical success.

Mechanisms of resistance

Resistance to ofloxacin is acquired through a stepwise process by target site mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also affect susceptibility to ofloxacin.

Susceptiblity testing breakpoints

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

Breakpoints set by EUCAST:

	MIC breakpoint (mg/L)
Microorganism	Susceptible <	Resistant >
Enterobacteriaceae	0.5	1
Staphylococcus spp.	1	1a
Streptococcus pneumoniaeb	0.125	4
Haemophilus influenzae	0.5	0.5
Moraxella catarrhalis	0.5	0.5
Neisseria gonorrheae	0.125	0.25

a.    Breakpoints relate to high dose therapy

b.    Wild type S. pneumonia are not considered susceptible to ofloxacin and are therefore categorized as intermediate

Susceptibility

The prevalence of resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Therapeutic doses of ofloxacin are devoid of pharmacological effects on the voluntary or autonomic nervous systems.

5.2    Pharmacokinetic properties

Maximum plasma concentrations occur within five minutes of the end of the infusion. The plasma half life is about five hours. Ofloxacin is primarily excreted unchanged in the urine.

Urinary clearance is reduced in renal insufficiency.

5.3    Preclinical safety data

None stated.

6    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

Sodium chloride, hydrochloric acid and water for injections

6.2    Incompatibilities

Tarivid IV should be administered alone unless compatibility with other infusion fluids has been demonstrated. Compatible infusion solutions include isotonic sodium chloride, Ringer's solution and 5 % glucose solution. Heparin and ofloxacin are incompatible.

6.3    Shelf life

3 years.

6.4    Special precautions    for    storage

Tarivid IV presented in glass infusion bottles should be protected from light.

6.5    Nature and contents of container

Clear, colourless Type I glass vials with grey chlorobutyl rubber closures and aluminium caps containing either 50 ml, 100ml or 200 ml infusion solution.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Aventis Pharma Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

or trading as:-

Sanofi-aventis or Sanofi

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04425/0215

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/04/2010

10 DATE OF REVISION OF THE TEXT

07/07/2016