Reforet – infusion solution

INSTRUCTIONS FOR MEDICAL USE

REFORET®

Trade name of the drug: REFORET ®.

Active ingredients (INN): ornidazole, levofloxacin

Dosage form: solution for infusion

Contents:

1 ml of the solution contains:

Active ingredients: ornidazole 5 mg, levofloxacin 2.5 mg;

Excipients: edetate disodium, sodium chloride, hydrochloric acid or sodium hydroxide, water for injection.

Description: colorless or light yellow transparent solution.

Pharmacotherapeutic group: antimicrobial agents

ATX code: J01RA05.

Pharmacological properties of Levofloxacin

Pharmacodynamics

Levofloxacin is a synthetic antibacterial drug from the group of fluoroquinolones and an S enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action

As an antibacterial drug from the group of fluoroquinolones, levofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.

Pharmacokinetics/pharmacodynamics ratio

The degree of bacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or area under the pharmacokinetic curve (AUC) to the minimum inhibitory concentration (MIC (MPC)).

Mechanism of Resistance

The primary mechanism of resistance is due to a mutation in the gyr-A gene. In vitro there is cross-resistance between levofloxacin and other fluoroquinolones.

Due to the mechanism of action there is usually no cross-resistance between levofloxacin and other classes of antibacterial agents.

Antibacterial spectrum

The prevalence of resistance may vary geographically and over time for selected species, and local information on resistance is desirable, especially when treating severe infections. Specialist advice should be sought when the local prevalence of resistance is such that the usefulness of the drug, at least for certain types of infections, is questionable.

Generally, the susceptible species are.

Aerobic Gram-positive bacteria.

Staphylococcus aureus methicillin-sensitive, Staphylococcus saprophyticus, Streptococci, group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes Aerobic Gram-negative bacteria

Burkholderia cepacia, Eikenella corrodens, Haemophilus influenzae, Haemophilus para- influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri

Anaerobic bacteria

Peptostreptococcus

Others

Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamidia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum

Species for which acquired (secondary) resistance may be problematic

Aerobic Gram-positive bacteria

Enterococcus faecalis, Staphylococcus aureus methylinresistant, Staphylococcus coagulase spp.

Aerobic Gram-negative bacteria

Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens

Anaerobic bacteria

Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotamicron, Bacteroides vulgatus, Clostridium difficile

Other data

Hospital infections caused by P. aeruginosa may require combination therapy.

Pharmacokinetics

Absorption

There are no significant differences in the pharmacokinetics of levofloxacin after intravenous and oral administration.

After intravenous administration the drug accumulates in the mucous membrane of the bronchi and bronchial secretion of lung tissue (concentration in lung exceeds that in blood plasma), urine. Cerebrospinal fluid does not readily absorb levofloxacin.

Distribution

Approximately 30-40% of levofloxacin is bound to serum protein. There is virtually no cumulative effect of levofloxacin with multiple administration of 500 mg once daily. There is a minor but presumed cumulative effect after administration of 500 mg twice daily doses. Stable condition is achieved within 3 days.

Penetration into tissues and body fluids

Penetration into bronchial mucosa, bronchial secretion of lung tissue (BSTL)

Maximum concentration of levofloxacin in bronchial mucosa and lung bronchial secretion after oral administration of 500 mg was 8.3 µg/g and 10.8 µg/ml, respectively. These values were reached within one hour after drug administration. Penetration into lung tissue

Maximum concentration of levofloxacin in lung tissue after oral administration of 500 mg was approximately 11.3 µg/g and was reached 4-6 hours after drug administration. Concentrations in the lungs are higher than in blood plasma.

Penetration into the bladder content

Maximal concentration of levofloxacin 4-6.7 mcg/ml in vesicular contents was reached 2-4 hours after 3 days of using the drug in doses of 500 mg once or twice a day, respectively.

Penetration into cerebrospinal (cerebrospinal) fluid

Levofloxacin poorly penetrates into cerebrospinal fluid.

Penetration into prostate tissue

After administration of 500 mg of levofloxacin once daily for 3 days, mean prostate tissue concentrations reached 8.7 µg/g, 8.2 µg/g, and 2 µg/g after 2 hours, 6 hours, and 24 hours, respectively; the mean prostate/plasma concentration ratio was 1.84.

Urinary concentrations.

Mean urinary concentrations 8 to 12 hours after a single oral dose of 150 mg, 300 mg, and 500 mg of levofloxacin were 44 mg/L, 91 mg/L, and 200 mg/L, respectively.

Biotransformation

Levofloxacin is metabolized to a very small extent, the metabolites being dismethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the drug excreted in the urine. Levofloxacin is stereochemically stable and is not subject to choral inversion.

Excretion

After oral and intravenous administration, levofloxacin is excreted relatively slowly from blood plasma (half-life is 6-8 hours). It is usually excreted by the kidneys (85% of the administered dose).

