Roxicef

INSTRUCTIONS for medical use of the medicinal product ROXICEF (ROXICEF)

Composition:

Active substance: cefuroxime;

1 vial contains cefuroxime (as cefuroxime sodium) 1.5 g.

Dosage form. Powder for solution for injection or infusion.

Main physicochemical properties: white or almost white slightly hygroscopic powder.

Pharmacotherapeutic group. Antibacterials for systemic use. Second-generation cephalosporins. ATC code J01D C02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Roxicef inhibits microbial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This inhibits peptidoglycan synthesis, leading to bacterial cell lysis and death.

Mechanism of resistance

• Bacterial resistance to cefuroxime may be associated with one or more of the following mechanisms:
• hydrolysis by beta-lactamases, including (but not limited to) extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes, which may be inducible or stably expressed in certain aerobic Gram-negative bacterial species;
• reduced affinity of PBPs for cefuroxime;
• outer membrane impermeability limiting access of cefuroxime to PBPs in Gram-negative bacteria;
• bacterial efflux pump systems.

Organisms resistant to other parenteral cephalosporins are expected to be resistant to cefuroxime. Depending on the resistance mechanism, organisms with acquired resistance to penicillins may exhibit decreased susceptibility or resistance to cefuroxime.

Cefuroxime sodium susceptibility breakpoints

Microorganism	Breakpoints (mg/l)
	Susceptible	Resistant
Enterobacteriaceae 1	≤82	>8
Staphylococcus spp.	Note3	Note3
Streptococcus A, B, C and G	Note4	Note4
Streptococcus pneumoniae	≤0.5	>1
Streptococcus (other)	≤0.5	>0.5
Haemophilus influenzae	≤1	>2
Moraxella catarrhalis	≤4	>8
Species-unrelated breakpoints1	≤45	>85
1Breakpoints for determining cephalosporin activity against Enterobacteriaceae detect all clinically important resistance mechanisms (including ESBLs and plasmid-mediated AmpC). Some strains producing beta-lactamases may be susceptible or moderately resistant to 3rd or 4th generation cephalosporins according to these breakpoints and should be reported as determined; thus, the presence or absence of ESBLs alone does not affect susceptibility categorization. In many regions, detection and characterization of ESBLs are recommended or mandatory for infection control purposes. 2 Breakpoints apply only to the 1.5 g × 3 dosage and to E. coli, P. mirabilis, and Klebsiella spp. strains. 3 Staphylococcal susceptibility to cephalosporins follows methicillin susceptibility, except for ceftazidime, cefixime, and cefditoren, which have no breakpoints and should not be used for treatment of staphylococcal infections. 4 Streptococcal susceptibility of groups A, B, C, and G to cephalosporins follows benzylpenicillin susceptibility. 5 Breakpoints apply to a daily intravenous dose of 750 mg × 3 and high-dose regimens of at least 1.5 g × 3.

• The minimum inhibitory concentration (MIC) breakpoints for cefuroxime established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are provided below:

Microbiological susceptibility

Acquired resistance to antibiotics varies by region and over time for individual microorganisms. Local antibiotic susceptibility data should be consulted, especially when treating severe infections. A specialist should be consulted if acquired resistance to the antibiotic is known and the benefit of using the medicinal product is at least questionable in the treatment of certain types of infections.

Cefuroxime generally has in vitro activity against the following microorganisms.

Susceptible strains

Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible)$, Streptococcus pyogenes, Streptococcus agalactiae

Gram-negative aerobes: Haemophilus parainfluenzae, Moraxella catarrhalis

Microorganisms for which acquired resistance may be a concern

Gram-positive aerobes: Streptococcus pneumoniae, Streptococcus mitis (viridans group)

Gram-negative aerobes: Citrobacter freundii, excluding C. freundii, Enterobacter spp., excluding E. aerogenes and E. cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Proteus mirabilis, Proteus spp., excluding P. penneri and P. vulgaris, Providencia spp., Salmonella spp.

