Sections 4.4 and 4.8 of the Summary of Product Characteristics (SmPC) and Section 4 of the Patient Information Leaflet (PIL) for Tarivid IV (ofloxacin hydrochloride) 2 mg/ml solution for infusion (PA 540/76/002) and Tarivid (ofloxacin) 200 mg film-coated tablets (PA 540/76/003), with regards to dysglycemia, psychotic reactions, memory impairment and delirium.

Minor update to Section 4.4 ‘Patients with history of psychotic disorder’

Introduction of benign intracranial hypertension adverse event in Section 4.8

4.4         Special warnings and special precautions for use

• Aortic aneurysm and dissection
  Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.
  Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).
  In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
   

4.         Clinical Particulars

4.1       Therapeutic indications

Ofloxacin is a synthetic 4-fluoroquinolone antibacterial agent.  It is effective in vitro against a wide range of Gram-negative and Gram-positive organisms.  It is indicated for the treatment of the following infections when caused by sensitive organisms:

The following indications are restricted to adults:

Respiratory tract: Acute, chronic or recurrent respiratory tract infections (bronchitis) caused by Haemophilus influenzae or other Gram-negative or multi-resistant pathogens, as well as by Staphylococcus aureus.  In respiratory tract infection ofloxacin is not recommended as first-line therapy for the treatment of pneumococcal pneumonia.  Streptococcus pneumoniae is the most frequent pathogen responsible for community acquired pneumonia.

In acute exacerbations of chronic obstructive pulmonary disease including chronic bronchitis Tarivid should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for treatment of these infections.

In community acquired pneumonia Tarivid should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.

Urinary tract:

Tarivid is indicated in adults for the treatment of the following bacterial infections (see sections 4.4 and 5.1):

•           Acute pPyelonephritis and complicated urinary tract infections

•           Bacterial pProstatitis, epididymo-orchitis

•           Pelvic inflammatory disease, in combination with other antibacterial agentstreatment

In uncomplicated cystitis Tarivid should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.

In urethritis Tarivid should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.

In complicated skin and soft tissue infections Tarivid should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.

For the below-mentioned infections Tarivid should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections (see section 4.4).

•           Uncomplicated cystitis

•           Urethritis

• Skin and soft-tissue infections
   
  Tarivid tablets are also indicated for infection prophylaxis of bacterial infection in neutropenic patients.

4.4       Special warnings and special precautions for use

• The use of ofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolones containing products (see section 4.8). Treatment of these patients with ofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).
   

• Prolonged, disabling and potentially irreversible serious adverse drug reactions
         Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. Ofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice.

• Tendinitis and tendon rupture
   
  Tendinitis, 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 ofloxacin and have been reported up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in patients aged over 60 years and in patients using corticosteroids..   Furthermore, as transplanted patients are at increased risk of tendinitis, caution is recommended when fluoroquinolones are used in this population. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section 4.2). Close monitoring of these patients is therefore necessary if they are prescribed ofloxacin. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, or at the first signs of pain or inflammation, treatment with ofloxacin must be halted immediately.  Appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon (see sections 4.3 and 4.8).
  Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.
  At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with ofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.
   

• 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). 
  Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with ofloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition. (see section 4.8)

1. 4.8    Undesirable Effects

* postmarketing experience[HKP1] 

**Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see Section 4.4).

Urinary tract: Tavanic Tarivid is indicated in adults for the treatment of the following bacterial infections (see sections 4.4 and 5.1):

For the below-mentioned infections Tavanic Tarivid should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections (see section 4.4).

•           Uncomplicated cystitis

•           Urethritis

•       Skin and soft-tissue infections

Tarivid tablets are also indicated for infection prophylaxis in neutropenic patients.

Skin and soft tissue infection.

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

4.2       Posology and method of administration

General dosage recommendations: Tarivid tablets are to be swallowed with sufficient amount of liquids.  They may be taken on an empty stomach or with meals.  Concomitant administration with antacids should be avoided (see section 4.5 : Interactions).  Ofloxacin should be administered approximately 2 hours apart from antacids. The dose of ofloxacin is determined by the type and severity of the infection.  The dosage range for adults with normal renal function is 200 mg to 800 mg daily.  A daily dose of  Uup to 400 mg may be given as a single dose., In this case, it is preferabley to administer ofloxacin in the morning.  Daily doses of more than 400mg must be divided into two separate doses and be given approximately equal intervals.

