Vancomycin 1000 Mg Powder For Concentrate For Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Vancomycin 1000 mg Powder for concentrate for solution for infusion.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 1000 mg vancomycin (as vancomycin hydrochloride) equivalent to 1,000,000 IU.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion ‘A white to cream coloured porous cake’
After reconstitution a solution is obtained with a pH of approximately 3.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Intravenous vancomycin is indicated in the following severe infections caused by gram-positive bacteria susceptible to vancomycin which cannot be treated or failed to respond or are resistant to other antibiotics such as penicillins and cephalosporins (see section 5.1).
- endocarditis
- infections of the bones (osteomyelitis)
- pneumonia
- soft tissue infections
Where appropriate, vancomycin should be co-administered with other antibacterial agents. Endocarditis caused by enterococci, Streptococcus viridans or S. bovis should be treated with a combination of vancomycin and an aminoglycoside.
Vancomycin may be used for the perioperative prophylaxis against bacterial endocarditis, in patients at high risk of developing bacterial endocarditis when they undergo major surgical procedures (e.g., cardiac and vascular procedures, etc) and are unable to receive a suitable beta-lactam antibacterial agent.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Method of administration: For intravenous use only.
Parenterally vancomycin shall only be administered as slow intravenous infusion (not more than 10 mg/min - over at least 60 min) which is sufficiently diluted (at least 100 ml per 500 mg or at least 200 ml per 1000 mg). Concentrations of no more than 5 mg/ml are recommended.
In selected patients in need of fluid restriction, concentration up to 10 mg/ml may be used; use of such higher concentrations may increase the risk of infusion-related events. Infusions should be given over at least 60 minutes. In adults, if doses exceeding 500 mg are used, a rate of infusion of no more than 10 mg/min is recommended.. Infusion related events may occur, however, at any rate or concentration.
The dose should be individually adapted according to weight, age and renal function. Vancomycin levels can be measured to aid dose adjustments.
For information about the preparation of the solution, please refer to section 6.6
Posology
Intravenous use (infusion) in patients with normal renal function:
Adults and adolescents above 12 years of age:
The recommended daily intravenous dose is 2000 mg; divided into doses of 500 mg every 6 hours or 1000 mg every 12 hours. Or 30 to 40 mg/kg/day in 2 to 4 daily administrations. Improvement is usually seen within 48 to 72 hours.
For bacterial endocarditis, the generally accepted regimen is 1000 mg vancomycin intravenously every 12 hours for 4 weeks either alone or in combination with other antibiotics (gentamicin plus rifampicin, gentamicin, streptomycin). Enterococcal endocarditis is treated for 6 weeks with vancomycin in combination with an aminoglycoside. Official guidance should be consulted.
If vancomycin is co-administrated with a aminoglycoside (e.a. gentamycine) patients should be monitored carefully for signs of neurotoxicity and ototoxicity. The dosage should be adjusted when renal disturbance occurs (see section 4.5).
Peri-operative prophylaxis against bacterial endocarditis: Adults receive 1000mg (1g) vancomycin intravenously prior to surgery (prior to induction of anaesthesia) and depending on time and type of surgery, the dose of 1000mg (1g) of vancomycin i.v. 12 hours postoperatively can be given.
Paediatric Population
Children one month to 12 years of age:
The usual intravenous dosage is 10mg/kg per dose given every six hours (total daily dosage 40mg/kg of body weight). Each dose should be administered over a period of at least 60 minutes.
Newborn infants (full-term):
• 0-7 days of age: A starting dose of 15 mg/kg, followed by 10 mg/kg every 12 hours.
• 7-30 days of age: A starting dose of 15 mg/kg, followed by 10 mg/kg every 8 hours.
Each dose should be administered over 60 minutes. Close monitoring of serum vancomycin concentrations may be warranted in these patients.
Pregnancy:
It has been reported that significantly increased doses may be required to achieve therapeutic serum concentrations in pregnant patients - see section 4.6. Special Populations
The elderly:
Dosage reduction may be necessary to a greater extent than expected because of decreasing renal function (see below).
Obese patients:
Modification of the usual daily doses may be required.
Patients with impaired liver function:
The availability of data in patients with impaired liver function is limited. Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment.
Patients with impaired renal function:
In patients with impaired renal function the dose must be adjusted to avoid toxic serum levels. Serum levels of vancomycin should be monitored regularly. For most patients with impaired renal function the following nomogram, based on creatinine clearance, can be used to determine the dose needed.
