Vancomycin

Overdose

Toxicity due to overdose has been reported. 500 mg IV to a child, 2 year of age, resulted in lethal intoxication. Administration of a total of 56 g during 10 days to an adult resulted in renal insufficiency. In certain high-risk conditions (e. g. in case of severe renal impairment) high serum levels and oto- and nephrotoxic effects can occur.

Measures in case of overdose

- A specific antidote is not known.

- Symptomatic treatment while maintaining renal function is required.

- Vancomycin is poorly removed from the blood by haemodialysis or peritoneal dialysis. Haemofiltration or haemoperfusion with polysulfone resins have been used to reduce serum concentrations of vancomycin.

Shelf life

Powder:

2 years

Reconstituted concentrate:

Should be used immediately after reconstitution with water for injections.

Further diluted solution:

Chemical and physical in-use stability has been demonstrated for 48 hours at 2°-8°C and 25°C with Sodium Chloride 9 mg/ml (0.9%) Injection and Glucose 50 mg/ml (5%) Injection.

From a microbiological point of view, unless the method of reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C.

Vancomycin price

Incompatibilities

Vancomycin has a low pH that may cause chemical or physical instability when it is mixed with other substances. Therefore, each parenteral solution should be checked visually for precipitations and discolouration prior to use.

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.

List of excipients

None.

Undesirable effects

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 use of vancomycin.

Tabulated List of Adverse reactions

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions listed below are defined using the following MedDRA convention and system organ class database:

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).

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.

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. 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 drug 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in: Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

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.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Glycopeptide antibacterials, ATC Code: J01XA01.

Mechanism of action

Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall in sensitive bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units. The drug is slowly bactericidal for dividing microorganisms. In addition, it impairs the permeability of the bacterial cell membrane and RNA synthesis.

Pharmacokinetic/ Pharmacodynamic relationship

Vancomycin displays concentration-independent activity with the area under the concentration curve (AUC) divided by the minimum inhibitory concentration (MIC) of the target organism as the primary predictive parameter for efficacy. On basis of in vitro, animal and limited human data, an AUC/MIC ratio of 400 has been established as a PK/PD target to achieve clinical effectiveness with vancomycin. To achieve this target when MICs are > 1.0 mg/l, dosing in the upper range and high trough serum concentrations (15-20 mg/l) are required.

Mechanism of resistance

Acquired resistance to glycopeptides is most common in enterococci and is based on acquisition of various van gene complexes which modifies the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine which bind vancomycin poorly. In some countries, increasing cases of resistance are observed particularly in enterococci; multi-resistant strains of Enterococcus faecium are especially alarming.

Van genes have rarely been found in Staphylococcus aureus, where changes in cell wall structure result in “intermediate” susceptibility, which is most commonly heterogeneous. Also, methicillin-resistant staphylococcus strains (MRSA) with reduced susceptibility for vancomycin were reported. The reduced susceptibility or resistance to vancomycin in Staphylococcus is not well understood. Several genetic elements and multiple mutations are required.

There is no cross-resistance between vancomycin and other classes of antibiotics. Cross-resistance with other glycopeptide antibiotics, such as teicoplanin, does occur. Secondary development of resistance during therapy is rare.

Synergism

The combination of vancomycin with an aminoglycoside antibiotic has a synergistic effect against many strains of Staphylococcus aureus, non-enterococcal group 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.

Susceptibility testing breakpoints

Vancomycin is active against gram-positive bacteria, such as staphylococci, streptococci, enterococci, pneumococci, and clostridia. Gram-negative bacteria are resistant.

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. This information only provides approximate guidance on the chance whether micro-organisms are susceptible to vancomycin.

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

1S. aureus with vancomycin MIC values of 2 mg/L are on the border of the wild type distribution and there may be an impaired clinical response.

Pharmacokinetic properties

Absorption

Vancomycin is administered intravenously for the treatment of systemic infections.

In the case of patients with normal renal function, intravenous infusion of multiple doses of 1g vancomycin (15 mg/kg) for 60 minutes produces approximate average plasma concentrations of 50-60 mg/L, 20-25 mg/L and 5-10 mg/L, immediately, 2 hours and 11 hours after completing the infusion, respectively. The plasma levels obtained after multiple doses are similar to those achieved after a single dose.

Distribution

The volume of distribution is about 60 L/1.73 m2 body surface. At serum concentrations of vancomycin of 10 mg/l to 100 mg/l, the binding of the drug to plasma proteins is approximately 30-55%, measured by ultra-filtration.

Vancomycin diffuses readily across the placenta and is distributed into cord blood. In non-inflamed meninges, vancomycin passes the blood-brain barrier only to a low extent.

Biotransformation

There is very little metabolism of the drug. After parenteral administration it is excreted almost completely as microbiologically active substance (approx. 75-90% within 24 hours) through glomerular filtration via the kidneys.

Elimination

The elimination half-life of vancomycin is 4 to 6 hours in patients with normal renal function and 2.2-3 hours in children. Plasma clearance is about 0.058 L/kg/h and kidney clearance about 0.048 L/kg/h. In the first 24 hours, approximately 80 % of an administered dose of vancomycin is excreted in the urine through glomerular filtration. Renal dysfunction delays the excretion of vancomycin. In anephric patients, the mean half-life is 7.5 days. Due to ototoxicity of vancomycin therapy-adjuvant monitoring of the plasma concentrations is indicated in such cases.

