Active ingredients: Levofloxacin
REFRAIN 250 mg film-coated tablets
REFRAIN 500 mg film-coated tablets
Why is Refrain used? What is it for?
REFRAIN tablets contain the active substance called levofloxacin. This medicine belongs to a group of medicines called antibiotics. Levofloxacin is a "quinolone" antibiotic. This medicine works by killing the bacteria responsible for infections in the body
REFRAIN tablets can be used to treat infections:
- of the facial sinuses
- lungs, in patients with chronic breathing problems or pneumonia
- urinary tract, including kidneys and bladder
- of the prostate, where a persistent infection can develop
- skin and subcutaneous tissue, including muscles. These are sometimes called "soft tissues".
In some special situations, REFRAIN tablets can be used to decrease the likelihood of getting a lung disease called anthrax or worsening of the disease after being exposed to the bacterium that causes anthrax.
Contraindications When Refrain should not be used
Do not take this medicine and tell your doctor if:
- you are allergic (hypersensitive) to levofloxacin, to any other quinolone antibiotic such as moxifloxacin, ciprofloxacin or ofloxacin or to any of the other ingredients of this medicine Signs of an allergic reaction include: rash, swallowing or breathing problems, swelling of the lips, face, throat or tongue
- have or have suffered from epilepsy
- have had tendon problems, such as tendonitis, related to treatment with a 'quinolone antibiotic'. Tendons are fibrous structures that connect the muscles of the skeleton
- is a growing child or adolescent
- are pregnant, may become pregnant or think you are
- are breastfeeding
Do not take this medicine if the above may in any way apply to you. If you have any further questions, ask your doctor or pharmacist before taking REFRAIN tablets.
Precautions for use What you need to know before taking Refrain
Talk to your doctor or pharmacist before taking this medicine if
- are 60 or older
- you are taking corticosteroids, sometimes called steroids (see "Other medicines and RFRAIN")
- has had seizures
- suffered brain damage from a stroke or other brain damage
- have kidney problems
- you suffer from a disease known as "glucose-6-phosphate dehydrogenase deficiency". Giving this medicine makes it more likely that you will develop serious blood problems
- suffered from mental problems
- have had heart problems: special care should be taken when using this type of medicine if you were born with or have a family history of prolonged QT interval (displayed on the ECG, an electrical record of the heart), have a saline imbalance in the blood (especially a low level of potassium or magnesium in the blood), have a very slow heart rhythm (called bradycardia), have a weak heart (cardiac failure), have a history of heart attack (myocardial infarction), if you are an elderly woman or patient or if or are taking other medicines that may cause abnormal changes in the ECG (see section "Taking other medicines")
- have diabetes
- have had liver problems
- has Myastenia gravis
If you have any questions that the above may in any way apply to you, ask your doctor or pharmacist before taking REFRAIN tablets.
If you have any questions that the above may in any way apply to you, ask your doctor or pharmacist before taking REFRAIN tablets.
While taking REFRAIN
If your vision decreases or if your eyes are otherwise impaired, consult an eye doctor immediately.
Interactions Which drugs or foods can modify the effect of Refrain
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines. This is because REFRAIN tablets can affect the way some other medicines work. Some medicines can also affect the way REFRAIN tablets work.
In particular, tell your doctor if you are taking any of the following medicines. This is because co-administration with REFRAIN tablets may increase the chance that you will experience side effects:
- corticosteroids, sometimes called steroids - used to treat inflammation. The chance that you develop inflammation and / or rupture of the tendons is greater.
- warfarin - used to thin the blood. The chance of "bleeding" is greater. Your doctor may ask you to have regular blood tests to check for blood clotting.
- theophylline - used for breathing problems. The chance of you having a seizure (seizure) is higher if you take theophylline in combination with REFRAIN.
- non-steroidal anti-inflammatory drugs (NSAIDs) - used for pain and inflammation such as aspirin, ibuprofen, fenbufen, ketoprofen and indomethacin. The chance that you will experience a fit (seizure) when taken in combination with REFRAIN tablets is greater.
- cyclosporine - used for organ transplants. You are more likely to experience the typical side effects of cyclosporine.
- medicines that can alter the heart rhythm: medicines belonging to the class of antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide and ibutilide), tricyclic antidepressants, some antimicrobials (belonging to the macrolide class), some antipsychotics.