Gram-positive anaerobes: Peptostreptococcus spp., Propionibacterium spp.

Gram-negative anaerobes: Fusobacterium spp., Bacteroides spp.

Microorganisms with inherent resistance

Gram-positive aerobes: Enterococcus faecalis, Enterococcus faecium

Gram-negative aerobes: Acinetobacter spp., Burkholderia cepacia, Campylobacter spp., Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii , Proteus penneri, Proteus vulgaris , Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia

Gram-positive anaerobes: Clostridium difficile

Gram-negative anaerobes: Bacteroides fragilis

Others: Chlamydia spp., Mycoplasma spp., Legionella spp .

$All methicillin-resistant S. aureus are resistant to cefuroxime.

In vitro, cefuroxime in combination with aminoglycoside antibiotics exerts at least an additive effect, sometimes with evidence of synergy.

Pharmacokinetics.

Absorption

After intramuscular administration of cefuroxime to healthy volunteers, mean peak serum concentrations ranged from 27 mcg/mL to 35 mcg/mL for a 750 mg dose and from 33 mcg/mL to 40 mcg/mL for a 1000 mg dose, achieved within 30–60 minutes after administration. Fifteen minutes after intravenous infusion of 750 mg and 1500 mg doses, serum concentrations were approximately 50 mcg/mL and 100 mcg/mL, respectively.

Following intramuscular and intravenous administration, the area under the pharmacokinetic concentration-time curve (AUC) and maximum concentration (Cmax) increase linearly with increasing dose within a single dose range of 250 mg to 1000 mg. There was no evidence of cefuroxime accumulation in serum in healthy volunteers after repeated intravenous infusions of 1500 mg every 8 hours.

Distribution

Protein binding ranges from 33% to 50%, depending on the methodology used. The mean volume of distribution ranges from 9.3 L to 15.8 L/1.73 m² after intramuscular or intravenous administration within a dose range of 250 mg to 1000 mg. Concentrations of cefuroxime exceeding the MIC for most common pathogenic microorganisms are achieved in tonsillar tissue, nasal sinuses, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum, and intraocular fluid. Cefuroxime penetrates the blood-brain barrier during inflammation of the meninges.

Biotransformation

Cefuroxime is not metabolized.

Elimination

Cefuroxime is eliminated via glomerular filtration and tubular secretion. The elimination half-life from serum after intramuscular or intravenous injection is approximately 70 minutes. Within 24 hours after administration, the drug is excreted almost completely (85–90%) unchanged in urine. Most of the drug is excreted within the first 6 hours. Mean renal clearance ranges from 114 to 170 mL/min/1.73 m² after intramuscular or intravenous injection within a dose range of 250 mg to 1000 mg.

Special patient groups

Sex

No differences in the pharmacokinetics of cefuroxime were observed between men and women after a single 1000 mg intravenous bolus injection of cefuroxime as cefuroxime sodium.

Elderly patients

After intramuscular or intravenous administration, absorption, distribution, and excretion of cefuroxime in elderly patients are similar to those observed in younger patients with equivalent renal function. Since elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection for this population, and renal function should be monitored (see section "Dosage and administration").

Children

The elimination half-life of cefuroxime in serum is significantly prolonged in neonates according to gestational age. However, in infants older than 3 weeks and in children, the serum half-life of the drug ranges from 60 to 90 minutes, similar to that observed in adults.

Renal impairment

Cefuroxime is primarily eliminated by the kidneys. As with other similar antibiotics, patients with severe renal impairment (e.g., creatinine clearance <20 mL/min) should receive reduced doses of cefuroxime to compensate for slower drug excretion (see section "Dosage and administration"). Cefuroxime is effectively removed by hemodialysis and peritoneal dialysis.

Hepatic impairment

Since cefuroxime is primarily eliminated by the kidneys, hepatic impairment is not expected to affect the pharmacokinetics of cefuroxime.

