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Ofloxacin 200mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ofloxacin 200 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 200 mg of ofloxacin.

Excipient with known effect:

Each tablet also contains 96.00 mg of lactose, anhydrous.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White biconvex capsule-shaped, film-coated tablet marked ‘OF’ breakline ‘200’on one side and ‘G’ on the reverse.

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ofloxacin is suitable for treatment of the following bacterial infections if these are caused by pathogens sensitive to ofloxacin (see section 5.1):

• Lower respiratory tract infections including pneumonia, bronchitits and acute exacerbations of chronic bronchitis caused by gram negative aerobic bacteria. (Ofloxacin 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 antibacterial agents.

4.2 Posology and method of administration

Posology

The dose of ofloxacin 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. This may be appropriate in infections due to pathogens known to have reduced or variable susceptibility to ofloxacin, 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:

Indications	Single and Daily Doses
Uncomplicated urethral/ cervical gonorrhoea	400 mg
Uncomplicated lower urinary tract infections	200 mg-400 mg daily
Complicated infections of the upper urinary tract	400 mg daily, increasing if necessary, to 400 mg twice a day
Lower respiratory tract infections	400 mg daily, increasing, if necessary, to 400 mg twice a day
Non-gonococcal urethritis and cervicitis	400 mg daily

A single dose of 400 mg of ofloxacin 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.

Creatinine Clearance	Plasma Creatinine	Maintenance Dose
20 to 50 ml/min	1.5 to 5 mg/dl	100 mg - 200 mg ofloxacin per day)
<20ml/min	>5 mg/dl	100 mg ofloxacin per day

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

Impaired liver function

The excretion of ofloxacin 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 ofloxacin daily.

Paediatric population

Ofloxacin is contraindicated for use in children or growing adolescents (see section 4.3).

Elderly

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

Duration

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.

Method of administration

For oral use.

Ofloxacin 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) since reduction of absorption of ofloxacin can occur (see section 4.5).

4.3 Contraindications

The use of ofloxacin is contraindicated as follows:

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

• 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 cartilage of joints in the growing subject.

• 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.

4.4 Special warnings and precautions for use

Ofloxacin tablets are not the drug of first choice in pneumonia caused by Streptococcus pneumoniae, Mycoplasma pneumoniae or Chlamydia pneumoniae.

Secondary infection

Use of ofloxacin may result in overgrowth of nonsusceptible organisms, especially enterococci, resistant strains of some organisms or candida. Careful monitoring of patients is essential and periodic in vitro susceptibility tests may be useful. If superinfection occurs, appropriate therapy should be instituted.

Tendonitis

If tendonitis is suspected, treatment with ofloxacin must be terminated immediately and the affected tendon should be appropriately treated (e.g. immobilisation). The risk of tendonitis is highest in the elderly and in those taking corticosteroids.

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 ofloxacin 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 ofloxacin, may indicate a condition caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis. If

pseudomembraneous colitis is suspected, treatment should be discontinued immediately. Medicinal products that inhibit peristalsis are contraindicated in such cases.

Patients predisposed to seizures

Ofloxacin is contraindicated in patients known to have epilepsy or with a known

predisposition to seizures. In addition as with other quinolones, ofloxacin should be used only with extreme caution in patients being concurrently treated with fenbufen or similar non-steroidal anti-inflammatory medicinal products (NSAIDs), or with agents that reduce the seizure threshold (e.g. theophylline) (see section 4.5).

In case of convulsive seizures, treatment with ofloxacin should be discontinued (see section 4.5).

Patients with impaired renal function

Since ofloxacin is eliminated primarily via the kidneys, the dose should be adjusted in patients with impaired renal function (see section 4.2).

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, pruritus or tender abdomen (see section 4.8).

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.

Prevention of photosensitisation

Although photosensitisation rarely occurs with the use of ofloxacin, it is recommended that patients should avoid strong sunlight or artificial UV radiation (e.g. sun lamps, solaria).

Cardiac disorders

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 sections 4.2 Elderly, section 4.5, section 4.8, section 4.9).

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 (see section 4.8).

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. This would minimize the possible risk of developing an irreversible condition (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. Ofloxacin should therefore be administered with caution in such patients.

Excipient with known effect

Ofloxacin 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.

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).

Antacids, Sucralfate, Metal Cations

Co-administered magnesium/aluminum antacids, sucralfate, zinc or iron preparations and didanosine chewable/buffered tablets can reduce absorption. Therefore, ofloxacin should be taken 2 hours before such preparations.

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs

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.

Probenecid, cimetidine, furosemide, or methotrexate

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).

Vitamin K antagonists

Prolongation of bleeding time has been reported during concomitant administration of ofloxacin and anticoagulants. Coagulation tests should be

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

Glibenclamide

Ofloxacin may induce a slight rise in plasma glibenclamide levels. Since hypoglycaemia is then more likely to occur, close monitoring of blood sugar levels is recommended in such cases.

Interaction with laboratory tests

Determinations of opiate or porphyrin levels 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.

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 (see section 5.3). Therefore ofloxacin must not be used during pregnancy (see section 4.3).

Breastfeeding

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

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 ofloxacin before they drive or operate machinery.

These effects may be enhanced by alcohol.