- probenecid - used to treat gout and cimetidine - used for ulcers and heartburn. Particular care should be taken when using any of these medicines in combination with REFRAIN. If you have kidney problems, your doctor may prescribe a lower dose;
Do not take REFRAIN tablets concomitantly with the following medicines. This is because the mechanism of action of REFRAIN tablets may be affected:
- iron salts in tablets (for anemia), zinc supplements, antacids containing magnesium or aluminum (for acidity or heartburn), didanosine or sucralfate (for stomach ulcers). See section 3 "If you are taking iron salts in tablets, zinc supplements, antacids, didanosine or sucralfate".
Urinalysis for opiates
Urine tests may show 'false positive' results for strong pain relievers called 'opiates' in patients taking REFRAIN. If your doctor thinks it necessary to have urine tests done, please tell him that you are taking REFRAIN tablets.
Tuberculosis test
This medicine may cause "false negative" results in some tests used in the laboratory to look for the bacterium causing tuberculosis.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not take this medicine if:
- you are pregnant, may become pregnant or think you are
- are breast-feeding or planning to breast-feed.
Driving and using machines
Some side effects may occur after taking this medicine which include dizziness, sleepiness, subjective sensation of movement (vertigo) or visual disturbances. Some of these side effects may affect your ability to concentrate and the speed of reaction. If this happens, do not drive vehicles or do activities that require a high level of attention.
Dosage and method of use How to use Refrain: Dosage
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
How to take this medicine
- take this medicine by mouth
- swallow the tablets whole with water
- the tablets can be taken with or between meals
Protect your skin from sunlight
Do not expose yourself to direct sunlight while taking this medicine and for 2 days after stopping treatment. This is because your skin will become much more sensitive to the sun and can burn, itch, or serious injuries can occur if you do not observe the following precautions:
- make sure you use a high protection factor sunscreen
- always wear a hat and clothing that covers your arms and legs
- avoid sun beds
If you are already taking iron tablets, zinc supplements, antacids, didanosine or sucralfate
- Do not take these medicines at the same time as REFRAIN. Take the prescribed dose of these medicines at least 2 hours before or after taking REFRAIN tablets.
How much medicine to take
- your doctor will decide how much REFRAIN tablets you should take
- the dose will depend on the type of infection you have and on the location of the infection in your body
- the duration of treatment will depend on the severity of the infection
- if you think the effect of the medicine is too weak or too strong, do not change the dosage yourself but talk to your doctor
Adults and the elderly
Infections of the facial sinuses
- two REFRAIN 250 mg tablets once a day
- or, one REFRAIN 500 mg tablet once a day
Lung infections, in patients with chronic breathing problems
- two REFRAIN 250 mg tablets once a day
- or, one REFRAIN 500 mg tablet once a day
Pneumonia
- two REFRAIN 250 mg tablets once or twice a day
- or, one REFRAIN 500 mg tablet once or twice a day
Urinary tract infections including kidney or bladder
- one or two REFRAIN 250 mg tablets once a day
- or, half or one REFRAIN 500 mg tablet once a day
Infections of the prostate
- two REFRAIN 250 mg tablets once a day
- or, one REFRAIN 500 mg tablet once a day
Infections of the skin and subcutaneous tissue, including muscles
- two REFRAIN 250 mg tablets once or twice a day
- or, one REFRAIN 500 mg tablet once or twice a day
Adults with kidney problems
The doctor may find it necessary to decrease the dosage.
Children and adolescents
This medicine should not be given to children or adolescents.
Overdose What to do if you have taken too much Refrain
If you take more REFRAIN tablets than you should
If you accidentally take more tablets than you should, tell your doctor immediately or seek medical advice elsewhere. Take the medicine pack with you. This will let the doctor know what you have taken. You may experience the following side effects: fits (seizures), confusion, dizziness, feeling faint and heart problems - which can lead to irregular heartbeats and feeling sick (nausea) or heartburn.
If you forget to take REFRAIN tablets
If you forget to take a dose, take it as soon as you remember unless it is time for your next dose. Do not take a double dose to make up for a forgotten dose.
If you stop taking REFRAIN tablets
Do not stop taking REFRAIN tablets just because you feel better. It is important that you complete the course of tablets that your doctor has prescribed for you. If you stop taking the tablets too soon, the infection can come back and your condition can get worse or the bacteria can develop resistance to the medicine.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Refrain
Like all medicines, REFRAIN can cause side effects, although not everybody gets them. These effects are usually mild or moderate in severity and often disappear after a short time.
