Edicin

Vancomycin hydrochloride.

Each Edicin 0.5 g vial contains 0.5 g of vancomycin in the form of hydrochloride.
Excipients/Inactive Ingredients: None.

Pharmacotherapeutic group: Glycopeptide antibacterials. ATC code: J01XA01.
PHARMACOLOGY: Pharmacodynamics: Mode of action: Vancomycin is a glycopeptide antibiotic. Vancomycin has a bactericidal effect on proliferating germs by inhibiting the biosynthesis of the cell wall. In addition, it impairs the permeability of the bacterial cell membrane and RNA synthesis.
Mechanism(s) of resistance: Acquired resistance to glycopeptides is based on acquisition of various van gene complexes. Van genes have rarely been found in Staphylococcus aureus, where changes in cell wall structure result in "intermediate" susceptibility, which is most commonly heterogeneous.
There is no cross-resistance between vancomycin and other antibiotics but cross-resistance with other glycopeptide antibiotics, such as teicoplanin, does occur. Secondary development of resistance during therapy is rare.
In some countries, increasing cases of resistance are observed particularly in enterococci; multi-resistant strains of Enterococcus faecium are especially alarming.
Synergism: The combination of vancomycin with an aminoglycoside antibiotic has a synergistic effect against many strains of Staphylococcus aureus, non-enterococcal D-streptococci, enterococci and streptococci of the Viridans group. The combination of vancomycin with a cephalosporin has a synergistic effect against some oxacillin-resistant Staphylococcus epidermidis strains, and the combination of vancomycin with rifampicin has a synergistic effect against Staphylococcus epidermidis and a partial synergistic effect against some Staphylococcus aureus strains. As vancomycin in combination with a cephalosporin may also have an antagonistic effect against some Staphylococcus epidermidis strains and in combination with rifampicin against some Staphylococcus aureus strains, preceding synergism testing is useful.
Specimens for bacterial cultures should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to vancomycin.
Breakpoints: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST, version 2.0, valid from 2012-01-01) for Staphylococcus spp. (including S. aureus, excluding Coagulase-negative staphylococci), Gram-positive anaerobes and Streptococcus spp. are Susceptible ≤ 2 mg/L and Resistant > 2 mg/L; for Enterococcus spp. and Coagulase-negative staphylococci are Susceptible ≤ 4 mg/L and Resistant > 4 mg/L.
Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent is at least some types of infections is questionable.
Vancomycin has a narrow spectrum of action.
Commonly susceptible species: Staphylococcus spp; Streptococcus pneumoniae; Streptococcus spp; Corynebacterium spp; Enterococcus spp.
Species for which acquired resistance may be a problem: Enterococcus faecium.
Inherently resistant organisms: Gram-negative bacteria, mycobacteria, fungi.
Pharmacokinetics: Distribution: Following intravenous administration, vancomycin is distributed to almost all tissues and diffuses in pleural, pericardial, ascitic and synovial fluid as well as in the cardiac muscle and in heart valves. Comparable high concentrations are achieved as in blood plasma. Data about the vancomycin concentrations in bone (spongiosa, compacta) vary widely. The apparent distribution volume in steady state is stated to be 0.43 (up to 0.9) L/kg. In non-inflamed meninges vancomycin passes the blood-brain barrier only to a low extent. Vancomycin is bound to plasma proteins at 30 to 55% and even higher.
Elimination: Vancomycin is metabolized only to a low extent. After parenteral administration it is excreted almost completely as microbiologically active substance (approx. 75-90% within 24 hours) through glomerular filtration via the kidneys.
Biliary excretion is insignificant (less than 5% of a dose).
In patients with normal renal function the half-life in serum is about 4-6 (5-11) hours, in children 2.2-3 hours. In impaired renal function, the half-life of vancomycin may be considerably prolonged (up to 7.5 days). Due to ototoxicity of vancomycin therapy-adjuvant monitoring of the plasma concentrations is indicated in such cases.
Mean plasma concentrations after i.v. infusion of 1000 mg vancomycin over 60 minutes were about 63 mg/L at the end of the infusion, about 23 mg/L after 2 hours and about 8 mg/L after 11 hours.
The clearance of vancomycin from plasma correlates nearly with the glomerular filtration rate.
The total systemic and renal clearance of vancomycin can be reduced in elderly patients.
As studies in anephric patients showed, the metabolic clearance seems to be very low.
No vancomycin metabolites have been identified so far in humans.
If vancomycin is given during a peritoneal dialysis via the intraperitoneal route, approx. 60% reaches the systemic circulation during 6 hours. After i.p. administration of 30 mg/kg BW, serum levels of approx. 10 mg/l are achieved.
In case of oral use, high-polar vancomycin is virtually not absorbed. It appears after oral administration in active form in the stool, and is therefore a suitable chemotherapeutic for pseudomembranous colitis and staphylococcal colitis.
Vancomycin diffuses readily across the placenta and is distributed into cord blood.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
Limited data on mutagenic effects show negative results, long-term studies in animals regarding a carcinogenic potential are not available. In teratogenicity studies, where rats and rabbits received doses approximately corresponding to the human dose based on body surface (mg/m²), no direct or indirect teratogenic effects were observed.
Animal studies of the use during the perinatal/postnatal period and regarding effects on fertility are not available.

