Vancocin 500 mg powder for concentrate for solution for infusion and powder for oral solution.

Vancomycin hydrochloride equivalent to 500mg vancomycin (525,000 IU). When reconstituted with 10ml water for injections, the concentrate for solution contains vancomycin 50mg/ml.

Powder for concentrate for solution for infusion and powder for oral solution.

An off-white lyophilised plug, when reconstituted in water, it forms a clear solution.

Vancomycin is indicated in potentially life-threatening infections which cannot be treated with other effective, less toxic antimicrobial drugs, including the penicillins and cephalosporins.

Vancomycin is useful in the therapy of severe staphylococcal infections in patients who cannot receive or who have failed to respond to the penicillins and cephalosporins, or who have infections with staphylococci resistant to other antibiotics.

Vancomycin is used in the treatment of endocarditis and as prophylaxis against endocarditis in patients at risk from dental or surgical procedures.

Its effectiveness has been documented in other infections due to staphylococci, including osteomyelitis, pneumonia, septicaemia and soft tissue infections.

Vancomycin may be used orally for the treatment of staphylococcal enterocolitis and pseudomembranous colitis due to Clostridium difficile. Parenteral administration of vancomycin is not effective for these indications.

Vancomycin is not significantly absorbed from the normal gastro-intestinal tract and is therefore not effective by the oral route for other types of infection. Intravenous administration may be used concomitantly if required.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

For intravenous infusion and oral use only and not for intramuscular administration.

Infusion-related adverse events are related to both concentration and rate of administration of vancomycin. Concentrations of no more than 5mg/ml are recommended. In selected patients in need of fluid restriction, a concentration up to 10mg/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 500mg are used, a rate of infusion of no more than 10mg/min is recommended. Infusion-related events may occur, however, at any rate or concentration.

Intravenous Infusion in Patients with Normal Renal Function

Adults: The usual intravenous dose is 500mg every six hours or 1g every 12 hours, in Sodium Chloride Intravenous Infusion BP or 5% Dextrose Intravenous Infusion BP. Each dose should be administered at no more than 10mg/min. Other patient factors, such as age, obesity or pregnancy, may call for modification of the usual daily dose. The majority of patients with infections caused by organisms sensitive to the antibiotic show a therapeutic response within 48-72 hours. The total duration of therapy is determined by the type and severity of the infection and the clinical response of the patient. In staphylococcal endocarditis, treatment for three weeks or longer is recommended.

Pregnancy: It has been reported that significantly increased doses may be required to achieve therapeutic serum concentrations in pregnant patients, but see 'Pregnancy and Lactation'.

The elderly: Dosage reduction may be necessary to a greater extent than expected because of decreasing renal function (see below). Monitor auditory function - see 'Warnings' and 'Precautions'.

Children: The usual intravenous dosage is 10mg/kg per dose, given every 6 hours (total daily dosage 40mg/kg of body weight). Each dose should be administered over a period of at least 60 minutes.

In neonates and young infants, the total daily dosage may be lower. An initial dose of 15mg/kg is suggested, followed by 10mg/kg every 12 hours in the first week of life and every 8 hours thereafter until one month of age. Each dose should be administered over 60 minutes. Close monitoring of serum vancomycin concentrations may be warranted in these patients.

Patients with impaired renal function: Dosage adjustments must be made to avoid toxic serum levels. In premature infants and the elderly, greater dosage reductions than expected may be necessary because of decreased renal function. Regular monitoring of serum levels is advised in such patients, as accumulation has been reported, especially after prolonged therapy. Vancomycin serum concentrations may be determined by use of a microbiological assay, radioimmunoassay, fluorescence polarisation immunoassay, fluorescence immunoassay or high-pressure liquid chromatography.

The following nomogram, based on creatinine clearance values, is provided:

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 7 to 10 days has been recommended.

Measurement of serum concentrations: Following multiple intravenous doses, peak serum concentrations, measured 2 hours after infusion is complete, range from 18-26mg/l. Trough levels measured immediately prior to the next dose should be 5-10mg/l. Ototoxicity has been associated with serum drug levels of 80-100mg/l, but this is rarely seen when serum levels are kept at or below 30mg/l.

Oral Administration

The contents of the 500mg vial for parenteral administration may be used.

Adults and the elderly: The usual daily dose given is 500mg in divided doses for 7 to 10 days, although up to 2g/day have been used in severe cases. The total daily dose should not exceed 2g. Each dose may be reconstituted in 30ml water and either given to the patient to drink, or administered by nasogastric tube.

Children: The usual daily dose is 40mg/kg in three or four divided doses for 7 to 10 days. The total daily dosage should not exceed 2g.

Capsules are also available.

Hypersensitivity to vancomycin.

Warnings

Patients receiving vancomycin hydrochloride should have regular monitoring of peripheral blood state, liver function and renal function.

Rapid bolus administration (e.g., over several minutes) may be associated with exaggerated hypotension, including shock, and, rarely, cardiac arrest. 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 'Posology and Method of Administration' and 'Undesirable Effects' sections).

Some patients with inflammatory disorders of the intestinal mucosa may have significant systemic absorption of oral vancomycin and, therefore, may be at risk for the development of adverse reactions associated with the parenteral administration of vancomycin. The risk is greater in patients with renal impairment. It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly.

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.

Vancomycin should also be avoided in patients with previous hearing loss. If it is used in such patients, the dose should be regulated, if possible, by periodic determination of the drug level in the blood. Deafness may be preceded by tinnitus. The elderly are more susceptible to auditory damage. Experience with other antibiotics suggests that deafness may be progressive despite cessation of treatment.

Usage 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 histamine-like flushing in children.

Usage 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 'Posology and Method of Administration').