Stop taking REFRAIN and go to your doctor or hospital straight away if you notice the following side effect:
Very rare (may affect up to 1 in 10,000 patients)
- have an allergic reaction. The signs may include: skin rash, trouble swallowing or breathing difficulties, swelling of the lips, face, throat or tongue
Stop taking REFRAIN and see your doctor or hospital straight away if you notice any of the following side effects - you may need urgent medical treatment:
Rare (may affect up to 1 in 1,000 patients)
- watery diarrhea with possible blood, possibly accompanied by stomach cramps and high fever. This can indicate a severe bowel problem
- pain and inflammation of the tendons or ligaments which in some cases can rupture. The Achilles tendon is most often affected.
- convulsions
Very rare (may affect up to 1 in 10,000 patients)
- burning, tingling, pain or numbness. These signs may indicate a disease called "neuropathy"
Other
- severe rash which may include lesions or peeling of the skin around the lips, eyes, mouth, nose and genitals
- loss of appetite, yellowing of the skin and eyes, dark urine, itchy or sore stomach (abdomen). These may be signs of liver problems which can include fatal liver failure (failure of the liver which can cause death)
If your vision becomes blurred or if you have any eye discomfort when taking REFRAIN, consult an ophthalmologist immediately.
Tell your doctor if any of the following side effects get worse or last more than a few days:
Common (may affect up to 1 in 10 patients)
- trouble sleeping
- headache, feeling dizzy
- feeling sick (nausea, vomiting) and diarrhea
- increased levels of liver enzymes in the blood
Uncommon (may affect up to 1 in 100 patients)
- Changes in the number of other bacteria or fungi, infection with a fungus called Candida, which may require treatment
- Change in the number of white blood cells shown in the results of some blood tests (leukopenia, eosinophilia)
- Feeling stressed (anxiety), feeling confused, feeling jittery, sleepy, shaking, dizzy
- Shortness of breath (dyspnoea)
- change in the taste of things, loss of appetite, upset stomach or indigestion (dyspepsia), pain in the stomach area, bloating (flatulence), constipation
- itching and rash, severe itching or hives, excessive sweating (hyperhidrosis)
- joint pain or muscle aches
- Blood tests may show abnormal results due to liver problems (increased bilirubin) or kidneys (increased creatinine)
- General weakness
Rare (may affect up to 1 in 1,000 patients)
- easy bruising and bleeding due to a reduction in the number of platelets in the blood (thrombocytopenia)
- low white blood cell count (neutropenia)
- exaggerated immune response (hypersensitivity)
- decreased blood sugar levels (hypoglycaemia). This is important for those with diabetes
- seeing or hearing things that are not there (hallucinations, paranoia), changes of opinion and second thoughts (psychotic reactions) with the possibility of developing suicidal ideation or suicidal acts
- feeling depressed, mental problems, feelings of restlessness (agitation), abnormal dreams or nightmares
- tingling sensation in the hands and feet (paraesthesia)
- problems with hearing (tinnitus) or vision (blurred vision)
- unusually fast heartbeat (tachycardia) or low blood pressure (hypotension)
- muscle weakness. This is important for patients suffering from myasthenia gravis (a rare disease of the nervous system).
- altered kidney function and occasional kidney failure which may be caused by an allergic kidney reaction called interstitial nephritis
- fever
Other side effects include:
- decrease in red blood cells (anemia). This can lead to pale or yellow skin due to damage to red blood cells and a decrease in the number of all types of blood cells (pancytopenia).
- fever, sore throat and a general feeling of being unwell that does not go away. This may be due to a decrease in the number of white blood cells in the blood (agranulocytosis)
- lack of blood supply (anaphylactic-type shock)
- increased blood sugar levels (hyperglycemia) or decreased blood sugar levels leading to like (hypoglycemic coma). This is important for those with diabetes
- change in the smell of things, loss of smell or taste (parosmia, anosmia, ageusia) difficulty moving or walking (dyskinesia, extrapyramidal disorders)
- temporary loss of consciousness or posture (syncope)
- temporary loss of vision
- worsening or loss of hearing
- unusually fast heartbeat, life-threatening irregular heartbeat including cardiac arrest, changes in heartbeat (called "QT prolongation" seen on electrocardiogram, electrical activity of the heart)
- difficulty in breathing or wheezing (bronchospasm)
- allergic reactions affecting the lungs
- pancreatitis
- inflammation of the liver (hepatitis)
- increased sensitivity of the skin to the sun or ultraviolet rays (photosensitivity)
- inflammation of the vessels that carry blood throughout the body due to an allergic reaction (vasculitis)
- inflammation of the internal tissues of the mouth (stomatitis)
- breakdown of muscles and destruction of muscles (rhabdomyolysis)
- joint redness and swelling (arthritis)
- pain, including pain in the back, chest and extremities
- attacks of porphyria in patients who already suffer from porphyria (a very rare metabolic disorder)
- persistent headache with or without blurred vision (benign intracranial hypertension)
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
Keep out of the reach and sight of children.