Dosage Posology in adults patients with renal insufficiency:

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:

                                                                                    weight(kg) x (140 -age in years)

Men:                         ClCr (ml/min) =                        ---------------------------------------

                                                                                   72 x serum creatinine (mg/dl)

                     or

                                                                                   weight(kg) x (140 -age in years)

                                 ClCr (ml/min) =                        --------------------------------------

                                                                                   0.814 x serum creatinine (µmol/l)

Women:                    ClCr (ml/min) =                        0.85 x (above value)
Posology in hepatic insufficiency Impaired liver function: the excretion of ofloxacin may be reduced in patients with severe renal liver function disorders (e.g. cirrhosis of the liver and ascites).

It is recommended that Aa maximum daily dose of 400 mg of ofloxacion should be therefore not be exceeded, because of possible reduction of excretion.

Children: Contra-indicated in children and growing adolescents.

Elderly: Dosage may need to be reduced in accordance with renal or hepatic function.  Age in itself does not impose to adapt the dosage of ofloxacin. However, special attention to renal function should be paid in elderly patients, and the dosage should be adapted accordingly. (See section 4.4 QT interval prolongation).

Duration of therapy varies according to the course of the disease. Ofloxacin should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.

4.3       Contra-indications

Ofloxacin must not be used

• In patients hypersensitive to ofloxacin, other quinolones, or any of the excipients listed in section 6.1.

Severe bullous reactionscutaneous adverse reactions Cases

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with ofloxacin (including several weeks after treatment), may be symptomatic of pseudo-membranous colitis (CDAD).  CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with ofloxacin. If pseudo-membranous colitis is suspected, ofloxacin must be stopped immediately.

In case of convulsive seizuresIf seizure develops, treatment with ofloxacin should be discontinued.

• Tendinitis 

Tendinitis, 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 ofloxacin and have been reported up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in patients aged over 60 years and in patients using corticosteroids..   Elderly patients are more prone to tendinitis.  The risk of tendon rupture may be increased by coadministration of corticosteroids.

If secondary infection occurs during therapy, appropriate measures should be taken.

• Risks of resistance
  The prevalence of acquired resistance may vary geographically and over time for selected species. Therefore, local information on resistance is required; microbiological diagnosis with isolation of the pathogen and demonstration of its susceptibility should be sought, especially for severe infections or failure to respond to treatment.
• QT interval prolongation
  Very rare Ccases of QT interval prolongation have been reported in patients taking fluoroquinolones including ofloxacin.
   DAs with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported with fluoroquinolones including ofloxacin., usually Iin diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin, c. ases of hypoglycaemic coma have been reported. In these diabetic patients, careful monitoring of blood glucose is recommended (see Section 4.8).

Ofloxacin should be used with caution in patients with a history of psychotic disorder or in patients with psychiatric disease. Caution is recommended if the drug is to be used in psychotic patients or in patients with a history of psychiatric disease.

Coagulation tests, therefore,  should be monitored in patients treated with vitamin K antagonists. because of a possible increase in the effect of coumarin derivatives.

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

• Anticoagulant Therapy

with this combinationofloxacin and glibenclamide should be closely monitored.be monitored particularly closely.

See section 4.3 Contraindications).

Breast-feeding

Because Oofloxacin is excreted in 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. , either breast-feeding or treatment of the mother must    be stopped because of the risk to the child.  (See Section 4.3 Contraindications).

(e.g. driving as car or operating a special machinemachinery).

1. 1. Overdose
       
      The most important signs to be expected following acute overdoseage are CNS symptoms such as confusion, dizziness, impairment of consciousness and convulsive seizures, increases in QT interval as well as gastrointestinal reactions such as nausea and mucosal erosions. 

CNS effects including confusional state, convulsion, hallucination, and tremor have been observed in post marketing experience

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.

The antibacterial spectrum of ofloxacin is as follows (the sensitivity to ofloxacin may vary, depending on the epidemiology and level of resistance in the country concerned.)

• Patients with rare hereditary disorders
  
  
  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
   

• Aortic aneurysm and dissection
   
  Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.
  Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).
  In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
   
  4.5       Interaction with other medicinal products and other forms of interaction