4.8 Undesirable effects

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

System organ class	Uncommon ( 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 lymphatic system disorders			Anaemia, Haemolytic anaemia, Leucopenia, Eosinophilia, Thrombo cytopenia	Agranulocytosis, Bone marrow failure
Immune system disorders		Anaphylactic * reaction , Anaphylactoid * reaction , Angioedema	Anaphylactic shock , Anaphylactoid shock
Metabolism and Nutrition disorders		Anorexia		Hypoglycaemia in diabetics treated with hypoglycaemic agents (see Section 4.4)
Psychiatric disorders	Agitation, Sleep disorder, Insomnia	Psychotic disorder (for e.g. hallucination), Anxiety, Confusional state, Nightmares, Depression		Psychotic disorder and depression with self-endangering behaviour including suicidal ideation or suicide attempt (see Section 4.4)
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
Eye disorders	Eye irritation	Visual disturbance
Ear and labyrinth disorders	Vertigo		Tinnitus, Hearing loss

System organ class	Uncommon ( 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)*
Cardiac disorders		Tachycardia		Ventricular arrhythmias and 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		Hypotension
Respiratory, thoracic and mediastinal disorders	Cough, Nasopharyngitis	Dyspnoea, Bronchospasm		Allergic pneumonitis, Severe dyspnoea
Gastrointestinal disorders	Abdominal pain, Diarrhoea, Nausea, Vomiting	Enterocolitis, sometimes haemorrhagic	Pseudo membranous colitis
Hepatobiliary disorders		Hepatic enzymes increased (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase), Blood bilirubin increased	Jaundice cholestatic	Hepatitis, which may be severe
Skin and subcutaneous tissue disorders	Pruritus, Rash	Urticaria, Hot flushes, Hyperhidrosis Pustular rash	Erythema multiforme, Toxic epidermal necrolysis, Photo-sensitivity reaction , Drug eruption , Vascular purpura, Vasculitis, which can lead in exceptional cases to skin necrosis	Stevens-Johnson syndrome; Acute generalized exanthemous pustulosis; drug rash

System organ class	Uncommon ( 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)*
Musculoskeletal 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
Renal and urinary disorders		Serum creatinine increased	Acute renal failure	Acute interstitial nephritis
Congenital, familial and genetic disorders				Attacks of porphyria in patients with porphyria

* postmarketing experience

4.9 Overdose

Symptoms

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

Management

In the case of overdose steps to remove any unabsorbed ofloxacin 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.

Elimination of ofloxacin may be increased by forced diuresis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: fluoroquinolones ATC code: J01 MA 01

Mechanism of action

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

Therapeutic doses of ofloxacin 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 ofloxacin:

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 ofloxacin or not.

Only those pathogens relevant to the indications are listed.

	European range of acquired bacterial resistance to ofloxacin
Normally susceptible
Aerobic Gram-positive micro organisms
S. aureus - methicillin-sensitive	0.3-12.6%
S. pyogenes	2-5%
Aerobic Gram-negative micro organisms
Acinetobacter spp	0.3-7.3%
Citrobacter spp.	3-15%
Enterobacter spp.	2-13%
E. coli	1-8%
H. influenzae	1%
Klebsiella spp.	1-10%
Moraxella spp.	0-0.2%
Morganella morganii	0-6.9%
N. gonorrhoeae	25%
Proteus spp.	1-15%

Serratia marcescens	2-2.4%
Others
Chlamydia spp
L. pneumophila

Intermediately susceptible
Aerobic Gram-positive micro organisms
S. pneumoniae	70%
Providentia	17.1%
Aerobic Gram-negative micro organisms
E. ^ faecalis	50%
P. aeruginosa	20-30%
Serratia spp.	20-40%
Stenotrophomonas maltophilia	5.1-11%
Others
Mycoplasma spp.	0-5.3%
Ureaplasma spp.	0-2.1%

Resistant
Anaerobic bacteria
S. aureus - methicillin-resistant	69.2-85.7%
T. pallidum

Resistance

The main mechanism of bacterial resistance to ofloxacin 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.

5.2 Pharmacokinetic properties

Absorption

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

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

Biotransformation

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

Elimination

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

Ofloxacin was present in the bile in glucuronidised form. The pharmacokinetics of ofloxacin 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 ofloxacin and theophylline.

5.3 Preclinical Safety Data

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. Ofloxacin exhibits a neurotoxic potential and causes reversible testicular alterations at high doses.

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

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

Reproduction toxicity

Ofloxacin has no effect on fertility, peri- or postnatal development, and therapeutic doses did not lead to any teratogenic or other embryotoxic effects in animals. Ofloxacin crosses the placenta and levels reached in the amniotic

fluid are about 30% of the maximal concentrations measured in maternal serum.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Tablet core Maize starch Lactose, anhydrous Hydroxypropylcellulose Croscarmellose sodium Magnesium stearate

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

6.2 Incompatibilities

Not applicable

6.3 Shelf-Life

2 years

6.4 Special precautions for storage

This medicine does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium PVC/PVDC blisters and polypropylene bottles with polyethylene tamper evident closure.

Obtainable in the following pack sizes: 5, 6, 7, 8, 10, 12, 14, 16, 20, 24, 30, 50, 100, 250 tablets.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04569/0549

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/06/2007

10 DATE OF REVISION OF THE TEXT

02/01/2013