Vancomycin is indicated for the treatment of severe infections caused by gram-positive microorganisms resistant to other antimicrobial drugs, and for patients with known allergy to penicillins and cephalosporins: endocarditis, sepsis, osteomyelitis, central nervous system infections, lower respiratory tract infections (pneumonia), skin and soft tissue infections.

The usual intravenous infusion dose is 500 mg every 6 hours or 1 g every 12 hours. Each dose should be administered slowly at the rate not exceeding 10 mg/min over a period of at least 60 minutes or longer.
Children: Neonates up to the age of 7 days: an initial dose of 15 mg/kg should be given followed by 10 mg/kg every 12 hours.
Neonates up to the age of 1 month: an initial dose of 15 mg/kg should be given followed by 10 mg/kg every 8 hours.
Infants older than 1 month of age: the recommended dosage is 40 mg/kg daily, divided to individual doses given every 6 or 12 hours.
Adults: The usual intravenous infusion dose is 500 mg every 6 hours or 1 g every 12 hours. Each dose should be administered slowly at the rate not exceeding 10 mg/min over a period of at least 60 minutes or longer.
In patients with impaired renal function, the dose and/or dose intervals should be adjusted carefully to the severity of impairment.
An initial dose of 15 mg/kg body weight should be given, later on the dose interval may be prolonged depending on creatinine clearance. (See table.)

Click on icon to see table/diagram/image

Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed from the blood by haemodialysis or peritoneal dialysis. Haemoperfusion with Amberlite resin XAD-4 has been reported to be of limited benefit.

Hypersensitivity to the active substance or to any of the excipients (see Precautions).
Vancomycin should not be administered intramuscularly due to the risk of necrosis at the site of administration.

Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions are possible (see Contraindications and Adverse Reactions). In case of hypersensitivity reactions, treatment with vancomycin must be discontinued immediately and the adequate emergency measures must be initiated.
In patients receiving vancomycin over a longer-term period or concurrently with other medications which may cause neutropenia or agranulocytosis, the leukocyte count should be monitored at regular intervals.
All patients receiving vancomycin should have periodic haematologic studies, urine analysis, liver and renal function tests.
Vancomycin should be used with caution in patients with allergic reactions to teicoplanin, since cross hypersensitivity, including fatal anaphylactic shock, may occur.
Spectrum of antibacterial activity: Vancomycin has a spectrum of antibacterial activity limited to Gram-positive organisms. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a high suspicion that the most likely pathogen(s) would be suitable for treatment with vancomycin.
The rational use of vancomycin should take into account the bacterial spectrum of activity, the safety profile and the suitability of standard antibacterial therapy to treat the individual patient.
Ototoxicity: Ototoxicity, which may be transitory or permanent (see Adverse Reactions) has been reported in patients with prior deafness, who have received excessive intravenous doses, or who receive concomitant treatment with another ototoxic active substance such as an aminoglycoside. Vancomycin should also be avoided in patients with previous hearing loss.
Deafness may be preceded by tinnitus. Experience with other antibiotics suggests that deafness may be progressive despite cessation of treatment.
To reduce the risk of ototoxicity, blood levels should be determined periodically and periodic testing of auditory function is recommended.
Infusion-related reactions: Rapid bolus administration (i.e. over several minutes) may be associated with exaggerated hypotension, including shock, and, rarely, cardiac arrest, histamine like responses and maculopapular or erythematous rash ("red man's syndrome" or "red neck syndrome").
Vancomycin should be infused slowly in a dilute solution (2.5 to 5.0 mg/ml) at a rate no greater than 10 mg/min and over a period not less than 60 minutes to avoid rapid infusion-related reactions. Stopping the infusion usually results in a prompt cessation of these reactions.
The frequency of infusion-related reactions (hypotension, flushing, erythema, urticaria and pruritus) increases with the concomitant administration of anaesthetic agents (see Interactions). This may be reduced by administering vancomycin by infusion over at least 60 minutes, before anaesthetic induction.
Severe bullous reactions: Stevens-Johnson syndrome (SJS) has been reported with the use of vancomycin (see Adverse Reactions). If symptoms or signs of SJS (e.g. progressive skin rash often with blisters or mucosal lesions) are present, vancomycin treatment should be discontinued immediately and specialised dermatological assessment be sought.
Administration site related reactions: Pain and thrombophlebitis may occur in many patients receiving intravenous vancomycin and are occasionally severe. The frequency and severity of thrombophlebitis can be minimised by administering the medicinal product slowly as a dilute solution (see Dosage & Administration) and by changing the sites of infusion regularly.
The efficacy and safety of vancomycin has not been established for the intrathecal, intralumbar and intraventricular routes of administration.
Nephrotoxicity: Vancomycin should be used with care in patients with renal insufficiency, including anuria, as the possibility of developing toxic effects is much higher in the presence of prolonged high blood concentrations. The risk of toxicity is increased by high blood concentrations or prolonged therapy.
Regular monitoring of the blood levels of vancomycin is indicated in high dose therapy and longer-term use, particularly in patients with renal dysfunction or impaired faculty of hearing as well as in concurrent administration of nephrotoxic or ototoxic substances, respectively (see Dosage & Administration).
Drug interactions with anaesthetic agents: Anaesthetic induced myocardial depression may be enhanced by vancomycin. During anaesthesia, doses must be well diluted and administered slowly with close cardiac monitoring. Position changes should be delayed until the infusion is completed to allow for postural adjustment (see Interactions).
Pseudomembranous enterocolitis: In case of severe persistent diarrhoea the possibility of pseudomembranous enterocolitis that might be life-threatening has to be taken into account (see Adverse Reactions). Anti-diarrhoeic medicinal products must not be given.
Superinfection: Prolonged use of vancomycin may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
In rare instances, there have been reports of pseudomembranous colitis, due to C. difficile, developing in patients who received intravenous vancomycin.
Effects on ability to drive and use machines: Vancomycin has negligible influence on the ability to drive and use machines.
Use in Children: The current intravenous dosing recommendations for the paediatric population, in particular for children below 12 years of age, may lead to sub-therapeutic vancomycin levels in a substantial number of children. However, the safety of increased vancomycin dosing has not been properly assessed and higher doses than 60 mg/kg/day cannot be generally recommended.
Vancomycin should be used with particular care in premature neonates and young infants, because of their renal immaturity and the possible increase in the serum concentration of vancomycin. The blood concentrations of vancomycin should therefore be monitored carefully in these children. Concomitant administration of vancomycin and anaesthetic agents has been associated with erythema and histamine-like flushing in children. Similarly, concomitant use with nephrotoxic agents such as aminoglycoside antibiotics, NSAIDs (e.g., ibuprofen for closure of patent ductus arteriosus) or amphotericin B is associated with an increased risk of nephrotoxicity (see Interactions) and therefore more frequent monitoring of vancomycin serum levels and renal function is indicated.
Use in the elderly: The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if the dose is not adjusted (see Dosage & Administration).
Ototoxicity: The elderly are particularly susceptible to auditory damage. Monitoring of vestibular and auditory function in the elderly should be carried out during and after treatment. Concurrent or sequential use of other ototoxic substances should be avoided.