There are no significant differences in levofloxacin pharmacokinetics after intravenous and oral administration, which indicates that these routes of administration (oral and intravenous) are interchangeable.

Linearity

Levofloxacin follows linear pharmacokinetics in the 50-600 mg range.

Patients with renal impairment

The pharmacokinetics of levofloxacin are affected by renal insufficiency. With decreased renal function, renal excretion and clearance are decreased and half-lives are prolonged.

Elderly patients

There are no significant differences in the pharmacokinetics of levofloxacin in younger and elderly patients, except for differences related to creatinine clearance.

Gender differences

A separate analysis for female and male patients demonstrated little difference in the pharmacokinetics of levofloxacin by gender. There is no evidence that these gender differences are clinically significant.

Ornidazole

Pharmacodynamics

The mechanism of action of ornidazole is associated with disruption of DNA structure in susceptible microorganisms. Ornidazole is active against Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia (Giardia intestinalis), and some anaerobic bacteria, such as Bacteroides, Fusobacterium spp.; anaerobic gram-positive bacteria Clostridium spp., sensitive strains of Eubacterium spp.; anaerobic gram-positive cocci Peptococcus spp., Peptostreptococcus spp.

It easily penetrates into microbial cell and by binding to DNA disrupts replication process.

Pharmacokinetics

Ornidazole penetrates well through the blood-brain and placental barriers, enters cerebrospinal fluid, bile, and is excreted with breast milk. When administered intravenously at a dose of 15 mg/kg and further administered at a dose of 7.5 mg per 1 kg every 6 hours, the equilibrium concentration is 18-26 µg/ml. About 30-60% of the drug is metabolized in the body by hydroxylation, oxidation and glucuronidation.

Excretion. Ornidazole is mainly excreted in the urine (60-80%), almost 20% is excreted unchanged, 6-15% – in the faeces.

Indications for use

Treatment of mixed urinary tract infections caused by pathogens (microorganisms and protozoa) sensitive to the drug components.

Prevention of pyo-inflammatory complications after gynecological surgery. Treatment of acute respiratory tract infections.

Dosage and administration method.

The drug is used intravenously by drip.

A daily dose of the drug is 100 ml (500 mg of ornidazole and 250 mg of levofloxacin). The duration of treatment depends on the course of the disease. After the condition has stabilized, it is necessary to switch to oral administration of levofloxacin and ornidazole. Treatment should be continued for 48-72 hours after disappearance of clinical symptoms or laboratory confirmation of pathogen disappearance.

Maximal daily dose of the drug is 200 ml (1000 mg of ornidazole and 500 mg of levofloxacin) in 1-2 injections per day in case of severe infection.

Dosage for adult patients with impaired renal function with creatinine clearance less than 50 ml/min (dose is calculated using levofloxacin):

Creatinine clearanceDosage regime
  50-20 ml/minfirst dose – 250 mg
next – 125 mg/24h
first dose – 500 mg
next – 250 mg/24h
first dose – 500 mg next – 250 mg/12h
  19-10  ml/minfirst dose – 250 mg
next – 125 mg/48h
first dose – 500 мг
next – 125 мг/24h
first dose – 500 mg
next– 125 mg/12h
  10 ml/min (as well as in hemodialysis and CAPD 1)first dose – 250 mg next– 125 mg/48h first dose – 500 mg next– 125 mg/24hfirst dose – 500 mg
next– 125 mg/24h

1 – No additional doses are needed after hemodialysis or chronic ambulatory peritoneal dialysis (CAPD).

Dosing for patients with impaired liver function. No dosage adjustment is required since levofloxacin is slightly metabolized in the liver.

Dosage for elderly patients. If renal function is not impaired there is no need for dose adjustment. The solution for intravenous administration is administered intravenously slowly by drop infusion. The duration of infusion of 100 ml of the solution (500 mg of ornidazole and 250 mg of levofloxacin) shall be at least 60 minutes.

According to the patient’s condition, after a few days it is possible to switch from intravenous administration to oral administration with the same dosage.

The duration of treatment depends on the course of the disease. As with other antibacterials, it is recommended to continue treatment for at least 48-72 hours after body temperature normalization or killing of pathogens by microbiological tests.

Side effects

Adverse reactions are described according to the MedRA organ system classes listed below. The frequency is determined based on this convention: very frequently (≥1/10), frequently (≥1/100, <1/10), infrequently (≥1/1000, ≤1/100), rarely (≥1/10000, ≤1/1000), very rarely (≤1/10000), unknown (cannot be estimated from available data).

Blood and lymphatic system disorders

Infrequent: leukopenia, eosinophilia.

Rare: thrombocytopenia, neutropenia.

Very rarely: agranulocytosis.

Unknown: pancytopenia, hemolytic anemia.