Pharmacokinetic/pharmacodynamic relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy is the percentage of the dosing interval (%T) during which the concentration of the free fraction of the drug exceeds the MIC of cefuroxime for specific target strains (i.e., %T > MIC).

Clinical characteristics.

Indications.

Roxicef is indicated for the treatment of the following infections in adults and children, including newborns (from birth) (see sections “Pharmacodynamics” and “Special precautions”).

• Community-acquired pneumonia.
• Acute exacerbation of chronic bronchitis.
• Complicated urinary tract infections, including pyelonephritis.
• Soft tissue infections: cellulitis, erysipelas, wound infections.
• Intra-abdominal infections (see section “Special precautions”).
• Prophylaxis of postoperative infectious complications following gastrointestinal surgery (including esophageal surgery), orthopedic, cardiovascular, and gynecological surgeries (including cesarean section).

When treating or preventing infections where anaerobic organisms are likely to be involved, cefuroxime should be administered together with additional appropriate antibacterial agents.

Official guidelines on the appropriate use of antibacterial agents should be considered.

Contraindications.

Hypersensitivity to cefuroxime or to any other component of the medicinal product.

Hypersensitivity to cephalosporin antibiotics.

History of severe hypersensitivity (e.g., anaphylactic reactions) to other beta-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interaction.

Roxicef may affect the intestinal flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Cefuroxime is eliminated by glomerular filtration and tubular secretion. Concomitant administration of probenecid is not recommended. Simultaneous administration of probenecid slows antibiotic excretion and results in increased serum concentrations.

Potentially nephrotoxic drugs and loop diuretics

Cephalosporin antibiotics in high doses should be administered with caution in patients receiving treatment with potent diuretics (such as furosemide) or potentially nephrotoxic drugs (such as aminoglycoside antibiotics), since renal function impairment cannot be excluded with such combinations.

Other types of interactions

For glucose plasma level determination, see section “Special precautions”.

Concomitant use with oral anticoagulants may lead to an increased international normalized ratio (INR).

Special precautions for use.

Hypersensitivity reactions

As with other beta-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. Hypersensitivity reactions progressing to Kounis syndrome – acute allergic coronary artery spasm, which may lead to myocardial infarction, have been reported (see section "Adverse reactions"). In case of severe hypersensitivity reactions, cefuroxime therapy should be discontinued immediately and appropriate emergency measures should be initiated.

Prior to starting treatment, patients should be questioned about previous history of severe hypersensitivity reactions to cefuroxime, other cephalosporins, or beta-lactam agents. The drug should be administered with caution to patients with a history of hypersensitivity reactions to other beta-lactam antibiotics.

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome, which may be life-threatening and fatal, have been reported during cefuroxime therapy (see section "Adverse reactions").

Patients should be informed about signs and symptoms of skin reactions, and closely monitored for their occurrence. If signs or symptoms suggestive of these reactions appear, cefuroxime should be discontinued immediately and alternative therapy considered. If a serious reaction such as SJS, TEN, or DRESS syndrome occurs during cefuroxime treatment, re-administration of cefuroxime in this patient is contraindicated.

Concomitant therapy with potent diuretics or aminoglycosides

Cephalosporin antibiotics in high doses should be administered with caution to patients receiving concomitant therapy with potent diuretics such as furosemide or aminoglycosides, as cases of renal function impairment have been reported with such combinations. Renal function should be monitored in these patients, as well as in elderly patients and in patients with existing renal impairment (see section "Dosage and administration").

Overgrowth of resistant microorganisms

Cefuroxime use may lead to overgrowth of Candida species. Prolonged use of cefuroxime may result in overgrowth of resistant microorganisms (such as Enterococci, Clostridium difficile), which may necessitate discontinuation of therapy (see section "Adverse reactions").

Cases of pseudomembranous colitis, ranging from mild to life-threatening, have been reported with antibiotic use. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy (see section "Adverse reactions"). Discontinuation of cefuroxime therapy and initiation of specific treatment against Clostridium difficile should be considered. Medicinal products that inhibit intestinal peristalsis are not recommended.

