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Ofloxacin 400mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ofloxacin 400 mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 400 mg of ofloxacin.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Film coated tablets

White, oval shaped film-coated tablets 18 mm length x 8 mm width, debossed “FXN 400” on one side and scoreline on the other.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

Ofloxacin is indicated for the treatment of the following infections when

caused by sensitive organisms (see Section 5.1.):

- upper and lower urinary tract infections;

- lower respiratory tract infections including pneumonia, bronchitis, and acute exacerbations of chronic bronchitis caused by gram-negative aerobic bacteria (Ofloxacin is not the first choice of medicinal product in pneumonia caused by Streptococcus pneumoniae, Mycoplasma pneumoniae or Chlamydia pneumoniae) ;

- uncomplicated urethral and cervical gonorrhoea;

- non-gonococcal urethritis and cervicitis;

- skin and soft tissue infections.

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

anti-bacterial agents.

4.2

Posology and method of administration

General dosage recommendations:

The dose of ofloxacin should be 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.

Indications	Single and daily doses	Usual duration of therapy
Uncomplicated lower urinary tract infections	200 - 400 mg daily	3 days
Complicated infections of the kidneys and urinary tract	400 mg daily, increasing if necessary, to 400 mg twice a day	7-10 days
Lower respiratory tract infections	400mg daily, increasing, if necessary, to 400 mg twice a day	7-10 days
Uncomplicated gonorrhoea	400 mg	Single dose
Non-gonococcal urethritis and cervicitis	400 mg daily	7-10 days
Skin and soft tissue infections	400 mg twice a day	7-10 days

Impaired renal function:

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

Indications	Plasma creatinine	Maintenance dose
20 to 50 ml/min	1.5 to 5 mg/dl	100-200 mg ofloxacin once a day
< 20 ml/min	> 5 mg/dl	100 mg ofloxacin once a day
Haemodialysis or peritoneal dialysis		100 mg ofloxacin once a 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.

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).

Children:

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

Duration of treatment:

Duration of treatment is dependent on the severity of the infection and the response to treatment.

The usual durations of treatment are stated in the table.

In some instances, a minimum of 5 days treatment may be sufficient.

Treatment should not exceed 2 months duration.

Method of administration

Ofloxacin Tablets should be swallowed with 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.

4.3 Contraindications

Ofloxacin must not be used

• in patients hypersensitive to ofloxacin, other quinolones, or any of the excipients

• in patients with history of epilepsy or with any existing central nervous system disorder that is associated with a lower seizure threshold

• in patients with history of tendon disorders related to fluoroquinolone administration

• in children or adolescents in the growth phase*

• during pregnancy*

• in breast-feeding women*

*because, judging from animal experiments, a risk of damage to the growth-plate cartilage in the growing organism cannot be entirely excluded.

Ofloxacin should not be given to patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity because they are prone to haemolytic reactions when treated with quinolone antibacterial agents.

4.4 Special warnings and precautions for use

• 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. The physician should inform the patient of this risk.

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

• Clostridium difficile -associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or up to 10 weeks after treatment with Ofloxacin Tablets, may be a symptom of Clostridium difficile enterocolitis, the most severe form being pseudomembraneous colitis. If pseudomembraneous colitis is suspected, treatment should be discontinued. Appropriate specific antibiotic therapy must be started without delay (e.g. oral vancomycin, oral teicoplanin or metronidazole). Medicinal products that inhibit peristalsis are contra-indicated in such cases.

• Patients predisposed to seizures

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. Elderly patients are more prone to tendonitis. The risk of tendon rupture may be increased by co-administration of corticosteroids.

If tendonitis is suspected, treatment with ofloxacin must be discontinued immediately.

Appropriate treatment (e.g. immobilization) must be initiated for the affected tendon.

• 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).

• Patients with history of psychotic disorders

Psychotic reactions have been reported in patients receiving fluoroquinolones, including ofloxacin. 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.

Caution is needed if ofloxacin is to be given to psychotic patients or those with a history of psychiatric disorder.

• Patients with impaired liver function/ serious liver damage

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 ofloxacin, 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).

• 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. Deterioration of myasthenia gravis may occur during ofloxacin use.

• 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).

• Secondary infection

As with other antibiotics, the use of ofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms, especially enterococci, resistant strains of some organisms or candida. Repeated evaluation of the patient’s condition is essential. If superinfection occurs or is suspected, in vitro susceptibility tests should be performed as appropriate and alternative treatment should be given.