Immune system disorders

Very rare: anaphylactic shock with signs such as urticaria, bronchospasm, and possibly severe choking.

Anaphylactic and anaphylactoid reactions may sometimes occur after the first dose.

Mental health effects

Infrequent: insomnia, nervousness.

Rare: psychotic disorders, depression, confusion, anxiety, agitation, restlessness.

Very rare: psychotic reactions with self-destructive behavior, including suicidal tendencies in thinking or acting, hallucinations.

Nervous system disorders

Infrequent: dizziness, headache, somnolence.

Rare: seizures, tremor, paresthesias, rigidity, coordination disorders.

Very rare: sensory or sensorimotor peripheral neuropathy, dysgeusia (subjective taste disorder), including agueusia (loss of taste), parosmia (sense of smell), including anosmia (absence of smell), temporary loss of consciousness.

Cardiovascular system disorders

Rare: tachycardia, decreased blood pressure.

Very rarely: collapse.

Unknown: prolongation of the QT interval.

Gastrointestinal tract / metabolism

Often: diarrhea, nausea.

Rare: nausea, vomiting, metallic taste in the mouth.

Very rare: bloody diarrhea as a manifestation of colitis, including pseudomembranous colitis, lack of appetite, dry mouth, coated tongue, vomiting, abdominal pain, digestive disorders, hypoglycemia, anorexia.

Hepatobiliary disorders

Often: increased liver enzymes (ALT, AST, ALP, GGTP).

Infrequent: increased bilirubin.

Very rarely: hepatitis.

Unknown: there may be cases of jaundice and severe liver damage, including cases of acute liver failure when using levofloxacin, a component of the drug, mainly in patients with severe underlying diseases.

Skin and subcutaneous tissue disorders

Infrequent: rash, itching, reddening of the skin.

Rare: urticaria.

Very rarely: angioedema of the skin and mucous membranes (e.g., face and pharyngeal mucosa), hypersensitivity to sunlight and ultraviolet radiation, porphyria.

Unknown: toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, erythema multiforme exudative, hyperhidrosis.

Skin and mucous reactions may sometimes occur, even after the first dose.

Musculoskeletal system disorders.

Rare: tendon damage, including inflammation, pain in the joints or muscles.

Very rare: tendon rupture (e.g. Achilles tendon). This side effect can happen within 48 hours of starting treatment and can affect Achilles tendon of both legs. Muscle weakness is possible, which may be particularly important in patients with severe myasthenia gravis, muscle lesions (rhabdomyolysis).

Renal and urinary system disorders

Infrequent: increased serum creatinine values.

Very rare: acute renal failure (due to interstitial nephritis).

General disorders and conditions at the place of administration

Infrequent: asthenia.

Very rare: pyrexia.

Unknown: pain (including back, chest and limb pain).

Infections and infestations

Infrequent: mycosis (and proliferation of other resistant microorganisms).

Visual organs

Very rare: visual disturbances.

Hearing and vestibular disorders

Infrequent: vertigo.

Very rare: hearing impairment. Frequency unknown: tinnitus.

Respiratory system disorders

Rare: bronchospasm, shortness of breath.

Very rare: allergic pneumonitis.

Other adverse effects: extrapyramidal symptoms and other movement coordination disorders, hypersensitive vasculitis, attacks of porphyria in patients with porphyria. The use of any antibacterial agents can lead to disorders associated with their effect on the normal microflora of the human body. For this reason, a secondary infection may develop, which will require additional treatment.

Contraindications

Hypersensitivity to levofloxacin or other fluoroquinolones, ornidazole and other components of the drug; deficiency of glucose-6-phosphate dehydrogenase, organic diseases of the central nervous system: epilepsy, multiple sclerosis; ruptures of tendons after application of fluoroquinolones in anamnesis, blood circulation disorders, chronic alcoholism.

Drug interactions

Levofloxacin

Concomitant administration of levofloxacin and theophylline may increase the concentration of the latter in blood plasma and increase its half-life. Probenecid, azlocillin increase plasma concentration of the drug. Non-steroidal anti-inflammatory drugs (NSAIDs) may increase the effect of levofloxacin on CNS. Levofloxacin increases nephrotoxicity of cyclosporine and neurotoxicity of some NSAIDs. When concomitant administration of warfarin, coagulation parameters should be monitored. When concomitant use of oral hypoglycemic agents, blood glucose levels should be monitored. Concomitant use of carboanhydrase inhibitors, sodium citrate increases the risk of crystalluria.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on excretion of levofloxacin. Renal clearance of levofloxacin is reduced with cimetidine by 24% and probenecid by 34%. This is because both drugs are able to block analgesic secretion of levofloxacin. However, at the doses tested in the study, it is not likely that statistically significant kinetic differences are clinically significant. Caution should be exercised when concomitant use of levofloxacin with drugs that affect tubular secretion, such as probenecid and cimetidine, especially in patients with renal insufficiency.

