Oflocet 400

The following indications are restricted to adults.

Oflocet 400 is suitable for treatment of the following bacterial infections if these are caused by pathogens sensitive to Oflocet 400 :

- Lower respiratory tract infections including pneumonia, bronchitits and acute exacerbations of chronic bronchitis caused by gram negative aerobic bacteria. (Oflocet 400 tablets are not the drug of first choice in pneumonia caused by Streptococcus pneumoniae, Mycoplasma pneumoniae or Chlamydia pneumoniae);

- Upper and lower urinary tract infections, including uncomplicated (cystitis) and complicated urinary tract infections.

- Uncomplicated urethral and cervical gonorrhoea, non-gonococcal urethritis and cervicitis.

Consideration should be given to official guidance on the appropriate use of anti-bacterial agents.

Posology

The dose of Oflocet 400 is determined by the type and severity of the infection. The dosage range for adults is 200 mg to 800 mg daily.

Up to 400 mg may be given as a single dose, preferably in the morning. Generally, individual doses should be given at approximately equal intervals.

In individual cases it may be necessary to increase the dose to a maximum total dose of 800 mg daily, which should be given as 400 mg twice daily, at approximately equal intervals. This may be appropriate in infections due to pathogens known to have reduced or variable susceptibility to Oflocet 400, in severe and/or complicated infections (e.g. of the respiratory or urinary tracts) or if the patient does not respond adequately.

The following doses are recommended:

A single dose of 400 mg of Oflocet 400 is sufficient for the treatment of uncomplicated gonorrhoea.

Special patient populations

Impaired renal function

Following a normal initial dose, dosage should be reduced in patients with impairment of renal function as determined by creatinine clearance or plasma creatinine level.

* According to indication or dose interval

** The serum concentration of Oflocet 400 should be monitored in patients with severe renal impairment and dialysis patients.

Patients undergoing haemodialysis or peritoneal dialysis should be given 100 mg Oflocet 400 per day.

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:

Impaired liver function

The excretion of Oflocet 400 may be reduced in patients with severe hepatic dysfunction.

(e.g. cirrhosis of the liver with ascites). In such cases, it is recommended that the dose should not exceed 400 mg Oflocet 400 daily, because of possible reduction of excretion.

Paediatric population

Oflocet 400 is contraindicated for use in children or growing adolescents.

Elderly

Duration

Treatment should not exceed 2 months duration.

A daily dose of up to 400 mg Oflocet 400 may be given as a single dose. In this case, it is preferable to administer Oflocet 400 in the morning.

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

Method of administration

For oral use.

Oflocet 400 tablets should be swallowed whole with sufficient liquid before or during meal times. They should not be taken within two hours of mineral antacids, sucralfate or metal ion preparations (aluminium, iron, magnesium or zinc), didanosine chewable or buffered tablets (for HIV), since reduction of absorption of Oflocet 400 can occur.

The use of Oflocet 400 is contraindicated as follows:

-

- In patients with a history of epilepsy or an existing central nervous system disorder with a lowered seizure threshold.

- In patients with a history of tendon disorders related to fluoroquinolone administration

- In children or growing adolescents, and in pregnant or breastfeeding women, since animal experiments do not entirely exclude the risk of damage to the growth-plate cartilage in the growing organism cannot be entirely excluded.

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

Oflocet 400 tablets are not the drug of first choice in pneumonia caused by Streptococcus pneumoniae or Chlamydia pneumoniae.

Methicillin-resistant S. aureus

Are very likely to possess co-resistance to fluoroquinolones, including Oflocet 400. Therefore Oflocet 400 is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to Oflocet 400 (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).

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.

Severe bullous reactions

Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with Oflocet 400. Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

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 Oflocet 400 and have been reported up to several months after discontinuation of Oflocet 400. 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. Close monitoring of these patients is therefore necessary if they are prescribed Oflocet 400. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with Oflocet 400 must be halted immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon.

Hypersensitivity

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 Oflocet 400 should be discontinued and suitable treatment (e.g. treatment for shock) should be initiated.

