OfloHEXAL

The following indications are restricted to adults.

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

- Lower respiratory tract infections including pneumonia, bronchitits and acute exacerbations of chronic bronchitis caused by gram negative aerobic bacteria. (OfloHEXAL 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.

OfloHEXAL^® ophthalmic solution is indicated for the treatment of infections caused by susceptible strains of the following bacteria in the conditions listed below:

Conjuctivitis

Gram-Positive Bacteria

Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae

Gram-Negative Bacteria

Enterobacter cloacae
Haemophilus influenzae
Proteus mirabilis
Pseudomonas aeruginosa

Corneal Ulcers

Gram-Positive Bacteria

Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae

Gram-Negative Bacteria

Pseudomonas aeruginosa
Serratia marcescens*

Anaerobic Species

Propionibacterium acnes

*Efficacy for this organism was studied in fewer than 10 infections

OfloHEXAL^® is indicated for the topical treatment of external ocular infections (such as conjunctivitis and keratoconjunctivitis) in adults and children caused by ofloxacin - sensitive organisms. Safety and efficacy in the treatment of ophthalmia neonatorum has not been established.

OCUFLOX^® ophthalmic solution is indicated for the treatment of infections caused by susceptible strains of the following bacteria in the conditions listed below:

Conjuctivitis

Gram-Positive Bacteria

Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae

Gram-Negative Bacteria

Enterobacter cloacae
Haemophilus influenzae
Proteus mirabilis
Pseudomonas aeruginosa

Corneal Ulcers

Gram-Positive Bacteria

Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae

Gram-Negative Bacteria

Pseudomonas aeruginosa
Serratia marcescens*

Anaerobic Species

Propionibacterium acnes

*Efficacy for this organism was studied in fewer than 10 infections

The use of OfloHEXAL 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.

OfloHEXAL (ofloxacin ophthalmic) solution is contraindicated in patients with a history of hypersensitivity to ofloxacin, to other quinolones, or to any of the components in this medication.

OfloHEXAL^® is contra-indicated in individuals who have shown hypersensitivity to ofloxacin, any of its excipients or any other quinolones.

OCUFLOX (ofloxacin ophthalmic) solution is contraindicated in patients with a history of hypersensitivity to ofloxacin, to other quinolones, or to any of the components in this medication.

OfloHEXAL 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 OfloHEXAL. Therefore OfloHEXAL is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to OfloHEXAL (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 OfloHEXAL. 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 OfloHEXAL and have been reported up to several months after discontinuation of OfloHEXAL. 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 OfloHEXAL. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with OfloHEXAL 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 OfloHEXAL 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 OfloHEXAL (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 OfloHEXAL. 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. OfloHEXAL 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 OfloHEXAL should be discontinued.

Patients with impaired renal function

Since OfloHEXAL 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 OfloHEXAL. In some cases these have progressed to suicidal thoughts or self-endangering behavior including suicide attempt, sometimes after a single dose of OfloHEXAL. In the event that a patient develops these reactions, OfloHEXAL should be discontinued and appropriate measures instituted.

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

Patients with impaired liver function

OfloHEXAL 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 OfloHEXAL, 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 OfloHEXAL, 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. OfloHEXAL is not recommended in patients with a known history of myasthenia gravis.

Superinfection

As with other antibiotics, the use of OfloHEXAL, 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 OfloHEXAL. 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 OfloHEXAL, 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 OfloHEXAL, 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 OfloHEXAL, which can be rapid in its onset. OfloHEXAL 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 OfloHEXAL has to be used in these patients, potential occurrence of haemolysis should be monitored.

Interference with laboratory tests

In patients treated with OfloHEXAL, 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

OfloHEXAL 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.

WARNINGS

NOT FOR INJECTION.

OfloHEXAL (ofloxacin ophthalmic) solution should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching. A rare occurrence of Stevens-Johnson syndrome, which progressed to toxic epidermal necrolysis, has been reported in a patient who was receiving topical ophthalmic ofloxacin. If an allergic reaction to ofloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management, including intubation should be administered as clinically indicated.

PRECAUTIONS

General

As with other anti-infectives, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. Ofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity reaction.

The systemic administration of quinolones, including ofloxacin, has led to lesions or erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. Ofloxacin, administered systemically at 10 mg/kg/day in young dogs (equivalent to 110 times the maximum recommended daily adult ophthalmic dose) has been associated with these types of effects.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies to determine the carcinogenic potential of ofloxacin have not been conducted.