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), an increase in coagulation tests (IF/INR) and/or bleeding, which may be significant, has been reported. Despite this, coagulation rates should be monitored in patients who receive concomitant vitamin K antagonists.

Drugs that prolong the QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients who are receiving medications known to prolong the QT interval (such as class IA and III antiarrhythmic agents, tricyclic antidepressants and macrolides).

Other information

Clinical pharmacology studies have demonstrated that there has been no clinically significant effect on the pharmacokinetics of levofloxacin when levofloxacin is taken together with calcium carbonate, digoxin, glibenclamide, ranitidine.

Ornidazole.

When concomitant use with indirect anticoagulants, ornidazole potentiates the effect of coumarin anticoagulants (warfarin and others), which requires appropriate adjustment of their doses. It prolongs the effect of vecuronium bromide.

Incompatibility. The drug should not be mixed with other injection solutions when administered.

Special indications

Use with caution only in the presence of direct indications in patients with marked liver dysfunction and in elderly patients.

It is necessary to monitor the renal and hepatic function during the whole course of treatment.

When using the drug should refrain from drinking alcohol.

UV radiation is contraindicated during treatment with the drug.

Tendinitis, which is rarely observed, may lead to rupture. Elderly patients are more prone to this complication. If tendinitis is suspected, treatment with the drug should be stopped immediately and treatment of the affected tendon should be started.

If severe and prolonged diarrhea occurs during treatment, the diagnosis of pseudomembranous colitis should be excluded, which requires immediate withdrawal of the drug.

During the period of using the drug, patients should get enough fluids to prevent crystalluria.

Patients prone to seizures

The drug is contraindicated in patients with a history of epilepsy and, as with other quinolones, the drug should be used with extreme caution in patients prone to seizures, such as patients with previous central nervous system lesions, during concurrent therapy with fenbufen and similar non-steroidal anti-inflammatory drugs or drugs that increase seizure readiness (lower the seizure threshold), such as theophylline. If seizures occur, treatment should be discontinued.

Hypoglycemia

Cases of hypoglycemia have been reported, especially in patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Close monitoring of blood glucose levels in patients with diabetes mellitus is recommended (see section “Adverse effects”).

Patients who received vitamin K antagonists

Due to a possible increase in coagulation test values (IF/INR) and/or bleeding in patients who have taken the drug in combination with a vitamin K antagonist (e.g., warfarin), coagulation tests should be observed if these drugs are used simultaneously.

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, they have progressed to suicidal ideation and self-destructive behavior, sometimes only after a single dose of levofloxacin. If a patient develops these reactions, levofloxacin should be discontinued and symptomatic therapy should be administered. It is recommended with caution to use levofloxacin in patients with psychotic disorders or patients with a history of mental illness.

QT interval prolongation

Caution should be used with fluoroquinolones, including levofloxacin, in patients with known risk factors for QT interval prolongation, such as:

  • Congenital QT interval prolongation syndrome;
  • Concomitant use of drugs known to prolong the QT interval (e.g., antiarrhythmic drugs, class IA and III, tricyclic antidepressants, macrolides);
  • Uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
  • Elderly age of patient;
  • Heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy has been reported in patients taking fluoroquinolones, including levofloxacin, which can occur rapidly. Levofloxacin should be discontinued if the patient has symptoms of neuropathy to prevent the occurrence of an irreversible condition.

Hepatobiliary disorders

Cases of necrotic hepatitis to life-threatening liver failure have been reported while taking levofloxacin, mostly in patients with severe underlying conditions such as sepsis. Patients should be advised to discontinue treatment and consult a physician if liver disease manifestations and symptoms such as anorexia, jaundice, black urine, itching, or abdominal pain occur.

Use during pregnancy or lactation

Use is contraindicated.

Children

The use is contraindicated.

Effect on the reaction rate while driving motor transport or operating other mechanisms.

The drug is used under hospital conditions.

Overdose

Levofloxacin

The most important suspected symptoms of overdose concern the central nervous system (dizziness, impaired consciousness and seizures). According to the research results, prolongation of the QT interval was observed when using doses exceeding the therapeutic ones. In cases of overdose it is necessary to carry out close monitoring of the patient, including ECG. Treatment is symptomatic.

Ornidazole

In case of overdose, loss of consciousness, headache, dizziness, trembling, convulsions, dyspeptic disorders are possible. Treatment: specific antidote is unknown; symptomatic therapy, diazepam in case of convulsions.

Form of production

Solution for infusion 100 ml, 200 ml (vials).

Storage conditions

Store in a dry, dark place at temperatures under 25°C. Keep out of the reach of children!

Shelf life

2 years. Do not use after the expiration date.

Conditions for dispensing from pharmacies

Released by a doctor’s prescription.

×