Diseases caused by Clostridium difficile

Diarrhoea, especially if severe, persistent and/or bloody, occurring during or after treatment with Oflocet 400 (including several weeks after treatment), may indicate a condition caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis (CDAD) CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis. It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with Oflocet 400. If pseudo-membraneous colitis is suspected, treatment should be discontinued immediately.

Appropriate specific antibiotic therapy must be started without delay (e.g. oral vancomycin, oral teicoplanin or metronidazole). Medicinal products that inhibit peristalsis are contraindicated in such cases.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and may trigger seizures. Oflocet 400 is contraindicated in patients with a history epilepsy or with a known predisposition to seizures.

Patients with a known predisposition to seizures may include those with pre-existing central nervous system lesions, concomitant treatment with fenbufen and similar non-steroidal anti-inflammatory drugs (NSAIDs), or with drugs which lower the cerebral seizure threshold, such as theophylline.

In case of convulsive seizures, treatment with Oflocet 400 should be discontinued.

Patients with impaired renal function

Since Oflocet 400 is eliminated primarily via the kidneys, the dose should be adjusted in patients with impaired renal function.

Patients with history of psychotic disorder

Psychotic reactions have been reported in patients receiving fluoroquinolones including Oflocet 400. In some cases these have progressed to suicidal thoughts or self-endangering behavior including suicide attempt, sometimes after a single dose of Oflocet 400. In the event that a patient develops these reactions, Oflocet 400 should be discontinued and appropriate measures instituted.

Oflocet 400 should be used with caution in patients with a history of psychotic disorder or in patients with psychiatric disease.

Patients with impaired liver function

Oflocet 400 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, pruritus or tender abdomen.

Patients treated with vitamin K antagonists

Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with fluoroquinolones, including Oflocet 400, in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomitantly.

Myasthenia gravis

Fluoroquinolones, including Oflocet 400, 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. Oflocet 400 is not recommended in patients with a known history of myasthenia gravis.

Superinfection

As with other antibiotics, the use of Oflocet 400, especially if prolonged, may result in overgrowth of non-susceptible organisms, especially Enteracci, resistant strains of some organisms or Candida. Repeated evaluation of the patient's condition is essential and periodic in vitro susceptibility tests may be useful. If secondary infection occurs during therapy, appropriate measures should be taken.

Prevention of photosensitisation

Photosensitisation has been reported with Oflocet 400. 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.

QT interval prolongation

Very rare cases of QT interval proplongation have been reported in patients taking fluoroquinolones.

Caution should be taken when using fluoroquinolones, including Oflocet 400, in patients with known risk factors for prolongation of the QT interval such as, for example:

- elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including Oflocet 400, in these populations.

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

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

Dysglycaemia

As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia 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.

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including Oflocet 400, which can be rapid in its onset. Oflocet 400 should be discontinued if the patient experiences symptoms of neuropathy. This would minimise the possible risk of developing an irreversible condition.

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 Oflocet 400 has to be used in these patients, potential occurrence of haemolysis should be monitored.

Interference with laboratory tests

In patients treated with Oflocet 400, determination of opiates or porphyrin levels in urine may give false-positive results. It may be necessary to confirm positive opiate or porphyrin screens by more specific methods.

Vision disorders

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

Excipient with known effect

Oflocet 400 contains lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

For treatment of severe and/or life-threatening infections parenteral therapy is indicated.

Since there have been occasional reports of drowsiness/somnolence, impairment of skills, dizziness/vertigo and visual disturbances, which may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery), patients should know how they react to Oflocet 400 before they drive or operate machinery. These effects may be enhanced by alcohol.

The information given below is based on data from clinical studies and on extensive post marketing experience.

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

Symptoms

The most important signs to be expected following acute overdose are CNS symptoms such as confusion, dizziness, impairment of consciousness and convulsive seizures increases in 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.