This medicine does not require any special storage conditions but it is best to keep REFRAIN in the original blister and carton in a dry place.
Do not use this medicine after the expiry date which is stated on the carton and aluminum foil.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What REFRAIN contains
The active ingredient is levofloxacin. Each REFRAIN 250 mg tablet contains 250 mg of levofloxacin and each REFRAIN 500 mg tablet contains 500 mg of levofloxacin.
The other ingredients are:
- for the tablet core: microcrystalline cellulose, crospovidone, hypromellose, talc, magnesium stearate.
- for the coating: hypromellose, titanium dioxide, macrogol 400, talc, yellow iron oxide, red iron oxide.
Description of the appearance of REFRAIN and contents of the pack
Carton containing a blister of 5 tablets.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
REFRAIN TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each REFRAIN film-coated tablet contains 250 mg of levofloxacin, as the active ingredient, corresponding to 256.23 mg of levofloxacin hemihydrate.
Each REFRAIN film-coated tablet contains 500 mg of levofloxacin, as the active ingredient, corresponding to 512.46 mg of levofloxacin hemihydrate.
For the full list of excipients, see section 6.1 "List of excipients".
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Light peach film-coated tablet with a score line.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
REFRAIN is indicated in adults for the treatment of the following infections (see sections 4.4 "Special warnings and precautions for use" and 5.1 "Pharmacodynamic properties"):
• Acute bacterial sinusitis
• Acute exacerbation of chronic bronchitis
• Community-acquired pneumonia
• Complicated skin and soft tissue infections.
For the infections mentioned above REFRAIN should only be used when the use of antibacterial agents commonly recommended for the initial treatment of these infections is considered inappropriate.
• Pyelonephritis and complicated urinary tract infections (see section 4.4 "Special warnings and precautions for use")
• Chronic bacterial prostatitis
• Uncomplicated cystitis (see section 4.4 "Special warnings and precautions for use")
• Inhalation of anthrax: post-exposure prophylaxis and curative treatment (see section 4.4 "Special warnings and precautions for use")
REFRAIN can also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin.
Before prescribing REFRAIN, official guidelines on the appropriate use of antibacterial agents should be considered.
04.2 Posology and method of administration
REFRAIN tablets are administered once or twice a day. The dosage depends on the type, severity of the infection and the sensitivity of the pathogen believed to be causing the infection.
REFRAIN tablets can also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin. Given the bioequivalence of the oral and parenteral formulations, the same dosage can be used.
Dosage
The following doses of REFRAIN are recommended:
Dosage in patients with normal renal function (Creatinine clearance> 50 ml / min)
Special populations
Impaired renal function (Creatinine clearance ≤ 50ml / min)
* No additional doses are required after hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
Impaired liver function
No dose modification is required as levofloxacin is not metabolised to any relevant amount by the liver and is mainly excreted by the kidney.
Senior citizens
No dose modification is required in the elderly other than that imposed by considerations of renal function (See section 4.4 "Tendonitis and tendon rupture" And "Prolongation of the QT interval').
Pediatric population
REFRAIN is contraindicated in growing children and adolescents (see section 4.3 "Contraindications").
Method of administration
REFRAIN tablets should be swallowed without chewing with a sufficient amount of liquid. They can be divided along the score line to adjust the dose. The tablets can be taken with or between meals. REFRAIN tablets should be taken at least two hours before or after taking iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only didanosine formulations containing aluminum or magnesium buffers) and sucralfate, as their absorption may be reduced (see section 4.5 "Interactions with other medicinal products and other forms of interaction").
04.3 Contraindications
REFRAIN tablets must not be administered:
• to patients who have experienced hypersensitivity to levofloxacin or to other quinolones or to any of the excipients listed in section 6.1,
• to epileptic patients,
• to patients with a history of tendon disorders related to the administration of fluoroquinolones,
• to children or adolescents in the period of growth,
• to pregnant women,
• to women who are breastfeeding.
04.4 Special warnings and appropriate precautions for use
It is very likely that Staphylococcus aureus resistant to methicillin (MRSA) demonstrates cross-resistance to fluoroquinolones, including levofloxacin. Therefore levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed the organism's susceptibility to levofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA infections are considered inappropriate) .
Levofloxacin can be used in the treatment of acute bacterial sinusitis and acute flare-up of chronic bronchitis if these infections have been adequately diagnosed.
Resistance to fluoroquinolones of AND. coli - the pathogen most commonly involved in urinary tract infections - is variable in different areas of the European Union. Prescribers should take into account the local prevalence of resistance to AND. coli to fluoroquinolones.