Ofloxacin was not mutagenic in the Ames test, in vitro and in vivo cytogenic assay, sister chromatid exchange assay (Chinese hamster and human cell lines), unscheduled DNA synthesis (UDS) assay using human fibroblasts, the dominant lethal assay, or mouse micronucleus assay. Ofloxacin was positive in the UDS test using rat hepatocyte, and in the mouse lymphoma assay. In fertility studies in rats, ofloxacin did not affect male or female fertility or morphological or reproductive performance at oral dosing up to 360 mg/kg/day (equivalent to 4000 times the maximum recommended daily ophthalmic dose).

Pregnancy

Teratogenic Effects. Pregnancy Category C

Ofloxacin has been shown to have an embryocidal effect in rats and in rabbits when given in doses of 810 mg/kg/day (equivalent to 9000 times the maximum recommended daily ophthalmic dose) and 160 mg/kg/ day (equivalent to 1800 times the maximum recommended daily ophthalmic dose). These dosages resulted in decreased fetal body weight and increased fetal mortality in rats and rabbits, respectively. Minor fetal skeletal variations were reported in rats receiving doses of 810 mg/kg/day. Ofloxacin has not been shown to be teratogenic at doses as high as 810 mg/kg/day and 160 mg/kg/day when administered to pregnant rats and rabbits, respectively.

Nonteratogenic Effects

Additional studies in rats with doses up to 360 mg/kg/day during late gestation showed no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn.

There are, however, no adequate and well-controlled studies in pregnant women. OfloHEXAL (ofloxacin ophthalmic) solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

In nursing women a single 200 mg oral dose resulted in concentrations of ofloxacin in milk which were similar to those found in plasma. It is not known whether ofloxacin is excreted in human milk following topical ophthalmic administration. Because of the potential for serious adverse reactions from ofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in infants below the age of one year have not been established.

Quinolones, including ofloxacin, have been shown to cause arthropathy in immature animals after oral administration; however, topical ocular administration of ofloxacin to immature animals has not shown any arthropathy. There is no evidence that the ophthalmic dosage form of ofloxacin has any effect on weight bearing joints.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

OfloHEXAL^® is not for injection.

Safety and effectiveness in infants below the age of one year have not been established.

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin.5, section 4.8, section 4.9).

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

Use OfloHEXAL^® with caution in patients who have exhibited sensitivities to other quinolone antibacterial agents.

Data are very limited to establish efficacy and safety of OfloHEXAL^® eye drops 0.3% in the treatment of conjunctivitis in neonates.

The use of OfloHEXAL^® eye drops in neonates with ophthalmia neonatorum caused by Neisseria gonorrhoeae or Chlamydia trachomatis is not recommended as it has not been evaluated in such patients.

Use in elderly: No comparative data are available with topical dosing in elderly versus other age groups.

Clinical and non-clinical publications have reported the occurrence of corneal perforation in patients with pre-existing corneal epithelial defect or corneal ulcer, when treated with topical fluoroquinolone antibiotics. However, significant confounding factors were involved in many of these reports, including advanced age, presence of large ulcers, concomitant ocular conditions (e.g. severe dry eye), systemic inflammatory diseases (e.g. rheumatoid arthritis), and concomitant use of ocular steroids or non-steroidal anti-inflammatory drugs. Nevertheless, it is necessary to advise caution regarding the risk of corneal perforation when using product to treat patients with corneal epithelial defects or corneal ulcers.

Corneal precipitates have been reported during treatment with topical ophthalmic ofloxacin. However, a causal relationship has not been established.

Long-term, high-dose use of other fluoroquinolones in experimental animals has caused lenticular opacities. However, this effect has not been reported in human patients, nor has it been noted following topical ophthalmic treatment with ofloxacin for up to six months in animal studies including studies in monkeys.

OfloHEXAL^® contains the preservative benzalkonium chloride which may cause ocular irritation and discolour soft contact lenses.

Sun or UV-exposition should be avoided during use of ofloxacin due to the potential for photosensitivity.

Use of contact lenses is not recommended in patients receiving treatment for an eye infection.

WARNINGS

NOT FOR INJECTION.

