Levofloxacin (When ATH S01AX19)

When ATH:
S01AX19

Characteristic.

Synthetic chemotherapeutic agent, fluorinated karboksihinolon, free from impurities S-enantiomer of racemic compounds — HP ofloxacin. Bright from yellowish white to yellowish-white crystals or crystalline powder. Molecular weight 370,38. The easily soluble in water at pH 0,6-6,7. The molecule exists in the form of Amphion at pH values, relevant environment of the small intestine. It has the ability to form stable compounds with many metals ions. The ability to form chelates in vitro decreases in the following order: To the⁺³>With⁺²>Zn⁺²>Mg⁺²>Ca⁺².

Pharmacological action.
Broad-spectrum antibacterial, bactericide.

Application.

According to Physicians Desk Reference (2009), levofloxacin oral and / in the introduction is indicated for the treatment of lung, moderate and severe infections, caused by susceptible strains of mikrooorganizmov, adult patients (18 and older).

Nosocomial pneumonia, caused by methicillin-susceptible strains Staphylococcus aureus, Pseudomonas aeruginosa, Serratia wilting, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae or Streptococcus pneumoniae. If Pseudomonas aeruginosa It is established or suspected pathogen, recommended combination therapy with a beta-lactam antibiotic, is active against Pseudomonas aeruginosa.

Community-acquired pneumonia (7-14-Day dosing regimen), caused by methicillin-susceptible strains Staphylococcus aureus, Streptococcus pneumoniae (including multirezistentne strains — MDRSP *), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Chlamydia pneumoniae or Mycoplasma pneumoniae.

Community-acquired pneumonia (5-day dosing regimen), caused Streptococcus pneumoniae (excluding MDRSP), Haemophilus influenzae, Haemophilus parainfluenzae, Chlamydia pneumoniae or Mycoplasma pneumoniae.

Ostryi baktyerialinyi sinusitis (5- and 10-14-day dosing regimens), caused Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis.

Exacerbation of chronic bronchitis, associated with bacterial infection (methicillin-susceptible strains Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis).

Complicated infections of the skin and its appendages, caused by methicillin-susceptible strains Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes or Proteus is wonderful.

Uncomplicated infections of the skin and its appendages (mild to moderate severity), including abscess, pannykulyt, furunkul, impetigo, pyoderma, wound infection, caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes.

Chronic bacterial prostatitis, caused Escherichia coli, Enterococcus faecalis or methicillin Staphylococcus epidermidis.

Complicated urinary tract infections (5-day dosing regimen), caused Escherichia coli, Klebsiella pneumoniae or Proteus is wonderful.

Complicated urinary tract infections (mild to moderate severity, 10-day dosing regimen), caused Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus is wonderful, Pseudomonas aeruginosa.

Acute pyelonephritis (mild to moderate severity, 5- and 10-day dosing regimens), caused Escherichia coli, including cases with concurrent bacteremia.

Uncomplicated urinary tract infections (mild to moderate severity), caused Escherichia coli, Klebsiella pneumoniae or Staphylococcus saprophyticus.

* — strains with multiple antibiotic resistance (Multi-drug resistant Streptococcus pneumoniae - MDRSP), including strains, formerly known as PRSR (Penicillin-resistant S. pneumoniae), strains and, resistant to two or more of the following antibiotics: penicillin (BMD at ≥2 mg / ml), II generation cephalosporins (eg cefuroxime), makrolidы, tetracyclines and trimethoprim / sulfamethoxazole.

According to Physicians Desk Reference (2009), levofloxacin in the form 0,5% eyedrops is indicated for the treatment of bacterial conjunctivitis, caused by the following susceptible microorganisms: Aerobic gram-positive microorganisms (Corynebacterium spp., Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus (group C/F), Streptococcus (Group G), Streptococcus viridans), Aerobic gram-negative microorganisms (Acinetobacter Iwoffii, Haemophilus influenzae, Serratia wilting.