Anthrax Inhalation: Use in humans is based on in vitro susceptibility data from Bacillus anthracis and on animal experiments together with limited human data. Prescribers should refer to national or international consensus documents on anthrax treatment.
Tendonitis and tendon rupture
Tendonitis can rarely occur. It most frequently involves the Achilles tendon and can lead to its tendon rupture. Tendonitis and tendon rupture, sometimes bilateral, can occur within 48 hours of starting levofloxacin therapy and have been reported for up to several months after the end of treatment. The risk of tendonitis and tendon ruptures is increased in patients with more than 60 years, in patients receiving daily doses of 1000 mg and in patients using corticosteroids. In elderly patients the daily dose should be adjusted according to creatinine clearance (see section 4.2 "Posology and method of administration"). Careful monitoring of these patients is therefore needed if levofloxacin is prescribed to them. All patients should consult their physician if they experience symptoms of tendonitis. If tendonitis is suspected, treatment with levofloxacin should be stopped immediately and specific measures should be taken for the affected tendon ( eg immobilization) (see sections 4.3 "Contraindications" and 4.8 "Undesirable effects erati ").
Clostridium difficile disease
If diarrhea occurs, particularly if severe, persistent and / or bleeding during or after levofloxacin therapy (even several weeks after treatment), this may be symptomatic of the disease. Clostridium difficile (CDAD). The severity of CDAD can range from mild to life-threatening; the most severe form is pseudomembranous colitis (see section 4.8 "Undesirable effects"). It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. In the event of suspected or confirmed CDAD, levofloxacin therapy should be discontinued immediately and immediate therapeutic measures implemented.
In this clinical context, products that inhibit peristalsis are contraindicated.
Patients predisposed to seizures
Quinolones can lower the seizure threshold and consequently can trigger seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section 4.3 "Contraindications") and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or in patients receiving concomitant therapy with active substances such as theophylline which reduce the cerebral seizure threshold (see section 4.5 "Interactions with other medicinal products and other forms of interaction"). In case of convulsions (see section 4.8 "Undesirable effects") the treatment with levofloxacin should be stopped.
Patients with glucose-6-phosphate-dehydrogenase deficiency
Patients with latent or known defects in glucose-6-phosphate dehydrogenase activity may be predisposed to haemolytic reactions when treated with quinolone class antibacterials. For this reason, if levofloxacin is to be used in this type of patient , the potential occurrence of haemolysis should be monitored.
Patients with renal impairment
Since levofloxacin is mainly excreted via the kidney, the doses of REFRAIN should be appropriately adjusted in case of renal impairment (see section 4.2 "Posology and method of administration").
Hypersensitivity reactions
Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (eg angioedema up to anaphylactic shock), occasionally after the initial dose (see section 4.8 "Undesirable effects"). Patients should immediately stop treatment and contact their doctor or go to the emergency room so that appropriate emergency treatments can be implemented.
Severe bullous reactions
Cases of severe bullous skin reactions such as Stevens-Johnson Syndrome or toxic epidermal necrolysis have been reported with levofloxacin (see section 4.8 "Undesirable effects"). Patients should be advised to contact their physician immediately if skin and / or mucosal reactions occur before continuing treatment.
Dysglycemia
As with all quinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia, have been reported, usually in diabetic patients who are on concomitant treatment with oral hypoglycemic agents (e.g. glibenclamide) or with insulin. Cases of hypoglycemic coma have been reported. It is recommended that blood glucose be monitored closely in diabetic patients (see section 4.8 "Undesirable effects").
Prevention of photosensitization
Photosensitivity has been reported during therapy with levofloxacin (see section 4.8 "Undesirable effects"). Patients are advised not to unnecessarily expose themselves to intense sunlight or U.V. artificial (eg sun lamp, solarium) during the treatment and for 48 hours after the end of the treatment in order to avoid the onset of photosensitization.
Patients treated with vitamin k antagonists
Due to a possible increase in coagulation test values (PT / INR) and / or bleeding in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are administered simultaneously (see section 4.5 "Interactions with other medicinal products and other forms of interaction").
Psychotic reactions
Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. These have, in very rare cases, progressed to suicidal thoughts and self-endangering behaviors, sometimes after only a single dose of levofloxacin (see section 4.8 "Undesirable effects"). If the patient develops these reactions, levofloxacin should be discontinued and appropriate measures instituted. Caution is advised if levofloxacin is to be used in psychotic patients or in patients with a history of psychiatric illness.