Intracameral administration and ocular adverse reactions

Roxicef is not intended for intracameral administration. Individual cases and a number of serious ocular adverse reactions have been reported following intracameral use of cefuroxime sodium intended for IV/IM administration. These reactions included macular edema, retinal edema, retinal detachment, retinal toxicity, visual disturbances, decreased visual acuity, blurred vision, corneal opacity, and corneal edema.

Intra-abdominal infections

Due to its spectrum of activity, cefuroxime is not used for the treatment of infections caused by gram-negative non-fermenting bacteria (see section "Pharmacodynamics").

Effect on diagnostic tests

Positive Coombs' test results have been reported during cefuroxime therapy. This phenomenon may interfere with cross-matching of blood (see section "Adverse reactions").

Minor interference with copper reduction methods (Benedict’s, Fehling’s, Clinitest) may occur. However, this should not lead to false-positive results as may occur with some other cephalosporins.

As false-negative results may occur with the ferricyanide test, glucose oxidase or hexokinase methods are recommended for determination of glucose levels in blood/plasma in patients receiving cefuroxime sodium.

Important information about excipients

The medicinal product Roxicef (1.5 g vial) contains 3.6 mmol (84 mg) of sodium per vial, which corresponds to 4.15% of the WHO recommended maximum daily sodium intake for adults – 2 g. This should be taken into account for patients on a controlled sodium intake diet.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of cefuroxime in pregnant women are limited. Reproductive toxicity has not been observed in animal studies. Roxicef should be administered to pregnant women only if the benefit outweighs the potential risk.

Cefuroxime crosses the placenta and reaches therapeutic concentrations in amniotic fluid and umbilical cord blood after intramuscular or intravenous dosing in the mother.

Breastfeeding

Cefuroxime is excreted in breast milk in small amounts. When therapeutic doses are used, adverse reactions are not expected, but the risk of diarrhea or fungal mucosal infections in the infant cannot be excluded. Therefore, a decision should be made whether to discontinue breastfeeding or to discontinue/abstain from cefuroxime therapy, taking into account the benefit of breastfeeding for the infant and the benefit of therapy for the mother.

Fertility

There are no data on the effect of cefuroxime sodium on fertility in humans. Studies on reproductive function in animals have not shown any effect of this medicinal product on fertility.

Ability to affect driving and operating machinery.

No studies have been conducted on the effect of cefuroxime on the ability to drive or operate machinery. However, considering the known adverse reactions, it can be concluded that cefuroxime is unlikely to affect the speed of reaction in driving or operating machinery.

Dosage and Administration.

General recommendations

Adults and children ≥ 40 kg

Indications	Doses
Community-acquired pneumonia and acute exacerbation of chronic bronchitis	750 mg every 8 hours (intravenously or intramuscularly)
Soft tissue infections: cellulitis, erysipelas, wound infections
Intra-abdominal infections
Complicated urinary tract infections, including pyelonephritis	1.5 g every 8 hours (intravenously or intramuscularly)
Complicated infections	750 mg every 6 hours (intravenously), 1.5 g every 8 hours (intravenously)
Prophylaxis of postoperative infectious complications following gastrointestinal surgery, gynecological surgeries (including cesarean section) and orthopedic surgeries	1.5 g with anesthesia; may be followed by two additional doses of 750 mg each (intramuscularly) at 8 and 16 hours, respectively.
Prophylaxis of postoperative infectious complications following esophageal surgery and cardiovascular surgeries	1.5 g with anesthesia; may be followed by two additional doses of 750 mg each (intramuscularly) every 8 hours during the first 24 hours

Children < 40 kg

	Infants and children > 3 weeks of age with body weight ≤ 40 kg	Neonates (from birth to 3 weeks)
Community-acquired pneumonia	30–100 mg/kg/day (intravenously), divided into 3–4 doses. For most infections, the optimal dose is 60 mg/kg/day.	30–100 mg/kg/day (intravenously), divided into 2–3 doses.
Complicated urinary tract infections, including pyelonephritis
Soft tissue infections: cellulitis, erysipelas, wound infections
Intra-abdominal infections

Renal function impairment

Cefuroxime is eliminated by the kidneys; therefore, as with other similar antibiotics, patients with impaired renal function should receive reduced doses of Roxicef to compensate for the slower drug excretion.