Pregnancy: No sufficient safety experience is available regarding vancomycin during human pregnancy. Reproduction toxicological studies on animals do not suggest any effects on the development of the embryo, foetus or gestation period (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).
However, vancomycin penetrates the placenta and a potential risk of embryonal and neonatal ototoxicity and nephrotoxicity cannot be excluded. Therefore vancomycin should be given in pregnancy only if clearly needed and after a careful risk/benefit evaluation.
Breast-feeding: Vancomycin is excreted in human milk and should be therefore used in lactation period only if other antibiotics have failed. Vancomycin should be cautiously given to breast-feeding mothers because of potential adverse reactions in the infant (disturbances in the intestinal flora with diarrhoea, colonisation with yeast-like fungi and possibly sensibilisation).
Considering the importance of this medicine for nursing mother, the decision to stop breastfeeding should be considered.

Summary of the safety profile: The most common adverse reactions are phlebitis, pseudo-allergic reactions and flushing of the upper body ("red-neck syndrome") in connection with too rapid intravenous infusion of vancomycin.
List of adverse reactions: Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The adverse reactions listed as follows are defined using the following MedDRA: 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 (cannot be estimated from the available data).
Blood and the lymphatic system disorder: Rare: Reversible neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, pancytopenia.
Immune system disorders: Rare: Hypersensitivity reactions, anaphylactic reactions.
Ear and labyrinth disorders: Uncommon: Transient or permanent loss of hearing.
Rare: Vertigo, tinnitus, dizziness.
Cardiac disorders: Very rare: Cardiac arrest.
Vascular disorders: Common: Decrease in blood pressure.
Rare: Vasculitis.
Respiratory, thoracic and mediastinal disorders: Common: Dyspnoea, stridor.
Gastrointestinal disorders: Rare: Nausea.
Very rare: Pseudomembranous enterocolitis.
Not known: Vomiting, diarrhoea.
Skin and subcutaneous tissue disorders: Common: Flushing of the upper body ("red man syndrome"), exanthema and mucosal inflammation, pruritus, urticaria.
Very rare: Exfoliative dermatitis, Stevens-Johnson syndrome, Lyell's syndrome, Linear IgA bullous dermatosis.
Not known: Eosinophilia and systemic symptoms (DRESS syndrome), AGEP (acute generalised exanthematous pustulosis).
Renal and urinary disorders: Common: Renal insufficiency manifested primarily by increased serum creatinine and serum urea.
Rare: Interstitial nephritis, acute renal failure.
Not known: Acute tubular necrosis.
General disorders and administration site conditions: Common: Phlebitis, redness of the upper body and face.
Rare: Drug fever, shivering, pain and muscle spasm of the chest and back muscles.
Description of selected adverse drug reactions: Reversible neutropenia usually starting one week or more after onset of intravenous therapy or after total dose of more than 25 g.
Intravenous vancomycin should be infused slowly. During or shortly after rapid infusion anaphylactic/anaphylactoid reactions including wheezing may occur.
The reactions abate when administration is stopped, generally between 20 minutes and 2 hours. Vancomycin should be infused slowly (see Dosage & Administration and Precautions). Necrosis may occur after intramuscular injection.
Tinnitus, possibly preceding onset of deafness, should be regarded as an indication to discontinue treatment.
Ototoxicity has primarily been reported in patients given high doses, or in those on concomitant treatment with other ototoxic medicinal product like aminoglycoside, or in those who had a pre-existing reduction in kidney function or hearing.
If a bullous disorder is suspected, the medicinal product should be discontinued and specialised dermatological assessment should be carried out.
Paediatric population: The safety profile is generally consistent among children and adult patients. Nephrotoxicity has been described in children, usually in association with other nephrotoxic agents such as aminoglycosides.