Heart ailments
Particular care should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for QT interval prolongation, such as:
• congenital long QT syndrome,
• concomitant use of drugs that are known to prolong the QT interval (eg class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics),
• incorrect electrolyte imbalance (eg hypokalaemia, hypomagnesaemia),
• heart disease (eg heart failure, myocardial infarction, bradycardia)
• Elderly patients and women may be more sensitive to QTc prolonging medicines. Therefore, special care should be taken when administering fluoroquinolones, including levofloxacin, to these populations.
• See section 4.2 "Posology and method of administration" - "Elderly", section 4.5 "Interactions with other medicinal products and other forms of interaction", section 4.8 "Undesirable effects" and section 4.9 "Overdose").
Peripheral neuropathy
Sensory or sensorimotor peripheral neuropathy, which can occur rapidly, has been reported in patients taking fluoroquinolones, including levofloxacin (see section 4.8 "Undesirable effects"). If the patient has symptoms of neuropathy, levofloxacin treatment should be stopped to prevent the development of an irreversible situation.
Hepatobiliary disorders
Cases of hepatic necrosis up to fatal hepatic failure have been reported with levofloxacin, mainly in patients with severe underlying diseases, such as sepsis (see section 4.8 "Undesirable effects"). Patients should be advised to discontinue treatment and contact their physician if signs and symptoms of liver distress develop, such as anorexia, jaundice, dark urine, itching, or palpation sensitive abdomen.
Exacerbation of myasthenia gravis
Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients withmyasthenia gravis. Post-marketing serious adverse reactions, including death and the need for respiratory support, have been associated with the use of fluoroquinolones in patients with myasthenia gravis. Levofloxacin is not recommended in patients with a history of myasthenia gravis.
Vision disorders
If vision becomes impaired or if any effects on the eyes occur, an ophthalmologist should be consulted immediately (see sections 4.7 "Effects on ability to drive and use machines" and 4.8 "Undesirable effects").
Superinfections
The use of levofloxacin, especially if prolonged, may result in the growth of non-sensitive organisms. If superinfection occurs during therapy, appropriate measures should be taken.
Interference with laboratory analysis
In patients treated with levofloxacin, the determination of opioids in urine may give false-positive results.To confirm positivity it may be necessary to perform the analysis by a more specific method.
Levofloxacin can inhibit the growth of Mycobacterium tuberculosis and, therefore, can give false negative results in the bacteriological diagnosis of tuberculosis.
04.5 Interactions with other medicinal products and other forms of interaction
Effect of other medicinal products on REFRAIN
Iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine
The absorption of levofloxacin is significantly reduced when REFRAIN tablets are administered concomitantly with iron salts, zinc salts, antacids containing magnesium or aluminum or didanosine (only didanosine formulations containing aluminum or magnesium buffers). Concomitant administration of fluoroquinolones with zinc-containing multi-vitamins appears to reduce oral absorption. It is therefore recommended that preparations containing divalent or trivalent cations, such as iron salts or antacids containing magnesium or aluminum or didanosine (only didanosine formulations containing aluminum or magnesium buffers) are not taken within 2 hours before or after taking REFRAIN tablets (see section 4.2 "Posology and method of administration"). Calcium salts have a minimal effect on the oral absorption of levofloxacin.
Sucralfate
Sucralfate significantly reduces the bioavailability of REFRAIN tablets when administered concurrently. Therefore in case of concomitant therapy it is recommended to administer sucralfate 2 hours after administration of REFRAIN tablets (see section 4.2 "Posology and method of administration").
Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs
No pharmacokinetic interactions between levofloxacin and theophylline were shown in a clinical study. However, a marked reduction in the seizure threshold may occur when quinolones are administered concomitantly with theophylline, NSAIDs or other agents capable of reducing this threshold.
Levofloxacin concentrations in the presence of fenbufen were 13% higher than those seen with administration of the drug alone.
Probenecid and cimetidine
Probenecid and cimetidine demonstrated a statistically significant effect on the elimination of levofloxacin.
Renal clearance of levofloxacin was reduced with cimetidine (24%) and probenecid (34%).
This is because both drugs are capable of blocking the secretion of levofloxacin in the renal tubules. However, at the doses used in clinical studies, the statistically significant kinetic differences are unlikely to be of clinical relevance.
Particular caution is required when levofloxacin is co-administered with medicinal products that may modify renal tubular secretion such as probenecid and cimetidine, especially in patients with impaired renal function.
Other relevant information
Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin are not changed in a clinically relevant way when levofloxacin is co-administered with the following medicinal products: calcium carbonate, digoxin, glibenclamide and ranitidine.