The starting dose should always be at least 15 mg/kg.
Creatinine Clearance (ml/min/kg)
Dosage nomogram for vancomycin in patients with impaired renal function
The nomogram is not valid for functionally anephric patients on dialysis. For such patients, a loading dose of 15mg/kg body weight should be given to achieve therapeutic serum levels promptly, and the dose required to maintain stable levels is 1.9mg/kg/24 hours. Since individual maintenance doses of 250mg to 1g are convenient, in patients with marked renal impairment a dose may be given every several days rather than on a daily basis. In anuria a dose of 1g every seven to ten days has been recommended.
If polysulfone membranes are used for hemodialysis (“high flux dialysis“), the half time of vancomycin is shortened. For patients with regular hemodialysis an additional maintenance dose may be necessary.
If serum creatinine level alone is available, the following formula may be applied to calculate the creatinine clearance:
Men: Weight(kg) x (140 - age (years))
72 x serum creatinine (mg/100ml)
Women: 0.85 x value calculated by the above formula Where possible, the creatinine clearance should always be determined.
For instructions on the preparation of solutions, see section 6.6.
Measurement of vancomycin serum concentrations:
Following multiple intravenous doses, peak serum concentrations, measured two hours after infusion is complete, range from 18-26 mg/l. Trough levels measured immediately prior to the next dose should be 5-10 mg/l. Ototoxicity has been associated with serum drug levels of 80-100 mg/l, but this is rarely seen when serum levels are kept at or below 30 mg/l.
The concentrations should normally be monitored twice or three times per week.
Duration of treatment
The total duration of the treatment depends on the type and severity of the infection as well as the clinical response of the patient.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Warnings
Rapid bolus administration (eg, 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 in a dilute solution over a period of not less than 60 minutes to avoid rapid infusion-related reactions. Stopping the infusion usually results in a prompt cessation of these reactions (see section 4.2. and section 4.8).
In case of severe acute hypersensitivity reactions (e.g. anaphylaxis), the treatment with vancomycin has to be discontinued immediately and the usual appropriate emergency measures have to be started.
As cases of cross hypersensitivity have been reported, Vancomycin must be administered with care in patients with known hypersensitivity or allergic reactions to Teicoplanin
Due to its potential ototoxicity and nephrotoxicity, vancomycin should be used with care in patients with renal insufficiency and the dose should be reduced according to the degree of renal impairment. The risk of toxicity is appreciably increased by high blood concentrations or prolonged therapy. Blood levels should be monitored and renal function tests should be performed regularly. Ototoxicity, which may be transitory or permanent (see section 4.8) 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. 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.
Vancomycin should be avoided in patients with previous hearing loss. If it is used in such patients, the dose should be regulated, by periodic determination of the drug level in the blood. The elderly are more susceptible to auditory damage.
Use in paediatrics: In premature neonates and young infants, it may be appropriate to confirm desired vancomycin serum concentrations. Concomitant administration of vancomycin and anaesthetic agents has been associated with erythema and histaminelike flushing in children (see section 4.5).
Use in the elderly: The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage is not adjusted (see section 4.2).
Precautions
Regular monitoring of the blood levels of vancomycin is indicated in 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.
Doses should be titrated on the basis of serum levels. Blood levels should be monitored and renal function tests performed regularly. It is general recommendation to monitor the concentrations 2-3 times weekly.
Patients with borderline renal function and individuals over the age of 60 should be given serial tests of auditory function and of vancomycin blood levels. All patients receiving the drug should have periodic haematological studies, urine analysis and renal function tests.
Vancomycin is very irritating to tissue, and causes injection site necrosis when injected intramuscularly; it must be infused intravenously. Injection site pain and thrombophlebitis may occur in many patients receiving vancomycin and are occasionally severe.
The frequency and severity of thrombophlebitis can be minimised by administering the medicinal product slowly as a dilute solution (2.5 to 5.0g/l) and by changing the sites of infusion regularly.
The frequency of infusion-related reactions (hypotension, flushing, erythema, urticaria and pruritus) increases with the concomitant administration of anaesthetic agents. This may be reduced by administering the vancomycin by infusion over 60 minutes, before anaesthetic induction.
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. Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of vancomycin. Antiperistaltics are contraindicated.
4.5 Interaction with other medicinal products and other forms of interaction
Anaesthetics
Concomitant administration of vancomycin and anaesthetic agents has been associated with erythema, histamine-like flushing and anaphylactoid reactions. Infusion-related events may be minimised by the administration of vancomycin as a 60-minute infusion prior to anaesthetic induction.