Contraindications.

Hypersensitivity (incl. to other quinolones).

Restrictions apply.

Age to 18 years (Safety and efficacy have not been determined); it should be understood, levofloxacin that cause arthropathy and osteochondrosis in young growing animals of different species. Carefully: Confirmed or suspected CNS disorders, accompanied by a predisposition to seizures or lowering the threshold of convulsive readiness (epilepsy, severe cerebral arteriosclerosis); the presence of other risk factors for seizures or lower the threshold of convulsive readiness (concomitant use of some drugs, impairment of renal function); Simultaneous treatment with corticosteroids (the increased risk of tendinitis), nedostatochnosty glucose-6-fosfatdegidrogenazы (possible hemolysis).

In ophthalmology: Age to 1 year (Safety and efficacy have not been determined).

Pregnancy and breast-feeding.

Application during pregnancy is possible only in case of, if the effect of therapy outweighs the potential risk to the fetus (Adequate strictly controlled safety studies in pregnant women have not been conducted).

Levofloxacin was not tertogennogo action in rats when administered in the dose 810 mg / kg / day (in 9,4 MRDC times based on body surface area) or in/in a dose of 160 mg / kg / day (in 1,9 MRDC times based on body surface area). Oral administration of pregnant rats at the dose of 810 mg/kg/day resulted in increased frequency of fetal death and reduce body weight of fruits. In experiments on rabbits have been detected tertogennogo action when administered at a dose of 50 mg / kg / day (in 1,1 times higher than MRDC, based on body surface area) or in/in a dose of 25 mg / kg / day, corresponding 0,5 MRDC, based on body surface area.

Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)

Levofloxacin was not detected in breast milk, but, taking into account the results of studies of ofloxacin, We can assume, levofloxacin that can penetrate into the breast milk of nursing women, and cause serious side effects in children, breastfed. Nursing women should stop any breastfeeding, or levofloxacin (Considering the importance of the drug to the mother).

Side effects.

The frequency of adverse reactions, associated with levofloxacin, in clinical trials Phase 3, conducted in North America, made 6,3%. Therapy was discontinued due to the occurrence associated with taking the drug side effects in 3,9% patients.

In clinical studies, the following side effects were considered likely related to levofloxacin: nausea (1,3%), diarrhea (1%), vaginitis (0,7%), insomnia (0,5%), abdominal pain (0,4%), flatulence (0,4%), itching (0,4%), dizziness (0,3%), dyspepsia (0,3%), rash (0,3%), Genital candidiasis (0,2%), taste disturbance (0,2%), vomiting (0,2%), constipation (0,1%), fungal infection (0,1%), itching in the genital area (0,1%), headache (0,1%), thrush (0,1%), nervousness (0,1%), erythematous rash (0,1%), hives (0,1%).

In clinical studies, the following side effects were observed without regard to medication.

From the nervous system and sensory organs: headache (6,4%), insomnia (4,6%), dizziness (2,7%), fatigue (1,2%) violation of taste sensitivity (1%); <1%: asthenia, incoordination, coma, convulsions, speech disorder, stupor, tremor, vertigo, confusion, aggression, excitation, anxiety, anorexia, delirium, depression, emotional lability, hallucinations, impaired concentration, craze, nervousness, paranoia, aphronia, unusual dreams, sleep disturbance, somnolence, diplopia, cerebrovascular disorders, noise in ears, hearing and visual impairment, conjunctivitis, parosmija.

Cardio-vascular system and blood <1%: hypertension, gipotenziya (incl. orthostatic), heart failure, circulatory failure, arrhythmia, bradycardia, tachycardia, Blockade, cardiac arrest, supraventricular tachycardia, ventricular fibrillation and atrial, palpitation, angina, koronarnыy thrombosis, myocardial infarction, thromboembolism, phlebitis, pathology of platelets, nose bleed, purpura, thrombocytopenia, leukocytosis, leukopenia, lymphopenia, granulocytopenia, lymphadenopathy.