Management

In the case of overdose steps to remove any unabsorbed Oflocet 400 e.g. gastric lavage, administration of adsorbants and sodium sulphate, if possible during the first 30 minutes, are recommended; antacids are recommended for protection of the gastric mucosa.

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 Oflocet 400 may be removed from the body with haemodialysis. Peritoneal dialysis and CAPD are not effective in removing Oflocet 400 from the body. No specific antidote exists.

Elimination of Oflocet 400 may be increased by forced diuresis.

Pharmacotherapeutic group: Quinolone Antibacterials, Fluoroquinolones

ATC code: J01 MA 01

Mechanism of action

Oflocet 400 inhibits bacterial DNA replication by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV. It is active after oral administration.

Therapeutic doses of Oflocet 400 are devoid of pharmacological effects on the voluntary or autonomic nervous system.

The NCCLS MIC breakpoint recommendations are as follows:

S ≤ 2 mg/l and R > 1 mg/l

Haemophilus influenzae and Neisseria gonorrhoea are exceptions with breakpoints at S ≤ 0.25 mg/l and R > 1 mg/l

The BSAC general recommendations are S ≤ 2 mg/l and R > 4 mg/l

According to DIN 58 940, the following limits apply for Oflocet 400:

S ≤ 1 mg/L, I = 2 mg/L, R > 4 mg/L.

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an approximate guidance on probabilities whether micro-organisms will be susceptible to Oflocet 400 or not.

Only those pathogens relevant to the indications are listed.

Resistance

The main mechanism of bacterial resistance to Oflocet 400 involves one or more mutations in the target enzymes, which generally confer resistance to other active substances in the class. Efflux pump and impermeability mechanisms of resistance have also been described and may confer variable resistance to active substances in other classes.

Absorption

The administration of oral doses to fasting volunteers was followed by a rapid and almost complete absorption of Oflocet 400. The peak plasma concentration after a single oral dose of 200mg averaged 2.6 µg/ml and was reached within one hour. The plasma elimination half-life was 5.7 to 7.0 hours and was not dose related.

Distribution

The apparent distribution volume was 120 litres. The plasma concentration did not materially rise with repeat doses (accumulation factor for twice daily dosage: 1.5). The plasma protein binding was approx. 25%.

Biotransformation

The biotransformation of Oflocet 400 was below 5%. The two main metabolites found in the urine were N-desmethyl-Oflocet 400 and Oflocet 400-N-oxide.

Elimination

Excretion is primarily renal. Between 80 and 90% of the dose were recovered from the urine as unchanged substance.

Oflocet 400 was present in the bile in glucuronidised form. The pharmacokinetics of Oflocet 400 after intravenous infusion are very similar to those after oral doses. The plasma half-life is prolonged in persons with renal insufficiency; total and renal clearance decrease in accordance with the creatinine clearance. In renal insufficiency the dose should be reduced.

No clinically relevant interactions were seen with food and no interaction was found between Oflocet 400 and theophylline.

Preclinical effects in conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, reproductive studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Joint toxicity was observed at exposure in the human therapeutic range in juvenile rats and dogs. Oflocet 400 exhibits a neurotoxic potential and causes reversible testicular alterations at high doses.

Mutagenicity studies showed no evidence for mutagenicity of Oflocet 400. However, like some other quinolones Oflocet 400 is phototoxic in animals at exposure in the human therapeutic range. The phototoxic, photomutagenic and photocarcinogenic potential of Oflocet 400 is comparable with that of other gyrase inhibitors.

Preclinical data from conventional genotoxicity studies reveal no special hazard to humans, carcinogen potential has not be investigated.

Reproduction toxicity

Oflocet 400 has no effect on fertility, peri- or postnatal development, and therapeutic doses did not lead to any teratogenic or other embryotoxic effects in animals. Oflocet 400 crosses the placenta and levels reached in the amniotic fluid are about 30% of the maximal concentrations measured in maternal serum.

Adverse reactions possible when combined with:

• Benzodiazepines

• CNS depressants

• Antidepressants

• MAO inhibitors

Dispose of the medication in accordance with local regulations for medical waste.