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.

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:

• Elderly

• uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)

• congenital long QT syndrome

• acquired QT prolongation

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

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

See also section 4.2 Elderly and section 4.5.

Patients being treated with ofloxacin should not expose themselves unnecessarily to strong sunlight and should avoid UV rays (sunlamps, solaria). Caution is recommended if the drug is to be used in psychotic patients or in patients with a history of psychiatric disease.

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.

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 antiarrhythmics, tricyclic antidepressants, macrolides).(See Section 4.4 QT interval prolongation).

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.

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.

The safety of this medicinal product for use in human pregnancy has not been established. Reproduction studies performed in rats and rabbits did not reveal any evidence of teratogenicity, impairment of fertility or impairment of peri- and post-natal development. However, as with other quinolones, ofloxacin has been shown to cause arthropathy in immature animals and therefore its use during pregnancy is not recommended. Studies in rats have indicated that ofloxacin is secreted in milk. It should therefore not be used during lactation.

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.

In rare cases after i.v. infusion, a reduction in blood pressure may occur. If this effect is marked, the infusion should be stopped. Pain, reddening of the infusion site and thrombophlebitis have been reported in rare cases.

The overall frequency of adverse reactions from the clinical trial data base is about 7%. The commonest events involved the gastrointestinal system (about 5.0%) and the nervous system (about 2.0%).

The following provides a tabulation based on post marketing experience where occasional represents a frequency of 0.1-1.0%, rare <0.1%, very rare <0.01% and isolated cases <0.01%.

Digestive and liver side effects:

Occasional: Nausea and vomiting, diarrhoea, abdominal pain, gastric symptoms. (Diarrhoea may sometimes be a symptom of enterocolitis which may, in some cases, be haemorrhagic).

Rare: Loss of appetite, increase in liver enzymes and/or bilirubin.

Very rare: cholestatic jaundice, hepatitis or severe liver damage may develop. A particular form of enterocolitis that can occur with antibiotics is pseudomembranous colitis (in most cases due to Clostridium difficile). Even if Clostridium difficile is only suspected, administration of ofloxacin should be discontinued immediately, and appropriate treatment given. Drugs that inhibit peristalsis should not be administered in such cases.

Central nervous system:

Occasional: Headache, dizziness, sleep disorders, restlessness.

Rare: Confusion, nightmares, anxiety, depression, hallucinations and psychotic reactions, drowsiness, unsteady gait and tremor (due to disorders of muscular co-ordination), neuropathy, numbness and paraesthesia, sensory or sensorimotor peripheral neuropathy (see Section 4.4 Special Warnings and Precautions for Use), visual disturbances, disturbances of taste and smell (including, in exceptional cases, loss of function), extrapyramidal symptoms.

Very rare: Convulsions, hearing disorders (including, in exceptional cases, loss of hearing).

Isolated cases: Psychotic reactions and depression with self-endangering behaviour including suicidal ideation or acts.

These reactions have occurred in some patients after the first dose of ofloxacin. In such cases, discontinue treatment immediately.

Cardiovascular system:

Tachycardia and a temporary decrease in blood pressure have been reported.

Rare: circulatory collapse (due to pronounced drop in blood pressure).

Haematological side effects:

Very rare: anaemia, leucopenia (including agranulocytosis), thrombocytopenia, pancytopenia. Only in some cases are these due to bone marrow depression. In very rare cases, haemolytic anaemia may develop.

Renal side effects:

Rare: Disturbances of kidney function.

Isolated cases: Acute interstitial nephritis, or an increase in serum creatinine, which may progress to acute renal failure.

Allergic and skin side effects:

Occasional: Skin rash, itching.

Very rare: Rash on exposure to strong sunlight, other severe skin reactions. Hypersensitivity reactions, immediate or delayed, usually involving the skin (e.g. erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome and vasculitis) may occur. In exceptional circumstances, vasculitis can lead to skin lesions including necrosis and may also involve internal organs. There are rarely other signs of anaphylaxis such as tachycardia, fever, dyspnoea, shock, angioneurotic oedema, vasculitic reactions, eosinophilia. In these cases treatment should be discontinued immediately and where appropriate, supportive treatment given.

Isolated cases: Pneumonitis.

Other side effects:

Rare: Malaise.

Very rare: Excessive rise or fall in blood-sugar levels. Weakness, joint and muscle pains (in isolated cases these may be symptoms of rhabdomyolysis).

Isolated cases: Tendon discomfort, including inflammation and rupture of tendons (e.g. the Achilles tendon) particularly in patients treated concurrently with corticosteroids. In the event of signs of inflammation of a tendon, treatment with Tarivid must be halted immediately and appropriate treatment must be initiated for the affected tendon.

The possibility cannot be ruled out that ofloxacin may trigger an attack of porphyria in predisposed patients.

Except in very rare instances (e.g. isolated cases of smell, taste and hearing disorders) the adverse effects observed subsided after discontinuation of ofloxacin.

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.

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 and 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

January 2008

POM