Tarivid^TM IV Infusion Solution.

Ofloxacin, 2 mg/ml.

For a full list of excipients, see section 6.1.

Solution for Infusion.

Ofloxacin is a synthetic 4-fluoroquinolone antibacterial agent with bactericidal activity against a wide range of Gram-negative and Gram-positive organisms. It is indicated for the treatment of the following infections when caused by sensitive organisms:

Lower Respiratory Tract: Acute and chronic infections.

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

Skin and soft tissue infections.

Microbiological results indicate that the following pathogens may be regarded as sensitive: Staphylococcus aureus (including methicillin resistant staphylococci), Staphylococcus epidermidis, Neisseria species, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Hafnia, Proteus (indole-negative and indole-positive strains), Salmonella, Shigella, Acinetobacter, Yersinia enterocolitica, Campylobacter jejuni, Aeromonas, Plesiomonas, Vibrio cholerae, Vibrio parahaemolyticus, Haemophilus influenzae, Chlamydiae, Legionella, Gardenerella.

Variable sensitivity is shown by Streptococci, Serratia marcescens, Pseudomonas aeruginosa, Clostridium species and Mycoplasmas.

Anaerobic bacteria (e.g. Fusobacterium species, Bacteroides species, Eubacterium species, Peptococci, Peptostreptococci) are normally resistant.

Tarivid is not active against Treponema pallidum.

General dosage recommendations: The dose of ofloxacin is determined by the type and severity of the infection.

Adults: The usual intravenous dosages in adults are:

Complicated urinary tract infection: 200 mg daily.

Lower respiratory tract infection: 200 mg twice daily.

Septicaemia: 200 mg twice daily.

Skin and soft tissue infections: 400 mg twice daily.

The infusion time for Tarivid IV should not be less than 30 minutes for 200 mg. 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.

Impaired renal function: Following a normal initial dose, dosage should be reduced in patients with impairment of renal function. When creatinine clearance is 20--50 ml/minute (serum creatinine 1.5--5.0 mg/dl) the dosage should be reduced by half (100--200 mg daily). If creatinine clearance is less than 20 ml/minute (serum creatinine greater than 5 mg/dl) 100 mg should be given every 24 hours. In patients undergoing haemodialysis or peritoneal dialysis, 100 mg should be given every 24 hours.

Impaired liver function: The excretion of ofloxacin may be reduced in patients with severe hepatic dysfunction.

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

Elderly: No adjustment of dosage is required in the elderly, other than that imposed by consideration of renal or hepatic function. (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.

Hypersensitivity to the active substance or to any of the excipients.

Ofloxacin should not be used in patients with a past history of tendinitis.

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.

Ofloxacin is not the drug of first choice for pneumonia caused by Pneumococci or Mycoplama, or angina tonsillaris caused by β-haemolytic Streptococci.

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.

Clostridium difficile-associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with ofloxacin, may be symptomatic of pseudo-membranous colitis. 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

In case of convulsive seizures, treatment with ofloxacin should be discontinued (see section 4.5 lowering of the cerebral seizure threshold).

Cardiac disorders

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, hypromagnesaemia)

• elderly

• cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)

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

Patients being treated with ofloxacin should not expose themselves unnecessarily to strong sunlight and should avoid UV rays (sunlamps, solaria).

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 behavior including suicide attempt, sometimes after a single dose. 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

Ofloxacin should be used with caution in patients with a history of myasthenia gravis.

Sudden reductions in blood pressure may occur when Tarivid IV is administered with hypotensive agents. In such cases, or if the drug is given concomitantly with barbiturate anaesthetics, cardiovascular function should be monitored.

Administration of antibiotics, especially if prolonged, may lead to proliferation of resistant micro-organisms. The patient's condition must therefore be checked at regular intervals. If a secondary infection occurs, appropriate measures must be taken.

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including ofloxacin. Ofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.

Hypoglycaemia

As with all quinolones, hypoglycaemia has been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. glibenclamide) or with insulin. In these diabetic patients, careful monitoring of blood glucose is recommended.

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. Ofloxacin should therefore be administered with caution in such patients.

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.

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.

There may be a further lowering of the cerebral seizure threshold when quinolones are given concurrently with other drugs which lower the seizure threshold, e.g. theophylline. However ofloxacin is not thought to cause a pharmacokinetic interaction with theophylline, unlike some other fluoroquinolones.

Further lowering of the cerebral seizure threshold may also occur with certain nonsteroidal anti-inflammatory drugs.

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

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

With high doses of quinolones, impairment of excretion and an increase in serum levels may occur when co-administered with other drugs that undergo renal tubular secretion (e.g. probenecid, cimetidine, frusemide and methotrexate).

Interaction with laboratory tests: Determination of opiates or porphyrins in urine may give false-positive results during treatment with ofloxacin. It may be necessary to confirm positive opiate or porphyrin screens by more specific methods.

Vitamin K antagonists

Coagulation tests should be monitored in patients treated with vitamin K antagonists because of a possible increase in the effect of coumarin derivatives.

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)

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)

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.

* postmarketing experience

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

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.

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

Ofloxacin is a quinolone-carboxylic acid derivative with a wide range of antibacterial activity against both Gram-negative and Gram-positive organisms. It inhibits bacterial DNA replication by blocking DNA topo-isomerases, in particular DNA gyrase.

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

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.

None stated.

Sodium chloride

Hydrochloric acid

Water for injections.

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.

3 years.

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

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

No special requirements.

Sanofi-aventis

One Onslow Street

Guildford

Surrey,

GU1 4YS,

UK

PL 04425/0215

28/06/2002

14^th April 2011

POM