Creatinine clearance	T1/2 (hours)	Dose (mg)
> 20 mL/min/1.73 m²	1.7–2.6	No need to reduce standard dose (750 mg – 1.5 g three times daily)
10–20 mL/min/1.73 m²	4.3–6.5	750 mg twice daily
< 10 mL/min/1.73 m²	14.8–22.3	750 mg once daily
Patients undergoing hemodialysis	3.75	750 mg intravenously or intramuscularly at the end of each dialysis session. In addition to parenteral administration, cefuroxime can be added to peritoneal dialysis fluid (usually 250 mg per 2 liters of dialysis fluid).
Patients with renal insufficiency undergoing continuous arteriovenous hemodialysis (CAVH) or high-flux hemofiltration (HFH) in intensive care units	7.9–12.6 (CAVH) 1.6 (HFH)	750 mg twice daily. Patients undergoing low-flux hemofiltration should follow the dosing regimen appropriate for impaired renal function.

Impaired liver function

Cefuroxime is primarily eliminated by the kidneys. No influence on the pharmacokinetic properties of Rocephin has been observed in patients with hepatic dysfunction.

Administration method

Rocephin should be administered intravenously over 3–5 minutes directly into a vein or via infusion over 30–60 minutes, or by deep intramuscular injection.

The site for intramuscular injection is the large gluteal muscle; no more than 750 mg should be administered at a single site. Doses exceeding 1.5 g should be administered intravenously.

Instructions for reconstituting the medicinal product prior to administration

	Additional volumes and concentrations that may be useful when fractional doses are required
Flacon volume	Route of administration	Physical state	Volume of water added (ml)	Approximate cefuroxime concentration (mg/ml)**
	1.5 g powder for solution for injection or infusion
1.5 g	intramuscular intravenous bolus intravenous infusion	suspension solution solution	6 ml at least 15 ml 15 ml*	216 94 94

* Reconstituted solution for addition to 50 mL or 100 mL of a compatible infusion fluid (see compatibility information below).

** The resulting volume of cefuroxime solution in the reconstituted medium increases due to the displacement factor of the drug, resulting in the listed concentrations in milligrams per milliliter.*

Compatibility

Roxicef is compatible with the most commonly used intravenous fluids and electrolyte solutions.

Cefuroxime sodium 1.5 g dissolved in 15 mL of water for injections can be used together with metronidazole injection (500 mg/100 mL); both drugs retain their activity for 24 hours at temperatures below 25 °C.

Cefuroxime sodium 1.5 g is compatible with 1 g azlocillin (in 15 mL solvent) or with 5 g (in 50 mL solvent) for 24 hours at 4 °C and for 6 hours at temperatures up to 25 °C.

Cefuroxime sodium (5 mg/mL) can be stored for 24 hours at 25 °C in 5 % or 10 % xylitol injection solution.

Cefuroxime sodium is compatible with solutions containing up to 1 % lidocaine hydrochloride.

Cefuroxime sodium is compatible with most commonly used intravenous solutions. It retains its properties for 24 hours at room temperature in the following solutions: 0.9 % sodium chloride injection solution; 5 % dextrose injection solution; 0.18 % sodium chloride with 4 % dextrose injection solution; 5 % dextrose with 0.9 % sodium chloride injection solution; 5 % dextrose with 0.45 % sodium chloride injection solution; 5 % dextrose with 0.225 % sodium chloride injection solution; 10 % dextrose injection solution; 10 % invert sugar solution in water for injections; Ringer's solution; Ringer's lactate solution; M/6 sodium lactate solution; Hartmann's solution.