Effect of REFRAIN on other medicinal products
Cyclosporine
The half-life of ciclosporin is increased by 33% when administered concomitantly with levofloxacin.
Vitamin K antagonists
Increases in coagulation test values (PT / INR) and / or bleeding, which can be serious, have been reported in patients treated with levofloxacin in combination with a vitamin K antagonist (eg warfarin). Therefore, coagulation tests should be monitored in patients treated with vitamin K antagonists (see section 4.4 "Special warnings and precautions for use").
Drugs known to prolong the QT interval
Levofloxacin, like other fluoroquinolones, should be used with caution in patients taking drugs known to prolong the QT interval (eg class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4 "Special warnings and precautions). "use").
Other relevant information
In a pharmacokinetic interaction study, levofloxacin did not change the pharmacokinetics of theophylline (which is a substrate of CYP1A2), indicating that levofloxacin is not a CYP1AE inhibitor.
Other forms of interaction
Food
As there are no clinically relevant interactions with food, REFRAIN tablets can be administered regardless of concomitant food intake.
04.6 Pregnancy and lactation
Pregnancy
There are limited data on the use of levofloxacin in pregnancy. Animal reproduction studies have shown no direct or indirect hazardous effects of reproductive toxicity (see section 5.3 "Preclinical safety data"). However, in the absence of data in humans and due to experimental risks of damage by fluoroquinolones to the weight-bearing cartilages of the growing organism, levofloxacin should not be used in pregnant women (see sections 4.3 "Contraindications" and 5.3 ". preclinical safety ").
Feeding time
REFRAIN is contraindicated in women who are breastfeeding. There is insufficient information on the excretion of levofloxacin in human milk; however other fluoroquinolones are excreted in human milk. In the absence of human data and due to experimental risks of damage by fluoroquinolones to the weight-bearing cartilages of the growing organism, Levofloxacin must not be used in women in breastfeeding women (see sections 4.3 "Contraindications" and 5.3 "Preclinical safety data").
Fertility
Levofloxacin did not cause decreased fertility or reproductive outcomes in rats.
04.7 Effects on ability to drive and use machines
Some undesirable effects of levofloxacin (eg dizziness / vertigo, somnolence, visual disturbances) can alter the patient's ability to concentrate and react with consequent risk in situations where these skills are of particular importance (while driving cars and using machinery).
04.8 Undesirable effects
The information can be traced back to clinical studies carried out on more than 8300 patients and extensive post-marketing experience.
The frequencies in the table are defined according to the following convention:
very common: ≥ 1/10,
common: ≥ 1/100,
uncommon: ≥ 1/1000, ≤ 1/100,
rare: ≥ 1/10000, ≤ 1/1000,
very rare: ≤ 1/10000,
not known: not estimable from available data.
Within the different frequency groups, undesirable effects are reported in order of decreasing severity.
a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first administration
b Mucocutaneous reactions may sometimes occur even after the first administration
Other side effects associated with fluoroquinolone administration include:
• attacks of porphyria in patients with porphyria.
04.9 Overdose
According to animal toxicity studies or clinical pharmacology studies, conducted with doses higher than therapeutic doses, the most important symptoms that occur after acute overdose with REFRAIN tablets are those at the level of the Central Nervous System such as: confusion , dizziness, impaired consciousness, seizures, prolongation of the QT interval and gastrointestinal reactions such as: nausea, mucosal erosions.
Central nervous system effects including confusion, convulsions, hallucinations and tremor have been observed in post-marketing experience.
In case of overdose, symptomatic treatment should be taken. ECG monitoring should be performed for the possibility of prolongation of the QT interval. Antacids may be used for the protection of the gastric mucosa. Hemodialysis, including peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD), are not effective in remove levofloxacin. No specific antidotes are known.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: quinolone antibacterials, fluoroquinolones.
ATC code: J01MA 12.
Levofloxacin is a synthetic antibacterial belonging to the class of fluoroquinolones and is the S (-) enantiomer of the ofloxacin raceme.
Mechanism of action
As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.
PK / PD relationship
The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).
Resistance mechanism
Resistance to levofloxacin is acquired through a step-by-step process with target site mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms such as permeability barriers (common in Pseudominas aeruginosa) and efflux mechanisms may modify susceptibility to levofloxacin.
C "is cross-resistance between levofloxacin and other fluoroquinolones. Due to the particular mechanism of action there is generally no cross-resistance between levofloxacin and other classes of antibacterial agents.
Breakpoint
The MIC breakpoint values (mg / l), recommended by EUCAST for levofloxacin, according to which we distinguish susceptible microorganisms from those with sensitivity from those with intermediate sensitivity and those with intermediate sensitivity from resistant, are shown in the table below. .