From the respiratory system: sinusitis (1,3%), rhinitis (1%); <1%: asthma, acute respiratory distress syndrome, cough, hemoptysis, breathlessness, gipoksiya, pleural effusion, respiratory insufficiency.

From the digestive tract: nausea (7,2%), diarrhea (5,6%), constipation (3,2%), abdominal pain (2,5%), dyspepsia (2,4%), vomiting (2,3%), flatulence (1,5%); <1%: dry mouth, dysphagia, swelling of the tongue, gastroenteritis, gastrointestinal bleeding, psevdomembranoznыy colitis, pechenochnaya coma, LDH increase, jaundice, abnormal liver function, cholelithiasis.

With the genitourinary system: vaginitis (1,8%); <1%: itching in the genital area, abnormal ejaculation, impotence, increase in serum creatinine, decreased kidney function, acute renal failure, hematuria.

On the part of the musculoskeletal system <1%: arthralgia, arthritis, arthrosis, muscular weakness, myalgia, osteomyelitis, synovitis, Tendinitis, raʙdomioliz, hyperkinesis, involuntary muscle contractions, increased muscle tone, paraesthesia, paralysis.

For the skin: itch (1,3%), rash (1,2%); <1%: uzlovataya эritema, peeling of the skin, skin ulceration, hives, increased perspiration.

Other: local reaction (3,5%), pain (1,7%) and inflammation (1,1%) at the injection site; pain (1,4%), chest pain (1,2%) and back (1,1%); <1%: hyperkalemia, kaliopenia, degidratatsiya, gipoglikemiâ, giperglikemiâ, worsening of diabetes, weight loss, cancer, fever, swelling of the face, withdrawal.

In post-marketing studies It reported the following side effects: hypersensitivity pneumonitis, anaphylactic shock, anaphylactoid reactions, disfonija, abnormal EEG, encephalopathy, eozinofilija, erythema multiforme, gemoliticheskaya anemia, multiple organ failure, an increase in the international normalized ratio (INR), Stevens-Johnson syndrome, tendon rupture, torsades de pointes, vasodilation.

Below are data 29 United clinical trials Phase 3 (n=7537). The average age of patients is 50 years (about 74% patients younger than 65 years), 50% -men, 71% -European race, 19% -Black. Patients received levofloxacin in the treatment of various infections at a dose 750 mg 1 once a day, 250 mg 1 once a day or 500 mg 2 once a day. Duration of therapy is usually 3-14 days (average 10 days).

The overall incidence of, the type and distribution of adverse reactions were similar in patients, treated with levofloxacin in the dose 750 mg 1 once a day, compared to patients, received on 250 mg 1 once a day or 500 mg 2 once a day. Therapy was discontinued due to the occurrence associated with taking the drug side effects in 4,3% Patients generally, in 3,8% patients, taking doses 250 and 500 mg, and 5,4% patients, taking 750 mg. The most common side effects, leading to discontinuation, at doses 250 and 500 mg were gastrointestinal complaints (1,4%), nausea (0,6%), vomiting (0,4%), dizziness (0,3%), headache (0,2%). The most common side effects, leading to discontinuation, at a dose 750 mg were gastrointestinal disorders (1,2%), nausea (0,6%), vomiting (0,5%), dizziness (0,3%), headache (0,3%).

Below are the side effects, noted in clinical trials, and observed with a frequency of more than 0,1%.

From the nervous system and sensory organs: headache (6%), dizziness (3%), insomnia (4%); 0,1–1%: alarm, ažitaciâ, confusion, depression, hallucinations, nightmares, sleep disturbance, anorexia, unusual dreams, tremor, convulsions, paraesthesia, vertigo, hypertension, hyperkinesia, dystaxia, drowsiness, fainting.

