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1. Ofloxacin Teva 400 Mg Tablets
2. Ofloxacin Teva 400 Mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ofloxacin Teva 400 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Film-coated Tablet contains 400 mg of Ofloxacin.

Excipient(s) with known effect

This product contains lactose monohydrate

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated Tablets

White, oval 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 such as acute exacerbation of chronic bronchitis or pneumonia if caused by Gram-negative bacteria. Ofloxacin is not the treatment of choice for community acquired pneumonia;

-    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

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. In individual cases it may be necessary to increase the dose to 600 mg (or even to a maximum total dose of 800 mg daily) for treatment of severe infections or in overwweight patients. Daily doses of more then 400 mg must be divided into two separate doses and be given at approximately equal intervals..

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	400 mg 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

Posology in patients with renal insufficiency :

In patients with impaired renal function, the following oral or I.V dosages are recommended:

Creatinine	Unit dose	Number	Intervals
clearance	mg*	/24 hours	hours
50 - 20 ml/min	100 - 200	1	24
< 20 ml/min**	100	1	24
or haemodialysis	or
or peritoneal	200	1	48
dialysis

* According to indication or dose interval

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

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:

Men:    CICr (ml/min) =

4.3 Contraindications

Ofloxacin must not be used

-    in patients with known hypersensitivity to ofloxacin, to other 4-quinolone antibacterials or to any of the excipients.

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

-    in patients with epilepsy

-    in children or adolescents in the growth phase¹

-    during pregnancy¹

-    in breast-feeding women¹

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

4.4 Special warnings and precautions for use

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

Prevention of photosensitisation

Because of the risk of photosensitisation, exposure to strong sunlight and UV radiation should be avoided during treatment with ofloxacin.

Clostridium difficile-associated disease

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

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)

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. immobilisation) 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 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).

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. Secondary infection

As with other antibiotics, the use of ofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If secondary infection occurs during therapy, appropriate measures should be taken.

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: ¹

•    congenital long QT syndrome

•    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, antipsychotics).

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 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. This would minimize the possible risk of developing an irreversible condition.

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 disorders of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 antiinflammatory drugs 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 antiinflammatory drugs, or other agents, which lower the seizure threshold.

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’).

Vitamin K antagonists

Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with ofloxacin in combination with a vitamin K antagonist (e.g. warfarin). Coagulation tests,therefore, should be monitored in patients treated with vitamin K antagonists (see section 4.4).

Glibenclamide

Ofloxacin may cause a slight increase in serum concentrations of glibenclamide administered concurrently; it is therefore recommended that patients treated concomitantly with ofloxacin and glibenclamide be monitored particularly closely.

Probenecid, cimetidine, furosemide, or methotrexate

Probenecid decreased the total clearance of ofloxacin by 24%, and increased AUC by 16%. The proposed mechanism is a competition or inhibition for active transport at the renal tubular excretion. Caution should be exercised when ofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid, cimetidine, furosemide or methotrexate.

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. Therefore ofloxacin should not be used during pregnancy (see section 4.3 Contraindications).

Breast-feeding

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).

4.7 Effects on ability to drive and use machines

Some adverse reactions (e.g. dizziness/vertigo, drowsiness, visual disturbances) 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).

4.8 Undesirable effects

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

System organ class	Common ( 1/100 to <1/10 )	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 the lymphatic system disorders				Anaemia Haemolytic anaemia, Leukopenia, Eosinophilia, Thrombo cytopenia	Agranulocytosis Bone marrow failure Bone marrow failure may lead to pancytopenia
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) Hyperglycaemia Hypoglycaemic coma
Psychiatric disorders		Agitation, Sleep disorder, Insomnia	Psychotic disorder (for eg. hallucination), Anxiety, Confusional state, Nightmares, Depression		Psychotic disorder and depression with self-endangering behaviour including suicidal ideation or suicide attempt (see section 4.4) Nervousness

System organ class	Common ( 1/100 to <1/10 )	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)*
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	Tremor Dyskinesia Ageusia Syncope
Eye disorders		Eye irritation	Visual disturbance
Ear and labyrinth disorders		Vertigo		Tinnitus, Hearing loss	Hearing impaired
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
Respiratory, thoracic and mediastinal disorders		Cough, Nasopharyngitis	Dyspnoea, Bronchospasm		Allergic pneumonitis, Severe dyspnoea
Gastro intestinal disorders		Abdominal pain, Diarrhoea, Nausea, Vomiting	Enterocolitis, sometimes haemorrhagic	Pseudomembranous colitis* Jaundice cholestatic	Dyspepsia Flatulence Constipation Pancreatitis

System organ class	Common ( 1/100 to <1/10 )	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)2
Hepato-bilary disorders			Hepatic enzymes increased (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase) Blood bilirubin increased		Hepatitis, which may be severe2
Skin and subcutaneous tissue disorders		Pruritus, Rash	Urticaria, Hot flushes, Hyperhidrosis Pustular rash	Erythema multiforme, Toxic epidermal necrolysis, Photo-sensitivity reaction2 , Drug eruption Vascular purpura, Vasculitis, which can lead in exceptional cases to skin necrosis	Stevens-Johnson syndrome; Acute generalized exanthemous pustulosis; drug rash Stomatitis
Musculoskeleta l 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 Ligament rupture Arthritis
Renal and Urinary disorders			Serum creatinine increased	Acute renal failure	Acute interstitial nephritis
Congenital and familial/ genetic disorders					Attacks of porphyria in patients with porphyria
General disorders and administration site conditions					Asthenia Pyrexia Pain (including pain in back, chest, and extremities)

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

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.

4.9 Overdose

Symptoms of overdose

The most important signs to be expected following acute overdosage are CNS symptoms such as confusion, dizziness, impairment of consciousness and 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.

Treatment of overdose

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: fluoroquinolones ATC code: J01 MA 01

Mechanism of action

Ofloxacin inhibits bacterial DNA replication in a range of gram-positive and gramnegative 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.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

	European range of acquired bacterial resistance to ofloxacin
Commonly susceptible species
Aerobic Gram-positive micro organisms
Providentia3	17.1%
S. aureus - methicillin-sensitive	0.3-12.6%
S. pneumoniae3	70%
S. pyogenes	2-5%
Aerobic Gram-negative micro organisms
Acinetobacter spp	0.3-7.3%
Citrobacter spp	3-15%
E. Faecalis3
Enterobacter spp	2-13%
E.coli	1-8%
H. influenzae	1%
Klebsiella spp	1-10%
Morazella spp	0-0.2%
N. gonorrhoeae	25%
P. aeruginosa3	20-30%
Proteus spp	1-15%
Serratia marcescens	2-2.4%
Serratia spp3	20-40%
Stenotrophomonas maltophilia3	5.1-11%
Others
Chlamydia spp
L. pneumophila
Mycoplasma spp3	0-5.3%
Ureaplasma spp3	0-2.1%
Inherently resistant organisms
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

Absorption:

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).

Distribution:

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

Biotransformation:

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:

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.

Patients with impaired renal function:

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 Preclinical 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 weight-bearing 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 to protect the tablets from light. Store in the original package.

6.5 Nature and contents 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 Special precautions for disposal and other handling

No special requirements

7. MARKETING AUTHORIZATION HOLDER

UK

Teva Pharma B.V.

Computerweg 10 3542 DR Utrecht The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 14776/0055

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 09/07/2006

10 DATE OF REVISION OF THE TEXT

21/10/2014

1

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

2

postmarketing experience

3

These species show natural intermediate susceptibility (in the absence of acquired mechanisms of resistance) to Ofloxacin.