Xevulan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XIXULAN (XIVULAN)

Composition:

Active substances: amoxicillin, clavulanic acid;

1 vial contains amoxicillin (as sodium amoxicillin) 1000 mg; clavulanic acid (as potassium clavulanate) 200 mg.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical properties: vial with white or almost white crystalline hygroscopic powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors.

ATC code J01CR02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (a beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, resulting in cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria; therefore, the spectrum of activity of amoxicillin as monotherapy does not include organisms producing these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates certain beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid, when used as monotherapy, does not exert a clinically useful antibacterial effect.

PK/PD relationship

Time above the minimum inhibitory concentration (T>MIC) is considered the primary factor determining the efficacy of amoxicillin.

Resistance mechanisms

There are two mechanisms of resistance to amoxicillin/clavulanic acid:

• inactivation by bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C, and D enzymes;
• modification of PBPs, reducing the affinity of the antibacterial agent for its target. Bacterial impermeability or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Microorganisms	Breakpoint susceptibility values (μg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae 1	≤1	-	> 1
Moraxella catarrhalis 1	≤1	-	> 1
Staphylococcus aureus 2	≤2	-	>2
Coagulase-negative staphylococci 2	≤ 0.25		> 0.25
Enterococcus 1	≤4	8	> 8
Streptococcus A, B, C, G 5	≤ 0.25	-	> 0.25
Streptococcus pneumoniae 3	≤ 0.5	1–2	>2
Enterobacteriaceae 1, 4	-	-	> 8
Gram-negative anaerobic bacteria 1	≤4	8	> 8
Gram-positive anaerobic bacteria 1	≤4	8	> 8
Breakpoints not specific to individual species 1	≤2	4–8	> 8
1 The reported values refer to amoxicillin concentrations. For susceptibility testing, the concentration of clavulanic acid is set at 2 mg/L. 2 The reported values refer to oxacillin concentrations. 3 The breakpoints listed in the table are based on ampicillin breakpoints. 4 The resistance breakpoint R>8 mg/L indicates that all strains with resistance mechanisms are classified as resistant. 5 The breakpoints listed in the table are based on benzylpenicillin breakpoints.

The prevalence of resistance may vary geographically and over time for individual species, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice may be necessary if local resistance prevalence is such that the benefit of the drug, at least for some types of infections, is questionable.

Usually susceptible species

Gram-positive aerobes: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible)£, Coagulase-negative staphylococci (methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae1, Streptococcus pyogenes and other beta-haemolytic streptococci, Streptococcus viridans group. Gram-negative aerobes: Actinobacillus actinomycetemcomitans, Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae2, Moraxella catarrhalis, Neisseria gonorrhoeae§, Pasteurella multocida. Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp.

Species for which acquired resistance may be a problem

Gram-positive aerobes: Enterococcus faecium$. Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris.

Naturally resistant microorganisms

Gram-negative aerobes: Acinetobacter sp., Citrobacter freundii, Enterobacter sp., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas sp., Serratia sp., Stenotrophomonas maltophilia. Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae

$ Natural moderate susceptibility in the absence of acquired resistance mechanisms. £ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. § All strains resistant to amoxicillin via non-beta-lactamase mechanisms are resistant to amoxicillin/clavulanic acid. 1 This medicinal formulation of amoxicillin/clavulanic acid may be inappropriate for treatment of penicillin-resistant Streptococcus pneumoniae (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use"). 2 Strains with reduced susceptibility have been reported in certain EU countries with a frequency greater than 10%.

Pharmacokinetics.

Absorption.

Pharmacokinetic data obtained in studies involving a group of healthy volunteers who were administered Xivulan 1000/200 mg (1.2 g) as an intravenous bolus injection are presented below.

Average pharmacokinetic parameters
Dose administered	Amoxicillin
	Dose	Mean peak plasma concentration, mcg/mL	T ½ , hours (elimination half-life)	AUC, h·mg/L (area under the concentration-time curve)	Urinary excretion 0–6 hours, %
KSIYUVLAN 1000/200 mg	1 g	105.4	0.9	76.3	77.4
Clavulanic acid
KSIYUVLAN 1000/200 mg	200 mg	28.5	0.9	27.9	63.8

Distribution. Approximately 25% of the total plasma volume of clavulanic acid and 18% of total plasma amoxicillin are protein-bound. The apparent volume of distribution is about 0.3–0.4 L/kg for amoxicillin and about 0.2 L/kg for clavulanic acid. After intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, abdominal tissue, skin, adipose tissue, muscle tissue, synovial and peritoneal fluid, bile, and pus. Amoxicillin does not distribute sufficiently into cerebrospinal fluid.