Cardio-vascular system and blood: 0,1–1%: anemia, arrhythmia, heartbeat, cardiac arrest, supraventricular tachycardia, phlebitis, nose bleed, thrombocytopenia, granulocytopenia.

From the respiratory system: breathlessness (1%).

From the digestive tract: nausea (7%), diarrhea (5%), constipation (3%), abdominal pain (2%), dyspepsia (2%), vomiting (2%); 0,1–1%: gastritis, stomatitis, pancreatitis, esophagitis, gastroenteritis, glossitis, psevdomembranoznыy colitis, abnormal liver function, elevated liver enzymes, increase in AP.

With the genitourinary system: vaginitis (1%); 0,1–1%: impairment of renal function, acute renal failure, Genital candidiasis.

On the part of the musculoskeletal system: 0,1–1%: arthralgia, Tendinitis, myalgia, pain in skeletal muscle.

For the skin: rash (2%), itch (1%); 0,1–1%: allergic reactions, Eden (1%), hives.

Other: candidiasis (1%), site reaction in / in (1%), chest pain (1%); 0,1–1%: gipoglikemiâ / giperglikemiâ, hyperkalemia.

In post-marketing studies It reported the following side effects.

From the nervous system and sensory organs: individual reports of encephalopathy, EEG abnormalities, peripheral neuropathy, psychosis, paranoia, isolated reports of suicide attempts and suicidal thoughts, blurred vision (incl. diplopia, reduced visual acuity, blurred vision, scotoma), hearing loss, tynnyt, parosmija, anosmia, loss of taste sensation, dysgeusia, disfonija.

Cardio-vascular system and blood: anecdotal reports twist of points, QT prolongation, tachycardia, vasodilation, an increase in INR, extension of prothrombin time, pancytopenia, aplasticheskaya anemia, leukopenia, gemoliticheskaya anemia, eozinofilija.

From the digestive tract: hepatic failure (including fatal cases), hepatitis, jaundice.

On the part of the musculoskeletal system: tendon rupture, muscle injury, including the gap, raʙdomioliz.

For the skin: bullous rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, photosensitivity / phototoxicity reactions.

Allergic reactions: hypersensitivity reactions (sometimes fatal), incl. anaphylactic / anaphylactoid reaction, anaphylactic shock, angioedema, syvorotochaya disease; individual reports of hypersensitivity pneumonitis.

Other: vasculitis, increased activity of muscle enzymes, hyperthermia, multiorgan failure, interstitial nephritis.

When applied in the form of levofloxacin 0,5% eye drops most frequently reported effects were: 1-3% are transient impairment, transient burning, pain or discomfort in the eye, foreign body sensation in the eye, fever, headache, pharyngitis, photophobia; <1% - Allergic reactions, swelling of the eyelids, dry eyes, itchy eyes.

Cooperation.

Loosen effect, reducing absorption from the gastrointestinal tract and the systemic concentration: sucralfate, magnesium- and aluminum-containing antacids, iron salts, zinc-containing multivitamins, didanosine (chewable / soluble tablets and powders for preparation of children's oral solutions) — It is necessary to observe an interval of not less than 2 hours between taking the above tools and levofloxacin.

There were no clinically significant effect on the pharmacokinetics of levofloxacin cyclosporin (It reported an increase of plasma levels of cyclosporine under the influence of other quinolones). Levofloxacin had no significant effect on the pharmacokinetics of theophylline, and vice versa.

In clinical studies in healthy volunteers were observed significant drug interactions between levofloxacin and theophylline. But, since the simultaneous use of theophylline with other quinolones accompanied by an increase in T_1/2 and serum concentrations of theophylline and a consequent increase in the risk of theophylline-dependent adverse reactions, while the application of levofloxacin and theophylline is necessary to conduct a thorough monitoring of theophylline and the appropriate dose adjustment. Adverse Reactions, incl. convulsions, may occur regardless of increasing serum theophylline.