OCUFLOX (ofloxacin ophthalmic) solution should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching. A rare occurrence of Stevens-Johnson syndrome, which progressed to toxic epidermal necrolysis, has been reported in a patient who was receiving topical ophthalmic ofloxacin. If an allergic reaction to ofloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management, including intubation should be administered as clinically indicated.

PRECAUTIONS

General

As with other anti-infectives, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. Ofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity reaction.

The systemic administration of quinolones, including ofloxacin, has led to lesions or erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. Ofloxacin, administered systemically at 10 mg/kg/day in young dogs (equivalent to 110 times the maximum recommended daily adult ophthalmic dose) has been associated with these types of effects.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies to determine the carcinogenic potential of ofloxacin have not been conducted.

Ofloxacin was not mutagenic in the Ames test, in vitro and in vivo cytogenic assay, sister chromatid exchange assay (Chinese hamster and human cell lines), unscheduled DNA synthesis (UDS) assay using human fibroblasts, the dominant lethal assay, or mouse micronucleus assay. Ofloxacin was positive in the UDS test using rat hepatocyte, and in the mouse lymphoma assay. In fertility studies in rats, ofloxacin did not affect male or female fertility or morphological or reproductive performance at oral dosing up to 360 mg/kg/day (equivalent to 4000 times the maximum recommended daily ophthalmic dose).

Pregnancy

Teratogenic Effects. Pregnancy Category C

Ofloxacin has been shown to have an embryocidal effect in rats and in rabbits when given in doses of 810 mg/kg/day (equivalent to 9000 times the maximum recommended daily ophthalmic dose) and 160 mg/kg/ day (equivalent to 1800 times the maximum recommended daily ophthalmic dose). These dosages resulted in decreased fetal body weight and increased fetal mortality in rats and rabbits, respectively. Minor fetal skeletal variations were reported in rats receiving doses of 810 mg/kg/day. Ofloxacin has not been shown to be teratogenic at doses as high as 810 mg/kg/day and 160 mg/kg/day when administered to pregnant rats and rabbits, respectively.

Nonteratogenic Effects

Additional studies in rats with doses up to 360 mg/kg/day during late gestation showed no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn.

There are, however, no adequate and well-controlled studies in pregnant women. OCUFLOX (ofloxacin ophthalmic) solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

In nursing women a single 200 mg oral dose resulted in concentrations of ofloxacin in milk which were similar to those found in plasma. It is not known whether ofloxacin is excreted in human milk following topical ophthalmic administration. Because of the potential for serious adverse reactions from ofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in infants below the age of one year have not been established.

Quinolones, including ofloxacin, have been shown to cause arthropathy in immature animals after oral administration; however, topical ocular administration of ofloxacin to immature animals has not shown any arthropathy. There is no evidence that the ophthalmic dosage form of ofloxacin has any effect on weight bearing joints.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

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 OfloHEXAL before they drive or operate machinery. These effects may be enhanced by alcohol.

No studies on the effects on the ability to drive and use machines have been performed.

Transient blurring of vision may occur on instillation of eye drops. Do not drive or operate hazardous machinery unless vision is clear.

Pharmacotherapeutic group: Quinolone Antibacterials, Fluoroquinolones

ATC code: J01 MA 01

Mechanism of action

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

Therapeutic doses of OfloHEXAL 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 OfloHEXAL:

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 OfloHEXAL or not.

Only those pathogens relevant to the indications are listed.

Resistance

The main mechanism of bacterial resistance to OfloHEXAL 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.

Pharmacotherapeutic group: Ophthalmologicals, anti-infectives, fluoroquinolones

ATC code: S01AE01.

Ofloxacin is a synthetic fluorinated 4-quinolone antibacterial agent with activity against a broad spectrum of Gram negative and to a lesser degree Gram positive organisms.

Ofloxacin has been shown to be active against most strains of the following organisms both in vitro and clinically in ophthalmic infections. Clinical trial evidence of the efficacy of OfloHEXAL^® against S. pneumoniae was based on a limited number of isolates.

Gram-negative bacteria: Acinetobacter calcoaceticus var. anitratum, and A. calcoaceticus var. iwoffi; Enterobacter Sp. including E. cloacae; Haemophilis Sp, including H. influenza and H. aegyptius; Klebsiella Sp., including K. Pneumoniae; Moraxella Sp., Morganella morganii; Proteus Sp., including P. Mirabilis; Pseudomonas Sp.; including P. Aeruginosa, P. cepacia, and P. fluoroscens; and Serratia Sp., including S. marcescens.