Animal studies have shown no evidence of significant retention of substances derived from any component of the drug in body tissues. Amoxicillin, like most penicillins, may be detected in breast milk. A small amount of clavulanic acid may also be present in breast milk (see section "Use during pregnancy or breastfeeding").

It has been demonstrated that both amoxicillin and clavulanic acid cross the placental barrier (see section "Use during pregnancy or breastfeeding").

Metabolism. Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in the human body and eliminated via urine, feces, and as carbon dioxide in exhaled air.

Elimination. The primary route of elimination for amoxicillin is renal, whereas clavulanic acid is eliminated both renally and through extrarenal mechanisms.

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately 1 hour, and the mean total clearance is about 25 L/h. Various studies have shown that urinary excretion accounts for 50–85% of the amoxicillin dose and 27–60% of the clavulanic acid dose within a 24-hour period. In the case of clavulanic acid, the greatest amount of the substance is excreted within the first 2 hours after administration.

Concomitant administration of probenecid slows the elimination of amoxicillin but does not affect the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other forms of interaction").

Age. The elimination half-life of amoxicillin is similar in children aged 3 months to 2 years, older children, and adults. For neonates (including premature infants) during the first week of life, the dosing frequency should not exceed twice daily due to immaturity of the renal elimination pathway. Since elderly patients are more likely to have decreased renal function, dosage selection should be cautious, and monitoring of renal function is recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with reduced renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a larger fraction of amoxicillin is eliminated by the kidneys. In renal impairment, dosing should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Posology and method of administration").

Hepatic impairment. Patients with hepatic insufficiency should be treated cautiously with this drug, and regular monitoring of liver function is recommended.

Clinical characteristics.

Indications.

Treatment of bacterial infections caused by microorganisms sensitive to Xivulan, such as:

• severe infections of the throat, nose, and ears (e.g., mastoiditis, peritonsillar infections, epiglottitis, and sinusitis with associated severe systemic signs and symptoms);
• exacerbations of chronic bronchitis (after diagnosis has been confirmed);
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including bacterial cellulitis, animal bites, severe dentoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis;
• intra-abdominal infections;
• genital tract infections in women.

Prophylaxis of bacterial infections during major surgical procedures in the following areas:

• gastrointestinal tract;
• pelvic organs;
• head and neck;
• biliary tract.

When prescribing antibacterial agents, principles of appropriate use should be followed.

Contraindications.

Hypersensitivity to the active substances, penicillin, or to other components of the medicinal product.

History of severe immediate-type allergic reaction (e.g., anaphylaxis) to another beta-lactam antibiotic (e.g., cephalosporin, carbapenem, or monobactam).

History of jaundice/liver function disorder induced by amoxicillin/clavulanic acid (see section "Adverse reactions").

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-class antibiotics are commonly used together in clinical practice, with no widespread reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant administration is necessary, prothrombin time or INR should be carefully monitored when starting or stopping amoxicillin. Additionally, dose adjustment of oral anticoagulants may be required (see sections "Special precautions" and

«Adverse reactions»).

• Methotrexate

Penicillins may reduce the excretion of methotrexate, potentially increasing its toxicity.

• Probenecid

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concomitant administration of probenecid may lead to increased blood levels and prolonged presence of amoxicillin (but not clavulanic acid).

• Mycophenolate mofetil

In patients treated with mycophenolate mofetil, initiation of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite mycophenolic acid by approximately 50%. This change in pre-dose levels may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of transplant dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use.

Before initiating therapy with Xivulan, it is essential to carefully assess the patient's history for hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see sections "Contraindications" and "Side effects").

Severe, and sometimes even fatal, hypersensitivity reactions (including anaphylactoid reactions and severe skin reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome – a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). These reactions are most likely to occur in individuals with a history of similar reactions to penicillins. If allergic reactions occur, therapy with Xivulan should be discontinued and appropriate alternative treatment initiated.

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin (see section "Side effects"). Drug-induced enterocolitis syndrome is an allergic reaction characterized mainly by persistent vomiting (1–4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases have been reported, including progression to shock.