In studies in healthy volunteers were observed significant drug interactions between levofloxacin and R- or S-isomers of warfarin. In post-marketing studies have reported cases, increase the effect of warfarin while the use of levofloxacin, The increase in prothrombin time was accompanied by episodes of bleeding. With simultaneous use of levofloxacin and warfarin should be closely monitored INR, prothrombin time and other coagulation parameters, and a monitoring of possible signs of bleeding.

Cimetidine and probenecid increase the AUC and T_1/2 levofloxacin and reduce its clearance (dose adjustment, while the appointment is not required).

NSAIDs may increase the risk of CNS stimulation and occurrence of seizures.

In diabetic patients, receiving oral hypoglycemic agents or insulin, in patients receiving levofloxacin possible hypo- and hyperglycemic state (we recommend careful monitoring of blood glucose).

Overdose.

Mice, rats, dogs and monkeys following administration of high doses of levofloxacin following symptoms: ataxia, ptosis, reduction in locomotor activity, breathlessness, prostration, tremor, convulsions. Doses, exceeding 1500 mg/kg inside and 250 mg/kg//much increased mortality in rodents.

Treatment Acute overdose: gastric lavage, adequate hydration. Not reported by hemodialysis and peritoneal dialysis.

Dosing and Administration.

Inside, I /, konъyunktyvalno Inside: without regard to food intake, 250-500 mg 1 once a day. B /: the slow drip 250-750 mg every 24 no (dose is 250-500 mg is injected for the 60 m, 750 mg for 90 m). Possible subsequent transition to oral at the same dose. The duration of treatment depends on the indications for use. If the kidney function requires an adjustment mode of administration, incl. dose reduction as a function of creatinine clearance. Konъyunktyvalno: during the first two days — buried in the affected eye during wakefulness — every 2 h 1-2 drops, to 8 once a day; then drop every 1-2 4 no, to 4 once a day. The duration of treatment is determined by the physician and generally 5 Nights.

Precautions.

It reported the occurrence of seizures and toxic psychosis in patients, receiving quinolones, incl. levofloxacin. Quinolones may also cause increased intracranial pressure and stimulation of the central nervous system with the appearance of tremor, worry, alarm, confusion, gallyutsinatsii, paranoji, depression, sleep disorders, rarely, suicidal thoughts and actions; These phenomena can occur after the first dose.

In clinical trials of other quinolones using multiple doses patients were marked ophthalmic disorders, including cataracts, Multiple point clouding of the lens. The relationship between these events and taking drugs is not installed.

It was reported on the development of severe or fatal hypersensitivity reactions and anaphylactic reactions in patients receiving quinolones, incl. levofloxacin, often developing after the first dose. Some reactions were accompanied by cardiovascular collapse, gipotenzieй, shock, cramps, loss of consciousness, tingling, angioedema (including language, throat, glottis, or swelling of the face), airway obstruction (bronchospasm, shortness of breath, acute respiratory distress syndrome), shortness of breath, krapivnicej, zudom, and other skin reactions. It was reported on the development of severe and fatal reactions in patients in patients receiving quinolones, incl. levofloxacin, due both to hypersensitivity reactions, and unknown causes; These reactions occurred mainly after administration of repeated doses and manifest in the form of the following symptoms: fever, rash or severe dermatologic reactions (acute epidermal necrolysis, Stevens-Johnson syndrome), vasculitis, arthralgia, myalgia, serum sickness, hypersensitivity pneumonitis, interstitial nephritis, acute renal failure, hepatitis, jaundice, acute liver necrosis and hepatic failure, anemia (incl. hemolytic and hypoplastic), thrombocytopenia (incl. trombotsitopenicheskaya purpura), leukopenia, agranulocytosis, pancytopenia, other changes in the blood. At the first signs of skin rash or other manifestations of hypersensitivity levofloxacin should be immediately repealed and the necessary measures.

