dysglycemia, psychotic reactions, memory impairment and delirium

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.

1. 4.4 Special Warnings and Precautions for Use

• Interference with laboratory tests
  In patients treated with ofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method.
   
• Patients with rare hereditary disorders
• Patients with rare hereditary disorders of galactose intolerance, the Lapp lactase deficiency or glucose­galactose malabsorption should not take this medicine.

• Tarivid IV contains sodium
  This medicinal product contains 15.4 mmol354 mg sodium per dosevial, equivalent to 18% of the WHO recommended maximum daily intake for sodium. The maximum daily dose of this product is equivalent to 71% of the WHO recommended maximum daily intake for sodium. Tarivid IV is considered high in sodium. This should be particularly taken into account for those on a low salt diet.
  . To be taken into consideration in patients on a controlled sodium diet.
   

• 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

• 1. Therapeutic Indications
      
     Ofloxacin is a synthetic 4-fluoroquinolone antibacterial agent.
      
     Tarivid solution for infusion 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 treatmentwith other antibacterial agents
• Sepsis due to above-mentioned genito-urinary infectionsUrosepsis
   
  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 the treatment of these infections.
   
  The treatment of acute and chronic infections of respiratory tract due to Gram-positive and Gram-negative micro organisms sensitive to ofloxacin.
   
  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.
   
  In the following infections, ofloxacin may be used as an alternative to other usual anti-infectives:
   

• Skin and soft tissue infections.

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

• 1. Special Warnings and 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 minimise 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

**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).

In the following infections, ofloxacin may be used as an alternative to other usual anti-infectives:

• Skin and soft tissue infections.

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

1. 1. Posology and Method of Administration
      Type and duration of treatment

The usual recommended dosages of Tarivid IV in adults with normal renal function are:

A daily dose of up to 400 mg ofloxacin may be given as a single dose. In this case, it is preferable to administer ofloxacin in the morning. Daily doses of more than 400mg must be divided into two separate doses and be given at approximately equal intervals.

Ofloxacin solution is only intended for slow SLOW intravenous infusion:  it is administered once or twice daily.  The infusion time must be at least 30 minutes for 200mg of ofloxacin solution.  This is of particular importance when ofloxacin is administered concomitantly with drugs that can lead to a reduction in blood pressure or with barbiturate-containing anaesthetics.

It is possible to switch from an initial intravenous application to the oral route at the same dosage after a few days, according to the condition of the patient.

Impaired renal function:  The dosage of Tarivid should be adjusted according to the degree of renal impairment.

Dosage in adultsPosology in patients with renal insufficiency:

The dosage of Tarivid should be adjusted according to the degree of renal impairment.

In patients with impaired renal function, the following oral or IV dosages are recommended:

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 iImpaired liver function:   The excretion of ofloxacin may be reduced in patients with severe liver function disorders (e.g. cirrhosis of the liver with ascites).  A maximum daily dose of 400mg ofloxacin should therefore not be exceeded.

Children:  Contra-indicated in children and growing adolescents.

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

1. 1. Contra-indications

Special Warnings and Special Precautions for Use

• Severe bullous reactionscutaneous adverse reactions

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, 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 co-administration of corticosteroids.

Patients with history of psychotic disorder
Psychotic reactions including suicidal ideation/attempt (see Section 11) have been reported in patients receiving fluoroquinolones including ofloxacin.  In some cases these have progressed to suicidal thoughts or self-endangering behaviour including suicide attempt, sometimes after a single dose of ofloxacin (see section 4.8).  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.

• 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.

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, cases of hypoglycaemic coma have been reported. . In diabetic patients, careful monitoring of blood glucose is recommended (see Section 4.8)..

Caution is recommended if the drug is to be used in psychotic patients with a history of psychiatric disease

• Vision disorders.
  If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).
• Interference with laboratory tests
  In patients treated with ofloxacin, determination of opiates in urine may give false-ppositive results. It may be necessary to confirm positive opiate screens by more specific method.
• Patients with rare hereditary disorders
  Patients with rare hereditary disorders of galactose intolerance, the Lapp lactase deficiency or glucose­galactose malabsorption should not take this medicine.

Coagulation tests, therefore,   should be monitored in patients treated with Vitamin K antagonists because of a possible increase in the effect of coumarin derivatives(see Section 4.4)..

• Anticoagulant Therapy
  Concurrent administration of anticoagulant therapy may require adjustment of the dose of the latter as prolongation of bleeding time has been reported.  In a study with phencourmarin no interactions were noted.

Concurrent administration of anticoagulant therapy may require adjustment of the dose of the latter as prolongation of bleeding time has been reported.  In a study with phencourmarin no interactions were noted.

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

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

1. 1. Effects on ability to drive and use machines
       
      Some adverse reactions (e.g. dizziness/vertigo, drowsiness, visual disturbance) 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 a special machinemachinery).
2.  

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, increase 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.)

This medicinal product contains 15.4 mmol sodium per vial. To be taken into consideration in patients on a controlled sodium diet.

• 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.
   
   
  1. Interactions with other medicinal products and other forms of interaction

Section 4.2    QT interval prolongation

Section 4.4    QT interval prolongation

Section 4.5    QT interval prolongation and interference with drug tests for opiates

Section 4.8    Sensory or sensorimotor peripheral neuropathy

Section 9       Editorial rearrangement of text

Section 10     Updated