If the infection is proven to be caused by microorganisms susceptible to amoxicillin alone, consideration should be given to switching from the combination amoxicillin/clavulanic acid to amoxicillin monotherapy in accordance with official guidelines.

This dosage form of Xivulan is not suitable for use when there is a high risk that the likely pathogens exhibit resistance to beta-lactam agents not mediated by beta-lactamases that are sensitive to inhibition by clavulanic acid. Since specific data regarding T> MIC are lacking and data on oral formulations are limited, this dosage form (without additional amoxicillin) may be inappropriate for the treatment of penicillin-resistant S. pneumoniae.

Seizures may occur in patients with impaired renal function or when high doses are administered.

Xivulan should be discontinued if infectious mononucleosis is suspected, as the development of a measles-like rash associated with this condition may be linked to amoxicillin intake.

Concomitant use of allopurinol during amoxicillin therapy may increase the risk of skin allergic reactions.

Prolonged use of the drug may occasionally lead to overgrowth of non-susceptible microorganisms.

Development of pustular polymorphic erythema at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (see section "Side effects"). In such cases, treatment must be discontinued, and subsequent administration of amoxicillin is contraindicated.

Xivulan should be used with caution in patients with impaired liver function. Hepatitis occurs predominantly in males and elderly patients and may be associated with prolonged treatment. Very rarely, such adverse reactions may occur in children. Signs and symptoms may appear during or immediately after treatment, but in some cases may manifest several weeks after completion of therapy. These effects are usually reversible. Fatal cases have been reported extremely rarely, always occurring in patients with severe underlying diseases or those receiving concomitant hepatotoxic drugs (see section "Side effects").

Antibiotic-associated colitis, ranging from mild to life-threatening, has been reported with nearly all antibacterial agents (see section "Side effects"). Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, Xivulan therapy should be immediately discontinued, medical advice sought, and appropriate treatment initiated.

During prolonged therapy, monitoring of organ and system functions, including kidneys, liver, and hematopoietic system, is recommended.

Rarely, patients receiving Xivulan and oral anticoagulants may experience excessive prolongation of prothrombin time (elevated international normalized ratio [INR]). Appropriate monitoring is required when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections "Side effects" and "Interaction with other medicinal products and other forms of interaction"). Dose adjustment should be based on the degree of renal impairment in patients with renal insufficiency.

Crystalluria (including acute kidney injury) may occur very rarely in patients with reduced urine output, primarily after parenteral administration. Therefore, adequate fluid intake and monitoring of urine output are recommended when high doses of amoxicillin are used, to minimize the risk of amoxicillin crystalluria (see sections "Side effects" and "Overdose").

When monitoring urinary glucose levels during amoxicillin therapy, enzymatic glucose oxidase-based methods should be used, as other methods may yield false-positive results.

False-positive results in Aspergillus antigen tests have been reported in patients receiving amoxicillin/clavulanic acid (using the Bio-Rad Laboratories Platelis Aspergillus EIA test). Therefore, such positive results in patients treated with amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

The presence of clavulanic acid in Xivulan may cause nonspecific binding of IgG and albumin to erythrocyte membranes, potentially leading to a false-positive Coombs test.

This medicinal product contains 62.9 mg (2.7 mmol) of sodium per vial. Caution is advised when administering to patients on a sodium-restricted diet.

This medicinal product contains 39.3 mg (1.0 mmol) of potassium per vial. Caution is advised when administering to patients with impaired renal function or those on a potassium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Reproductive studies in animals with oral and parenteral forms of Xivulan revealed no teratogenic effects. In one study involving women with premature rupture of membranes, prophylactic use of Xivulan was associated with an increased risk of necrotizing enterocolitis in newborns. As with other medicinal products, Xivulan should be avoided during pregnancy, especially in the first trimester, unless in the physician’s opinion the potential benefit justifies the potential risk.

Breastfeeding period.

Both active components of the drug are excreted in breast milk (no information is available on the effect of clavulanic acid on the breastfed infant). Diarrhea and mucosal fungal infections may therefore occur in the breastfed infant, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered. Xivulan may be used during breastfeeding only if, in the physician’s opinion, the benefit outweighs the risk.

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, adverse effects such as allergic reactions, dizziness, and seizures may occur, which could impair the ability to drive or operate machinery (see section "Side effects").