Other potentially nephrotoxic or ototoxic medicinal products
Concurrent or sequential systemic or topical use of other potentially ototoxic, neurotoxic, or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin or cisplatin, may potentiate the nephrotoxicity and/or ototoxicity of vancomycin and consequently, requires careful monitoring. See also section 4.2 with regard to dosage adjustment in case of use with an aminoglycoside.
Muscle relaxants
There is an increased potential of neuromuscular blockade with concomitant administration of vancomycin and neuromuscular blocking agents.
4.6 Fertility, pregnancy and lactation
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 section 5.3).
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.Caution should be exercised when 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.
4.7 Effects on ability to drive and use machines
Vancomycin has negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The adverse reactions listed below is defined using the following MedDRAfrequency 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)
Intravenous infusion:
The most common adverse reactions are phlebitis and pseudo-allergic reactions in connection with too rapid intravenous infusion of vancomycin. Infections and infestations:
Not known: Overgrowth of resistant bacteria or fungi.
Blood and the lymphatic system disorder:
Rare: Thrombocytopenia, neutropenia, agranulocytosis, eosinophilia.
Immune system disorders
Rare: anaphylactic reactions, hypersensitivity reactions Ear and labyrinth disorders:
Uncommon: Transient or permanent loss of hearing.
Rare: Tinnitus, dizziness.
Cardiac disorders:
Very rare: Cardiac arrest
Vascular disorders:
Common: Decrease in blood pressure, thrombophlebitis very rare: Vasculitis
Respiratory, thoracic and mediastinal disorders:
Common: Dyspnoea, stridor.
Gastrointestinal disorders:
Rare: Nausea, diarrhoea.
Very rare: Pseudomembranous enterocolitis.
Skin and subcutaneous tissue disorders:
Common: Exanthema and mucosal inflammation, pruritus, urticaria.
Very rare: Exfoliative dermatitis, Stevens-Johnson syndrome,
Lyell's syndrome Linear IgA bullous dermatosis,
Not known: Drug rash with eosinophilia and systemic symptoms (DRESS syndrome)
has been reported during post-marketing experience.
Renal and urinary disorders:
Common: Renal insufficiency manifested primarily by increased serum creatinine.
Rare: Interstitial nephritis, acute renal failure.
General disorders and administration site conditions:
Common: Phlebitis, redness of the upper body and the face, pain and spasm of the chest and back muscles.
Rare: Drug fever, shivering.
Description of selected adverse reactions
Infusion related events:
During or shortly after rapid infusion anaphylactoid reactions may occur, including hypotension, dyspnoea, urticaria or pruritus. Redness of the skin on the upper body (Red man syndrome), pain and cramps in chest or back muscle can occur.
The reactions abate when administration is stopped, generally between 20 minutes and 2 hours. Vancomycin should be infused slowly (for more than 60 minutes - see section 4.4). Rapid bolus administration (e.g. over several minutes) may be associated with exaggerated hypotension, including shock, and, rarely, cardiac arrest.
Ototoxicity may be reversible or permanent, and has been reported mainly in patients given an overdose in patients with a history of reduced hearing, and with concomitant therapy with other ototoxic drugs, 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Toxicity due to overdose has been reported. 500mg IV to a child, 2 year of age, resulted in lethal intoxication. Administration of a total of 56g 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.
• Supportive care is advised, with maintenance of glomerular filtration. 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group, Antibacterials for systemic use Glycopeptide Antibacterials^ ATC Code: J01X A01.
Mode of action
Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the syntesis 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 bactericidal for dividing microorganisms.
PK/PD relationship
Vancomycin activity is considered to be time-dependent.
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. Cross-resistance with teicoplanin has been reported for some van genes. Van genes have rarely been found in Staphylococcus aureus, where changes in cell wall structure result in “intermediate” susceptibility, which is most commonly heterogeneous.
Susceptibility:
Vancomycin is particularly active against gram-positive bacteria, such as staphylococci, streptococci, enterococci, pneumococci, and clostridia and diphtheroides. 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.