Concomitant administration of vancomycin and anaesthetic agents has been associated with erythema, histamine-like flushing and anaphylactoid reactions.
There have been reports that the frequency of infusion-related events increases with the concomitant administration of anaesthetic agents. Infusion-related events may be minimised by the administration of vancomycin as a 60-minute infusion prior to anaesthetic induction.
Concurrent or sequential systemic or topical use of other potentially ototoxic, neurotoxic, or nephrotoxic medicinal products, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin or cisplatin, when indicated, requires careful monitoring.
There is an increased potential of neuromuscular blockade with concomitant administration of vancomycin and neuromuscular blocking agents.

Incompatibilities: Vancomycin solutions have a low pH value. This may lead to chemical or physical instability if mixed with other substances. Therefore, each parenteral solution should be checked visually for precipitations and discolouration prior to use.
This medicinal product must not be mixed with other medicinal products except those mentioned in Instructions for use and handling as follows.
Combination therapy: In case of combination therapy of vancomycin with other antibiotics/chemotherapeutics, the preparations should be administered separately.
Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous lines between administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less.
Instructions for use and handling: The product must be reconstituted and the resulting concentrate must then be diluted prior to use.
Preparation of the reconstituted solution: Dissolve Vancomycin 500 mg Powder for solution for infusion in 10 ml of sterile Water for injection.
One ml of reconstituted solution contains 50 mg of vancomycin.
Appearance of reconstituted solution: After reconstitution the solution is clear and colorless to slightly yellowish brown without visible particles.
For storage conditions of the reconstituted medicinal product, see Shelf-life under Storage.
Preparation of final diluted Solution for infusion: Reconstituted solutions containing 50 mg/ml of vancomycin should be further diluted.
Suitable diluents are: 5% Glucose Injection or 0.9% Sodium Chloride Injection or 5% Glucose Injection with 0.9% Sodium Chloride Injection.
Intermittent infusion: Reconstituted solution containing 500 mg of vancomycin (50 mg/ml) must be diluted further with at least 100 ml diluent (to 5 mg/ml).
The concentration of vancomycin in Solution for infusion should not exceed 5 mg/ml.
The desired dose should be administered slowly by intravenous use at a rate of no more than 10 mg/minute, for at least 60 minutes or even longer.
Continuous infusion: This should be used only if treatment with an intermittent infusion is not possible. Dilute 1000 mg to 2000 mg of dissolved vancomycin in a sufficient amount of the previously mentioned suitable diluent and administer it in the form of a drip infusion, so that the patient will receive the prescribed daily dose in 24 hours.
Appearance of diluted solution: After dilution the solution is clear and colorless without visible particles.
For storage conditions of the diluted medicinal product, see Shelf-life under Storage.
Before administration, the reconstituted and diluted solutions should be inspected visually for particulate matter and discoloration. Only clear, and colorless solution free from particles should be used.
Disposal: Vials are for single use only. Unused medicinal products must be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Powder: Do not store above 25°C.
For storage conditions of the reconstituted and diluted medicinal product, see Shelf-life as follows.
Shelf-life: Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C and 96 hours at 2-8°C.
Further diluted solution: Solutions for infusion that are diluted to 5 mg/mL with 5% Glucose Injection or 0.9% Sodium Chloride Injection are chemically and physically stable in a refrigerator (2°C - 8°C) for 48 hours, or at 25°C for 24 hours.
Solutions for infusion that are diluted to 5 mg/mL with 5% Glucose Injection + 0.9% Sodium Chloride Injection are chemically and physically stable in refrigerator (2°C - 8°C) for 48 hours, or at 25°C for 24 hours.
From a microbiological point of view the medicinal product should be used immediately unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.
If not used immediately, in-use storage times and conditions are the responsibility of the user.

Other Antibiotics

J01XA01 - vancomycin ; Belongs to the class of glycopeptide antibacterials. Used in the systemic treatment of infections.

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