Severe hepatotoxicity, recorded in the postmarketing surveillance (including acute hepatitis and fatal outcomes) typically occurs in the first 14 days of treatment, the majority of cases within 6 days. They most often observed in patients aged 65 and older and are not associated with hypersensitivity.

It is necessary to bear in mind the possibility of pseudomembranous colitis, if the patient has diarrhea occurs in patients receiving antibacterial agents. Treatment antibacterial agents leads to modification of the normal colonic flora, and can lead to increased growth of clostridia. If the diagnosis "pseudomembranous colitis", Levofloxacin should be abolished and start appropriate treatment.

Cases of tendon rupture shoulder, hands, Achilles tendon, require surgical treatment or leads to a prolonged disruption of limb function, patients, receiving quinolones, incl. levofloxacin. In posmarketingovyh studies noted an increased risk of tendon rupture in the background simultaneously receiving corticosteroids, especially in elderly patients. When the pain, inflammation, or rupture of a tendon levofloxacin should be lifted immediately; the patient should be at rest and avoid stress to the complete exclusion of the diagnosis "tendinitis" or "tendon rupture". Tendon rupture is possible both during treatment quinolones (incl. levofloxacin), and after completion of treatment.

Despite the fact that the solubility of levofloxacin above, than other quinolones, It is necessary to maintain adequate hydration during treatment with levofloxacin in order to avoid an excessively concentrated urine.

The caution is indicated for kidney failure; since the elimination of levofloxacin may be reduced, careful clinical observation and appropriate laboratory studies should be performed before and during therapy. In patients with decreased renal function (Cl creatinine < 50 ml / min) in order to avoid accumulation of dose adjustment is necessary.

Patients, exposed to direct sunlight during the treatment of a number of quinolone drugs, phototoxic reactions were observed moderate and severe. In clinical studies, phototoxic reactions observed in less than 0,1% patients, treated with levofloxacin.

In patients receiving quinolones, incl. levofloxacin, It noted an increase in the QT interval on the electrocardiogram, and rare cases of arrhythmia. In post-marketing studies have reported rarely flicker-ventricular flutter patients, treated with levofloxacin. Do not appoint levofloxacin at the same time by other means, prolonging the QT interval, incl. antiarrhythmics IA and Class III. If a patient has risk factors for flicker-ventricular flutter, such as hypokalemia, vыrazhennaya bradycardia, cardiomyopathy, Levofloxacin should be avoided.

As the reception of other quinolones, It reported about changes (violations) Blood Glucose, including symptomatic hyper-- and gipogilikemiyu, in most cases it is observed in diabetic patients, while receiving perooralnye hypoglycemic agents (such as glyburide) or insulin. It is recommended that careful monitoring of blood glucose levels in these patients. If background levofloxacin developed hypoglycemic reaction, Levofloxacin should be lifted immediately and start appropriate therapy.

As well as receiving any strong antimicrobial drugs, periodic evaluation of suitable functions of body systems, including kidney, hepatic, hematopoietic.

Patients should be warned:

- The advisability of increasing fluid intake;

- About, that levofloxacin can cause neurological side effects (such as dizziness of varying severity), in connection with the patient should know, it responds to levofloxacin, before they engage in activities, requiring quick response and related high concentration of attention;

- During treatment should avoid strong sunlight or artificial UV radiation; when a phototoxic reactions (eg, skin rash) you need to stop treatment.

Cautions.

Prior to initiation of therapy should be carried out appropriate tests to identify the causative agent of the disease and assess the sensitivity to levofloxacin. Treatment with levofloxacin may be initiated before the results of these tests. After receiving the results of tests must be chosen appropriate therapy. Conducted periodically during therapy with levofloxacin testing culture provides information on the continuing sensitivity of the pathogen to levofloxacin and the possible emergence of bacterial resistance.

Cooperation