Breakpoints
EUCAST (European Committee on Antimicrobial Susceptibility testing) recommendations
|
Susceptible |
Resistant | |
|
Staphylococcus spp. |
< 2 mg/L |
> 2 mg/L |
|
Enterococcus spp. |
< 4 mg/L |
> 4 mg/L |
|
Streptococcus spp |
< 2 mg/L |
> 2 mg/L |
|
Streptococcus pneumoniae |
< 2 mg/L |
> 2 mg/L |
|
Grampositive anaerobes |
< 2 mg/L |
< 2 mg/L |
|
Non species related* |
< 2 mg/L |
> 4 mg/L |
*Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific
breakpoint and not for those species where susceptibility testing is not recommended.
Classes
Commonly susceptible species Gram positive
Enterococcus faecalis Staphylococcus aureus
Staphylococcus coagulase negative 5.2 Streptococcus spp.
Streptococcus pneumoniae
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 plasmatic concentrations of 50-60 mcg/mL, 20-25 mcg/mL and 5-10 mcg/mL, immediately, 2 hours and 11 hours after completing the infusion, respectively. Intravenous infusion of multiple doses of 500 mg for 30 minutes produces average plasmatic concentrations of around 40-50 mg/l, 19-20 mg/l and 10-11 mg/l immediately, 2 hours and 6 hours after completing the infusion, respectively. The plasmatic levels obtained after multiple doses are similar to those achieved after a single dose.
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.
Clostridium spp.
Enterococcus faecium
Inherently resistant
Gram-negative bacteria Chlamydia spp. Mycobacteria Mycoplasma spp. Rickettsia spp._
Distribution
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.
After intravenous administration of vancomycin hydrochloride, inhibitory concentrations are found in the pleural, pericardial, ascitic and sinovial fluids, in the urine and the peritoneal dialysis fluid and in the tissue of the atrial appendix.
In non-inflamed meninges vancomycin passes the blood-brain barrier only to a low extent.
Elimination
The elimination half-life of vancomycin is 4 to 6 hours in patients with normal renal function. 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. There is very little metabolism of the drug. Approximately 35-65% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is
absorbed systemically in six hours. Serum concentrations of approximately 8 mg/litre are achieved through intraperitoneal injection of 30 mg/kg vancomycin. 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. Total systemic and renal clearance of vancomycin may be reduced in persons of advanced age.
5.3 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
None
6.2 Incompatibilities
Vancomycin solution has a low pH that may cause chemical or physical instability when it is mixed with other compounds. Mixing with alkaline solutions should be avoided. Therefore, each parenteral solution should be checked visually for precipitation and discolouration prior to use.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Powder as packaged for sale: 2 years
The reconstituted concentrate should be further diluted immediately after reconstitution.
Diluted product:
From a microbiological and physicochemical point of view, the product should be used immediately.
6.4 Special precautions for storage
Powder as packaged for sale:
Store below 25°C.
Keep the vial in the outer carton in order to protect from light.
Reconstituted concentrate and diluted product:
For storage conditions of the reconstituted concentrate and diluted product, see section 6.3.
6.5 Nature and contents of container
Colourless type 1, 20 ml glass vial, with a chlorobutyl type 1 silicone coated stopper and a green aluminium/polypropylene flip-off cap.
Pack sizes: 1 vial
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The product must be reconstituted and the resulting concentrate must then be diluted further prior to use.
Preparation of the reconstituted concentrate:
Dissolve the content of each 1000 mg vial in 20 ml of sterile water for injections.
Appearance of reconstituted concentrate:
Clear and colourless solution free from particles.
One ml of reconstituted concentrate contains 50 mg of vancomycin.
Preparation of final diluted solution infusion:
Reconstituted concentrate containing 50 mg/ml of vancomycin should be further diluted immediately after reconstitution.
Suitable diluents are:
Sodium Chloride 9 mg/ml (0.9%) Injection, Glucose 50 mg/ml (5%) Injection, Sodium Chloride 9 mg/ml (0.9 %) and Glucose 50 mg/ml (5%) Injection or Ringer acetate Injection.
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.
Intermittent infusion:
Reconstituted concentrate containing 1000 mg of vancomycin (50 mg/ml) must be diluted further with at least 200 ml diluent immediately after reconstitution.
The concentration of vancomycin in Solution for infusion should not exceed 5 mg/ml.
The desired dose should be administered slowly by intravenous infusion at a rate of no more than 10 mg/minute, for at least 60 minutes or even longer.
For storage conditions of the diluted medicinal product, see sections 6.3
Disposal
Vials are for single use only. Unused product must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road, Hampden Park, Eastbourne,
East Sussex, BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/1859
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/02/2011
10 DATE OF REVISION OF THE TEXT
23/10/2015
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)