Method of Administration and Dosage

Dosages are expressed as the content of amoxicillin/clavulanic acid, unless the dose of an individual component is specified.

When selecting the dose of Xivulan for treating a specific infection, the following factors should be considered:

• the likely pathogens and their expected susceptibility to antibacterial agents (see section "Special Instructions");
• the severity and site of infection;
• the patient's age, body weight, and renal function status, as described below.

If necessary, alternative formulations of Xivulan (e.g., with higher doses of amoxicillin and/or a different ratio of amoxicillin to clavulanic acid) may be used.

These Xivulan formulations can be administered at a maximum daily dose of 3000 mg of amoxicillin and 600 mg of clavulanic acid. If higher doses of amoxicillin are required, another formulation of Xivulan should be prescribed to avoid excessively high daily doses of clavulanic acid.

The duration of treatment is determined individually by the physician. Certain infections (e.g., osteomyelitis) may require prolonged treatment. The duration of treatment should not exceed 14 days without re-evaluation of treatment response and clinical status (see section "Special Instructions").

Dosing for adults and children with body weight ≥ 40 kg

Standard dose – 1000/200 mg every 8 hours.

Prophylaxis of complications during surgical procedures

For surgeries lasting less than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at anesthesia induction (the 2000/200 mg dose may be achieved using another intravenous formulation of Xivulan).

For surgeries lasting more than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at anesthesia induction, followed by 1000/200 mg every 8 hours (three doses within 24 hours).

If clinical signs of infection are present during surgery, a full course of treatment with intravenous or oral administration of the drug should be initiated in the postoperative period.

Dosing for children with body weight < 40 kg

Children aged 3 months and older – 25/5 mg/kg body weight every 8 hours.

Children under 3 months of age or with body weight less than 4 kg – 25/5 mg/kg body weight every 12 hours.

Geriatric patients Dose adjustment is not required.

Renal impairment

Dosage adjustment is based on the maximum recommended doses of amoxicillin. Creatinine clearance > 30 mL/min – no dosage adjustment required.

Adults and children with body weight ≥ 40 kg

Creatinine clearance 10–30 mL/min	Initial dose – 1000/200 mg, then 500/100 mg twice daily
Creatinine clearance < 10 mL/min	Initial dose – 1000/200 mg, then 500/100 mg every 24 hours
Hemodialysis	Initial dose – 1000/200 mg, then 500/100 mg every 24 hours + 500/100 mg after dialysis

Adults and children with body weight <40 kg

Creatinine clearance 10–30 mL/min	25/5 mg/kg every 12 hours
Creatinine clearance < 10 mL/min	25/5 mg/kg every 24 hours
Hemodialysis	25/5 mg/kg every 24 hours + 12.5/2.5 mg after dialysis

Hepatic impairment

Caution is required in dosing and continuous monitoring of liver function at regular intervals.

Xevulan should be administered by intravenous injection (bolus) or by intermittent infusion (intravenous drip). Xevulan must not be administered intramuscularly.

In children under 3 months of age, Xevulan should be administered only as an intravenous infusion. Treatment with Xevulan may be initiated by intravenous administration and continued with oral formulations.

Preparation of solution for intravenous injection

1000/200 mg: dissolve the contents of the vial in 20 ml of water for injections (final volume 20.9 ml). A temporary pinkish discoloration may or may not appear during dissolution, which disappears. Xevulan solutions are usually colorless or have a yellow color.

The prepared Xevulan solution must be used within 20 minutes after reconstitution.

Preparation of solution for intravenous infusion

The reconstituted solution of 1000/200 mg, as described above, should be immediately added without delay to 100 ml of infusion fluid (preferably using a mini-bag or burette). The infusion should be administered over 30–40 minutes. Xevulan is chemically and physically stable for 3 hours at 25 °C or for 6 hours at 5 °C after reconstitution. From a microbiological standpoint, the prepared solution should be administered immediately.

Intravenous infusions of Xevulan may be carried out using various intravenous fluids. Adequate antibiotic concentration is maintained at 5 °C and at room temperature (25 °C) in the recommended volumes of the infusion fluids listed in the table below. When the drug is reconstituted and stored at room temperature, infusions should be administered within the time specified below.