Biliary excretion is insignificant (less than 5% of a dose).

Although the vancomycin is not eliminated efficiently by haemodialysis or peritoneal dialysis, there have been reports of an increase in vancomycin clearance with haemoperfusion and haemofiltration.

Linerarity/non-linearity

Vancomycin concentration generally increases proportionally with increasing dose. Plasma concentrations during multiple dose administration are similar to those after the administration of a single dose.

Characteristics in specific groups

Renal impairment

Vancomycin is primarily cleared by glomerular filtration. Posology and method of administration.

Hepatic impairment

Vancomycin pharmacokinetics is not altered in patients with hepatic impairment.

Pregnant Women

Significantly increased doses may be required to achieve therapeutic serum concentrations in pregnant women.

Overweight patients

Vancomycin distribution may be altered in overweight patients due to increases in volume of distribution, in renal clearance and possible changes in plasma protein binding. In these subpopulations vancomycin serum concentration was found higher than expected in male healthy adults.

Paediatric population

Vancomycin PK has shown wide inter-individual variability in preterm and term neonates. In neonates, after intravenous administration, vancomycin volume of distribution varies between 0.38 and 0.97 L/kg, similar to adult values, while clearance varies between 0.63 and 1.4 ml/kg/min. Half-life varies between 3.5 and 10 h and is longer than in adults, reflecting the usual lower values for clearance in the neonate.

In infants and older children, the volume of distribution ranges between 0.26-1.05 L/kg while clearance varies between 0.33-1.87 ml/kg/min.

Date of revision of the text

03/05/2018

Marketing authorisation holder

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó n.° 8, 8A e 8B - Fervença

2705-906 Terrugem SNT

Portugal

Tel.: ++351 21 960 84 10

Fax: ++351 21 961 51 02

E-mail: [email protected]

Special precautions for storage

Powder before opening:

Store below 25°C.

Keep the vial in the outer carton in order to protect from light.

Reconstituted concentrate and diluted product:

Nature and contents of container

Type I, colourless glass vials, of 20 ml, with rubber stopper and aluminium cap, with "flip-off" like, easy opening plastic device.

Pack sizes:

Powder in 20 ml glass vial, carton boxes of 1 or 10 vials.

Not all pack sizes may be marketed.

Marketing authorisation number(s)

PL 15413/0008

Fertility, pregnancy and lactation

Pregnancy

There is insufficient safety experience 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.

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.

In a study conducted in neonates of women who were administered the drug during pregnancy, no sensorineural hearing loss or nephrotoxicity were reported. One infant, whose mother received vancomycin in the third trimester, experienced conductive hearing loss, but no cause/effect relation was established.

Breastfeeding

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, a decision to stop breast feeding should be considered.

Vancomycin is excreted in breast milk, therefore it is not recommended the use in nursing women.

Effects on ability to drive and use machines

Vancomycin has no or negligible influence on the ability to drive and use machines.

Special precautions for disposal and other handling

The product must be reconstituted and the resulting concentrate must then be diluted immediately prior to use.

Preparation of the reconstituted concentrate

Dissolve Vancomycin 1000 mg Powder for concentrate for solution for infusion in 20 ml of sterile Water for injection.

One ml of reconstituted concentrate contains 50 mg of vancomycin.

Appearance of reconstituted concentrate

After reconstitution, the solution is clear and colourless to slightly yellowish brown without visible particles.

Preparation of final diluted Solution for infusion

Reconstituted solutions containing 50 mg/ml of vancomycin should be further diluted.

Suitable diluents are:

Sodium Chloride 9 mg/ml (0.9%) Injection

Glucose 50 mg/ml (5%) Injection

Intermittent infusion:

Reconstituted solution containing 1000 mg vancomycin (50 mg/ml) must be diluted further with at least 200 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 above 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, free from extraneous particles.

Before administration, the reconstituted and diluted solutions should be inspected visually for particulate matter and discoloration. Only clear and colourless 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.

Date of first authorisation/renewal of the authorisation

17/10/2012 / 28/12/2017

Interaction with other medicinal products and other forms of interaction

Other potentially nephrotoxic or ototoxic medications

Concurrent or sequential administration of vancomycin with other potentially neurotoxic or/and nephrotoxic active substances particularly gentamycin, amphotericin B, streptomycin, neomycin, kanamycin, amikacin, tobramycin, viomycin, bacitracin, polymyxin B, colistin and cisplatin may potentiate the nephrotoxicity and/or ototoxicity of vancomycin and consequently requires careful monitoring of the patient.

Because of synergic action (e.g. with gentamycin) in these cases the maximum dose of vancomycin has to be restricted to 500 mg every 8 hours.

Anaesthetics

Concurrent administration of vancomycin and anaesthetic agents has been associated with erythema, histamine like flushing and anaphylactoid reactions. This may be reduced if the vancomycin is administered over 60 minutes before anaesthetic induction.

Muscle relaxants

If vancomycin is administered during or directly after surgery, the effect (neuromuscular blockade) of muscle relaxants (such as succinylcholine) concurrently used can be enhanced and prolonged.