Gram-positive bacteria: Bacillus Sp.; Corynebacterium Sp.; Micrococcus Sp.; Staphylococcus Sp., including S. aureus and S. epidermidis; Streptococcus Sp., including S. Pneumoniae (see above), S. viridans and Beta-haemolytic.

The primary mechanisms of action is through inhibition of bacterial DNA gyrase, the enzyme responsible for maintaining the structure of DNA.

Ofloxacin is not subject to degradation by beta-lactamase enzymes nor is it modified by enzymes such as aminoglycoside adenylases or phosphorylases, or chloramphenicol acetyltransferase.

Absorption

The administration of oral doses to fasting volunteers was followed by a rapid and almost complete absorption of OfloHEXAL. 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 OfloHEXAL was below 5%. The two main metabolites found in the urine were N-desmethyl-OfloHEXAL and OfloHEXAL-N-oxide.

Elimination

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

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

Serum, urine and tear concentrations of ofloxacin were measured in 30 healthy women at various time points during a ten-day course of treatment with OfloHEXAL® solution. The mean serum ofloxacin concentration ranged from 0.4 ng/mL to 1.9 ng/mL. Maximum ofloxacin concentration increased from 1.1 ng/mL on day one to 1.9 ng/mL on day 11 after QID dosing for 10 1/2 days. Maximum serum ofloxacin concentrations after ten days of topical ophthalmic dosing were more than 1000 times lower than those reported after standard oral doses of ofloxacin.

Tear ofloxacin concentrations ranged from 5.7 to 31 mcg/g during the 40 minute period following the last dose on day 11. Mean tear concentration measured four hours after topical ophthalmic dosing was 9.2 mcg/g.

Corneal tissue concentrations of 4.4 mcg/mL were observed four hours after beginning topical ocular application of two drops of OfloHEXAL® ophthalmic solution every 30 minutes. Ofloxacin was excreted in the urine primarily unmodified.

After ophthalmic instillation, ofloxacin is well maintained in the tear-film.

In a healthy volunteer study, mean tear film concentrations of ofloxacin measured four hours after topical dosing (9.2 µg/g) were higher than the 2µg/ml minimum concentration of ofloxacin necessary to inhibit 90% of most ocular bacterial strains (MIC₉₀) in-vitro.

Maximum serum ofloxacin concentrations after ten days of topical dosing were about 1000 times lower than those reported after standard oral doses of ofloxacin, and no systemic side-effects attributable to topical ofloxacin were observed.

Serum, urine and tear concentrations of ofloxacin were measured in 30 healthy women at various time points during a ten-day course of treatment with OCUFLOX® solution. The mean serum ofloxacin concentration ranged from 0.4 ng/mL to 1.9 ng/mL. Maximum ofloxacin concentration increased from 1.1 ng/mL on day one to 1.9 ng/mL on day 11 after QID dosing for 10 1/2 days. Maximum serum ofloxacin concentrations after ten days of topical ophthalmic dosing were more than 1000 times lower than those reported after standard oral doses of ofloxacin.

Tear ofloxacin concentrations ranged from 5.7 to 31 mcg/g during the 40 minute period following the last dose on day 11. Mean tear concentration measured four hours after topical ophthalmic dosing was 9.2 mcg/g.

Corneal tissue concentrations of 4.4 mcg/mL were observed four hours after beginning topical ocular application of two drops of OCUFLOX® ophthalmic solution every 30 minutes. Ofloxacin was excreted in the urine primarily unmodified.

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

Mutagenicity studies showed no evidence for mutagenicity of OfloHEXAL. However, like some other quinolones OfloHEXAL is phototoxic in animals at exposure in the human therapeutic range. The phototoxic, photomutagenic and photocarcinogenic potential of OfloHEXAL 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

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

There are no toxicological safety issues with this product in man as the level of systemic absorption from topical ocular administration of ofloxacin is minimal.

Animal studies in the dog have found cases of arthropathy in weight bearing joints of juvenile animals after high oral doses of certain quinolones. However, these findings have not been seen in clinical studies and their relevance to man is unknown.

Not applicable

None known.

No special requirements.

There is no special requirement for disposal.

Any unused product or waste material should be disposed of in accordance with local requirements.