Clinical breakpoints, expressed in MIC (minimum inhibitory concentration), for levofloxacin, recommended by EUCAST (version 2.0-01-01-2012):
The prevalence of resistance for selected species can vary geographically and with time. Information on the local prevalence of resistance is desirable, particularly when severe infections are to be treated.
As necessary, it is advisable to consult an expert in cases where the local prevalence of resistance phenomena is such as to question the usefulness of the product in at least some types of infections.
# S.Aureus resistant methicillin most likely possesses cross-resistance to fluoroquinolones, including levofloxacin.
05.2 Pharmacokinetic properties
Absorption
Administered orally, levofloxacin is rapidly and almost completely absorbed with a peak plasma concentration occurring within 1-2 hours.
Absolute bioavailability is approximately 99-100%.
Food has little effect on the absorption of levofloxacin.
Steady state is achieved within 48 hours with a 500 mg once or twice daily dosing regimen.
Distribution
The serum protein binding of levofloxacin is approximately 30-40%.
The mean volume of distribution of levofloxacin is approximately 100 l after single and repeated doses of 500 mg, indicating "wide distribution in body tissues".
Penetration into the tissues and liquids of the body :
Levofloxacin has been shown to penetrate bronchial mucosa, lining epithelial fluids, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue and urine.
However, levofloxacin has poor penetration into the cerebrospinal fluid.
Biotransformation
Levofloxacin is metabolised to a small extent to the desmethyl levofloxacin and levofloxacin N-oxide metabolites. These metabolites are
Elimination
Following oral and intravenous administration, levofloxacin is eliminated from plasma slowly (t ½: 6-8 hours).
Excretion is predominantly renal (> 85% of the administered dose).
The mean apparent total body clearance of levofloxacin following a single 500 mg dose is 175 +/- 29.2 mL / min.
Since there are no major pharmacokinetic differences following oral or intravenous administration, this suggests that the oral and intravenous routes of administration are interchangeable.
Linearity
Levofloxacin exhibits linear pharmacokinetics over the range of 50 to 1000 mg.
Special populations
Subjects with renal insufficiency
The pharmacokinetics of levofloxacin are affected by renal impairment. As renal function decreases, renal elimination and clearance are reduced, while the elimination half-life increases as described in the following table.
Pharmacokinetics in renal insufficiency after a single oral dose of 500 mg
Elderly subjects
There are no significant differences in levofloxacin kinetics between elderly and young subjects, except those associated with changes in creatinine clearance.
Differences between the sexes
Separate analyzes between male and female subjects revealed small and marginal differences in the pharmacokinetics of levofloxacin.
There is no evidence of the clinical relevance of these differences.
05.3 Preclinical safety data
Non-clinical data showed no particular hazard to humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential and toxicity for reproduction and development.
Levofloxacin did not cause impairment of fertility or reproduction in the rat and the only effect on the fetus was delayed maturation as a result of maternal toxicity.
Levofloxacin did not induce gene mutations in bacterial or mammalian cells, but did induce chromosomal aberrations in Chinese hamster lung cells in vitro. These effects can be attributed to the inhibition of topoisomerase II.
In vivo tests (micronucleus, cell chromatid exchange, unscheduled DNA synthesis, dominant lethal test) do not show any genotoxic potential.
Studies in mice have shown a phototoxic activity of levofloxacin only at very high doses.
Levofloxacin shows no potential genotoxic activity in photomutagenesis tests while it reduces tumor development in photocarcinogenesis tests.
As with other fluoroquinolones, levofloxacin showed some effects on cartilage (bubbles and cavities) in rats and dogs, especially in young animals.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
REFRAIN film-coated tablets contain the following ingredients:
Core of the tablet:
Microcrystalline cellulose, crospovidone, hypromellose, talc, magnesium stearate.
Coating: Hypromellose, macrogol 400, titanium dioxide (E 171), talc, yellow iron oxide (E 172), red iron oxide (E 172).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Cardboard box and PVC / Aluminum blister containing 5 tablets.
06.6 Instructions for use and handling
As with all medicines, the unused medicine and the waste derived from it must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
NEOPHARMED GENTILI S.r.l.
Via S.G. Cottolengo, 15 - 20143 Milan
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 040131017 REFRAIN 250 mg film-coated tablets - 5 tablets
AIC n. 040131029 REFRAIN 500 mg film-coated tablets - 5 tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
AIFA determination of 4/10/2011
10.0 DATE OF REVISION OF THE TEXT
March 2015