• Cardiac disorders

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

• uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)

• 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 antiarrhythmics, tricyclic antidepressant, macrolides, antipsychotics).

(See also section 4.2 elderly, section 4.5, section 4.8 and section 4.9).

• Hypoglycemia

As with all quinolones, hypoglycemia has been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic 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 in order to prevent the development of an irreversible condition (see section 4.8).

• Patients with glucose-6-phosphate-dehydrogenase deficiency

Patients with a 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 problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

During prolonged therapy (more than two weeks and up to two months), regular monitoring of haematological parameters and blood chemistry is recommended.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids, Sucralfate, Metal Cations:

Antacids containing aluminium (including sucralfate) and magnesium hydroxides, aluminium phosphate, zinc, iron, are liable to reduce the absorption of ofloxacin tablets. Ofloxacin should be administered approximately 2 hours apart from antacids.

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

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. However, ofloxacin does not cause any relevant changes in theophylline plasma concentrations.

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, antipsychotics). (See section 4.4 QT interval prolongation).

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:

Prolongation of bleeding time has been reported during concomitant administration of ofloxacin and anticoagulants (e.g. coumarin derivatives). 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 cause a slight increase in serum concentrations of glibenclamide administered concurrently; it is therefore recommended that patients treated with this combination should be closely monitored as hypoglycaemia is more likely to occur.

Probenecid, cimetidine, furosemide, or methotrexate:

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

4.6 Pregnancy and lactation

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).

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.

Studies in rats have indicated that ofloxacin is secreted in milk.

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/vertigo, drowsiness and visual disturbances, which may impair the patients 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 ofloxacin before they drive or operate machinery. These effects may be enhanced by alcohol.

4.8 Undesirable effects

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 frequencies of adverse events are ranked according to the following: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10 000, < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from the available data) including isolated reports.

System organ class	common (> 1/100, to < 1/10)	uncommon (> 1/1000, < 1/100)	rare (> 1/10 000, < 1/1000)	very rare (> 1/10, 000)	Not known (cannot be estimated from the available data)
Infections and infestations		fungal infection, pathogen resistance
Blood and lymphatic system disorders				anaemia, haemolytic anaemia, leucopenia, eosinophilia, thrombocytope nia, pancytopenia	agranulocytosis, bone marrow failure
Immune system disorders			anaphylactic reaction, anaphylactoid reaction, angioedema*	anaphylactic shock, anaphylactoid shock
Metabolism and nutrition disorders			anorexia	Hyperglycaemi a (especially in patients with diabetes mellitus)	Hypoglycaemia in diabetics treated with Hypoglycaemic agents*
Psychiatric		restlessness,	psychotic	abnormal	psychotic

disorders		sleep disorder, agitation, insomnia	disorder (for ^eg. hallucination), anxiety, confusional state, nightmares, depression	dreams, psychotic behaviour	disorders and depression with self-endangering behaviour including suicidal ideation or suicide attempt*
Nervous system disorders		headache, dizziness	somnolence, paraesthesia, dysgeusia, parosmia, drowsiness	tremor, peripheral sensory neuropathy, peripheral sensory motor neuropathy, convulsion*, extrapyramidal symptoms or other disorders of muscular coordination.
Eye disorders		eye irritation	visual disturbances (e.g. double vision, blurred vision)	allergic conjunctivitis
Ear and labyrinth disorders		vertigo		tinnitus, hearing impaired, hearing loss
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			Hypotension	circulatory collapse, flushing
Respiratory, thoracic and mediastinal disorders		cough, nasopharyngi tis	dyspnoea, bronchospasm,		allergic pneumonitis, severe dyspnoea
Gastrointestinal disorders	epigastric discomfort	nausea, vomiting, diarrhoea,	enterocolitis, sometimes haemorrhagic	pseudomembra nous colitis*

	abdominal pain
Hepatobiliary disorders		hepatic enzymed increased (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase), blood bilirubin increased	cholestatic jaundice, liver damage	Hepatitis, which May be severe*
Skin and subcutaneous tissue disorders	rash, pruritus	urticaria, hot flushes, hyperhidrosis, pustular rash	toxic epidermal necrolysis, photosensitivity reaction*, drug eruption, vascular purpura, vasculitis, which can lead in exceptional cases to skin necrosis, vesiculobullous rash, erythema multiforme	Stevens-Johnson syndrome, acute generalised exanthemous pustulosis, drug rash
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,	muscle weakness, rhabdomyolysis and/or myopathy, muscle tear, muscle rupture
Renal and urinary disorders		serum creatinine increased	renal function disorder, acute renal failure	acute interstitial nephritis
Congenital and familial/ genetic disorders				attacks of prophyria in patients with prophyria
General disorders and administration site conditions			unsteady gait