The stability of cefuroxime sodium in 0.9 % sodium chloride injection solution with 5 % dextrose is not affected by the presence of sodium hydrocortisone phosphate.

Cefuroxime sodium is also compatible for 24 hours at room temperature when diluted in infusion solution:

• with heparin (10 or 50 units/mL) in 0.9 % sodium chloride injection solution;
• with potassium chloride solution (10 or 40 mEq/L) in 0.9 % sodium chloride injection solution.

Children.

Can be used in children from the first days of life. The safety profile of cefuroxime in children corresponds to that in adult patients.

Overdose.

Neurological complications, including encephalopathy, seizures, and coma, may occur in case of overdose. Symptoms of overdose may arise if the drug dose has not been appropriately adjusted in patients with impaired renal function (see sections "Special instructions" and "Dosage and administration"). Serum cefuroxime levels can be reduced by hemodialysis and peritoneal dialysis.

Adverse Reactions

The most commonly reported adverse reactions are neutropenia, eosinophilia, and transient elevations in liver enzymes or bilirubin, particularly in patients with pre-existing liver disease. However, there is no evidence of harmful effects on the liver or reactions at the site of administration.

The frequency of adverse reactions listed below is approximate, as sufficient data are not available to provide precise estimates for most reactions. In addition, the frequency of adverse reactions associated with cefuroxime varies depending on the indication.

Classification of adverse effects from very common to very rare is based on data from clinical trials. The frequency of other adverse effects (e.g., <1 in 10,000) is primarily derived from post-marketing data and reflects the reporting rate rather than the actual incidence.

All treatment-related adverse reactions are listed below by system organ class, frequency, and severity according to the MedDRA classification. The following frequency classification is used: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); and frequency not known (cannot be estimated from available data).

Organ system class	Common	Uncommon	Frequency unknown
Infections and infestations			Overgrowth of Candida or Clostridium difficile
Blood and lymphatic system disorders	Neutropenia, eosinophilia, decreased hemoglobin levels	Leukopenia, positive Coombs test	Thrombocytopenia, hemolytic anemia
Immune system disorders			Drug fever, interstitial nephritis, anaphylaxis, cutaneous vasculitis
Gastrointestinal disorders		Discomfort in the gastrointestinal tract	Pseudomembranous colitis (see section "Special warnings and precautions for use")
Hepatobiliary and biliary disorders	Transient elevation of liver enzymes	Transient elevation of bilirubin levels
Skin and subcutaneous tissue disorders		Skin rashes, urticaria, and pruritus	Multiform erythema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema Drug-induced eosinophilia with systemic symptoms (DRESS syndrome)
Renal and urinary disorders			Increased serum creatinine and blood urea nitrogen levels, decreased creatinine clearance (see section "Special warnings and precautions for use")
General disorders and administration site reactions	Reactions at the injection site, which may include pain and thrombophlebitis
Cardiac disorders			Kounis syndrome
Description of selected adverse reactions Cephalosporins as a class have the property of being absorbed on the surface of erythrocyte membranes and interacting with antibodies, which may lead to a positive Coombs test result (which may affect cross-matching of blood) and very rarely to hemolytic anemia. Transient increases in serum liver enzymes or bilirubin levels were reversible in nature. The likelihood of pain at the intramuscular injection site is greater with higher doses. However, this is unlikely to be a reason for discontinuation of treatment.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

Roxicef must not be mixed in the same syringe with aminoglycoside antibiotics.

The pH of 2.74% sodium bicarbonate solution for injection significantly affects the color of the solution; therefore, this solution is not recommended for dilution of Cefuroxime. However, if necessary, when a patient is receiving intravenous infusion of sodium bicarbonate solution, Cefuroxime may be administered directly into the infusion line.

Packaging.

Vial; 1 or 10 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ANTIBIOTICE SA

ANTIBIOTICE SA

Manufacturer's address and place of business.

1, Valea Lupului Street, 707410, Iasi, Romania