Solution for intravenous (i.v.) administration	Stability period at 25 °C, hours
Water for injections	3
0.9 % sodium chloride solution	3
Compound sodium chloride solution (Ringer's solution)	3

If stored at 5 °C, the 1000/200 mg solution may be added to a previously cooled infusion solution (water for injections or 0.9 % sodium chloride solution); the resulting preparation may be stored at the specified temperature for up to 6 hours.

After the solution reaches room temperature, it should be used immediately. The stability of Xivulan solutions depends on the concentration. If a solution of higher concentration is prepared, the stability period of the solution increases proportionally.

Any unused solution should be disposed of according to current requirements.

Children.

Can be used in children from the first days of life.

Overdose.

Symptoms

Gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Crystalluria associated with amoxicillin administration has been observed, which in some cases led to renal failure (see section

"Special precautions for use").

Seizures may occur in patients with impaired renal function and in patients receiving high doses of the drug.

Precipitation of amoxicillin in urinary catheters has been reported, mainly after intravenous administration in high doses. The patency of catheters should be checked regularly (see section "Special precautions for use").

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Adverse Reactions

The most commonly reported adverse reactions to the medicinal product are diarrhoea, nausea and vomiting. The list of known adverse reactions to the medicinal product, identified from clinical trials of Xyvulan and post-marketing surveillance, classified by MedDRA System Organ Class, is provided below.

The following classification of adverse reaction frequency is applied:
Very common ≥ 1/10;
Common ≥ 1/100 to < 1/10;
Uncommon ≥ 1/1,000 to < 1/100;
Rare ≥ 1/10,000 to < 1/1,000;
Very rare < 1/10,000;
Not known (frequency cannot be estimated from available data).

Infections and infestations
Common: Cutaneous and mucocutaneous candidiasis.
Not known: Overgrowth of microorganisms not sensitive to the medicinal product.

Blood and lymphatic system disorders
Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia.
Not known: Reversible agranulocytosis and haemolytic anaemia; prolonged bleeding time and prothrombin index^1.

Immune system disorders^10
Not known: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders
Uncommon: Dizziness, headache.
Not known: Seizures^2, aseptic meningitis.

Vascular disorders
Rare: Thrombophlebitis^3.

Gastrointestinal disorders
Common: Diarrhoea.
Uncommon: Nausea, vomiting, gastric disturbances.
Not known: Antibiotic-associated colitis^4, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders
Uncommon: Increased levels of AST and/or ALT^5.
Not known: Hepatitis^6 and cholestatic jaundice^6.

Skin and subcutaneous tissue disorders^7
Uncommon: Skin rashes, pruritus, urticaria.
Rare: Erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis^9, drug reaction with eosinophilia and systemic symptoms (DRESS), linear immunoglobulin A (IgA) disease.

Renal and urinary disorders
Very rare: Interstitial nephritis.
Not known: Crystalluria (including acute kidney injury).

Cardiac disorders
Not known: Quincke's oedema (angioedema).

^1 See section "Special warnings and precautions for use".
^2 See section "Special warnings and precautions for use".
^3 At the injection site.
^4 Including pseudomembranous colitis and haemorrhagic colitis (see section "Special warnings and precautions for use").
^5 Mild elevations in AST and/or ALT levels have been observed more frequently in patients receiving beta-lactam antibiotics; however, the clinical significance of these findings is unknown.
^6 These events have been observed with other penicillin and cephalosporin antibiotics (see section "Special warnings and precautions for use").
^7 If hypersensitivity reactions (dermatitis) occur, discontinue the medicinal product (see section "Special warnings and precautions for use").
^8 See section "Overdose".
^9 See section "Special warnings and precautions for use".
^10 See section "Contraindications" and "Special warnings and precautions for use".

Shelf life. 3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibilities
Xyvulan must not be mixed with blood products, other protein-containing solutions, including protein hydrolysates, or fat emulsions for intravenous administration.

If Xyvulan is administered concomitantly with an aminoglycoside, the antibiotics must not be mixed in the same syringe, intravenous container, or other receptacle, as the aminoglycoside activity may be lost.

Packaging.
Vial; pack of 1, 10 or 25 vials in a cardboard box labelled in Ukrainian and English.

Prescription status. Prescription only.

Manufacturer. ANTIMICOTICE SA ANTIBIOTICE SA

Manufacturer's address and place of business.
1, Valea Lupului Street, 707410, Iasi, Romania
1, Valea Lupului Street, 707410, Iasi, Romania