* see section 4.4

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

Overdose

4.9

Symptoms of overdose

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.

In the event of overdose symptomatic treatment should be implemented, ECG monitoring should be undertaken, because of the the possibility of QT interval prolongation.

Treatment of overdose

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

Elimination of ofloxacin may be increased by forced diuresis.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Mode of action

Pharmacotherapeutic group: fluoroquinolones ATC code: J01 MA 01

Ofloxacin inhibits bacterial DNA replication in a range of gram-positive and gram-negative pathogenic bacteria by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV.

The NCCLS MIC breakpoint recommendations are as follows :

S < 2 mg/l and R > 8 mg/l Intermediate susceptibility at 4 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

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

Ofloxacin is absorbed rapidly and almost completely when administered to fasting volunteers. The mean peak plasma concentration following a single oral dose of 200 mg is 2.6 pg/ml and is achieved within an hour. The plasma concentration does not increase significantly with multiple dosing (accumulation factor with twice daily dosage: 1.5).

The apparent volume of distribution is 120 litres. Plasma protein binding is approximately 25%.

Ofloxacin is less than 5% biotransformed. The two principal metabolites found in the urine are N-desmethyl-ofloxacin and ofloxacin-N-oxide. Ofloxacin is found as the glucuronide in the bile.

Elimination is primarily by the renal route in that 80 to 90 % of the dose is excreted unchanged in the urine. The plasma elimination half-life is 5.7 to 7.0 hours, irrespective of dose. The plasma elimination half-life is prolonged in individuals with impaired renal function; total and renal clearance decrease in accordance with creatinine clearance.

5.3. Pre-clinical Safety Data

Ofloxacin exhibits a neurotoxic potential and causes reversible testicular alterations at high doses. Aside from this, preclinical studies with single and repeated use in adult animals as well as safety pharmacological investigations, yielded no indications of further specific risks in connection with the administration of ofloxacin.

Like other gyrase inhibitors, ofloxacin can also cause damage to large weightbearing joints of juvenile animals during the growth period. The extent of the cartilage damage caused is dependent on age, species, and dose. In addition, stress relief of the joints considerably reduces cartilage damage.

Ofloxacin has no influence on fertility or perinatal and postnatal development and has no teratogenic or other embryotoxic effects in animal experiments, if administered at therapeutic doses.

Ofloxacin has not been evaluated in long-term carcinogenicity studies. In-vitro and in-vivo studies showed that ofloxacin is not mutagenic. Phototoxicity, photomutagenicity, and photocarcinogenicity data of ofloxacin indicate only slight photomutagenic and phototumorigenic effects in vitro and/or in vivo, as compared to other fluoroquinolones.

There are no indications of cataractogenic or co-cataractogenic effects following exposure to ofloxacin.

Preclinical investigations performed with ofloxacin have, to date, demonstrated only a slight QT-prolonging potential.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Lactose monohydrate Pregelatinised starch Hypromellose Croscarmellose sodium Colloidal anhydrous silica Magnesium stearate Titanium dioxide E171 Macrogol 3000 Triacetin.

6.2. Incompatibilities

Not applicable

6.3. Shelf-Life

3 years

6.4. Special Precautions for Storage

Keep container in the outer carton.

6.5. Nature and Content of Container

Transparent PVC/PVdC-aluminium blisters / white opaque PVC/PVdC-aluminium blisters

Blister packs of 5, 10, 20 and 50 tablets

Not all pack sizes may be marketed.

6.6. Instruction for Use, Handling and Disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited,

Brampton Road, Hampden Park,

Eastbourne, East Sussex,

BN22 9AG

8. MARKETING AUTHORISATION NUMBER

PL 00289/0354

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/04/2009

10 DATE OF REVISION OF THE TEXT

25/10/2012