Vancomycin should be administered with caution in patients allergic to teicoplanin, since allergic cross reactions between vancomycin and teicoplanin have been reported.

Precautions

Clinically significant serum concentrations have been reported in some patients being treated for active C. difficile-induced pseudomembranous colitis after multiple oral doses of vancomycin. Therefore, monitoring of serum concentrations may be appropriate in these patients.

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 occur in many patients receiving vancomycin and are occasionally severe.

The frequency and severity of thrombophlebitis can be minimised by administering the drug slowly as a dilute solution (2.5 to 5.0g/l) and by rotating the sites of infusion.

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.

Concomitant administration of vancomycin and anaesthetic agents in young infants have been associated with erythema, histamine-like flushing and anaphylactoid reactions.

There have been reports that the frequency of infusion-related events in all age groups 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 neurotoxic or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymixin B, colistin, viomycin or cisplatin, when indicated, requires careful monitoring.

Usage in pregnancy: Teratology studies have been performed at 5 times the human dose in rats and 3 times the human dose in rabbits and have revealed no evidence of harm to the foetus due to vancomycin. In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin hydrochloride on infants were eva luated when the drug was administered to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. Vancomycin hydrochloride was found in cord blood.

No sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. One infant, whose mother received vancomycin in the third trimester, experienced conductive hearing loss that was not attributable to vancomycin.

Because vancomycin was administered only in the second and third trimesters, it is not known whether it causes foetal harm. Vancomycin should be given in pregnancy only if clearly needed and blood levels should be monitored carefully to minimise the risk of foetal toxicity. It has been reported, however, that pregnant patients may require significantly increased doses of vancomycin to achieve therapeutic serum concentrations.

Usage in nursing mothers: Vancomycin hydrochloride is excreted in human milk. Caution should be exercised when vancomycin is administered to a nursing woman. It is unlikely that a nursing infant can absorb a significant amount of vancomycin from its gastro-intestinal tract.

Not applicable.

Infusion-related events: During or soon after rapid infusion of vancomycin, patients may develop anaphylactoid reactions including hypotension, wheezing, dyspnoea, urticaria or pruritus. Rapid infusion may also cause flushing of the upper-body ('red-neck syndrome') or pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours. In animal studies, hypotension and bradycardia occurred in animals given large doses of vancomycin at high concentrations and rates. Such events are infrequent if vancomycin is given by slow infusion over 60 minutes. In studies of normal volunteers, infusion-related events did not occur when vancomycin was administered at a rate of 10mg/min or less.

Rapid bolus injection may give hypotension and rarely cardiac arrest.

Nephrotoxicity: Rarely, renal failure, principally manifested by increased serum creatinine or blood urea concentrations, have been observed, especially in patients given large doses of intravenously administered vancomycin. Rare cases of interstitial nephritis have been reported. Most occurred in patients who were given aminoglycosides concomitantly or who had pre-existing kidney dysfunction. When vancomycin was discontinued, azotaemia resolved in most patients.

Ototoxicity: Hearing loss associated with intravenously administered vancomycin has been reported. Most of these patients had kidney dysfunction, pre-existing hearing loss, or concomitant treatment with an ototoxic drug. Vertigo, dizziness and tinnitus have been reported rarely. Tinnitus, possibly preceding onset of deafness, may occur and should be regarded as an indication to discontinue treatment.

Haematological: Reversible neutropenia, usually starting one week or more after onset of intravenous therapy or after a total dose of more than 25g. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has rarely been reported. Reversible agranulocytosis (less than500 granulocytes per mm³) has been reported rarely, although causality has not been established. Eosinophilia has been reported.

Miscellaneous: Phlebitis, hypersensitivity reactions anaphylaxis, nausea, chills, drug fever, rashes (including exfoliative dermatitis) rare cases of vasculitis. Vancomycin has been associated with the bullous eruption disorders Stevens-Johnson syndrome, toxic epidermal necrolysis and linear 1gA bullous dermatosis. If a bullous disorder is suspected, the drug should be discontinued and specialist dermatological assessment should be carried out.

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.

Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis. The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin may alter bacterial cell membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other classes of antibiotics.

In vitro vancomycin is generally active against gram-positive microorganisms including: Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains), Streptococcus pyogenes, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus agalactiae, the viridans group, Streptococcus bovis, and enterococci (e.g. Enterococcus faecalis); Clostridium difficile (e.g. toxigenic strains implicated in pseudomembranous enterocolitis) and diptheroids. Other organisms that are susceptible to vancomycin in vitro include Listeria monocytogenes, Lactobacillus species, Acintomyces species, Clostridium species and Bacillus species.

In vitro resistance to vancomycin has been reported among some enterococcal and staphylococcal isolates. The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many strains of S. aureus, nonenterococcal group D streptococci, enterococci, and Streptococcus species (viridans group).

Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria or fungi.

Vancomycin is given intravenously for therapy of systemic infections.

The mean elimination half-life of vancomycin from the plasma is 4 to 6 hours in patients with normal renal function. About 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration in the first 24 hours.

Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. Renal vancomycin clearance is fairly constant and accounts for 70% to 80% of vancomycin elimination. The volume of distribution ranges from 0.3 to 0.43 L/kg. There is no apparent metabolism of the drug. Vancomycin is 55% protein bound as measured by ultrafiltration at vancomycin serum levels of 10 to 100 mg/L.

After IV administration of vancomycin hydrochloride, inhibitory concentrations are present in pleural, pericardial, ascitic, atrial appendage tissue and synovial fluid, as well as urine and peritoneal fluid. Vancomycin does not readily penetrate the cerebrospinal fluid unless the meninges are inflamed.

Renal dysfunction slows excretion of vancomycin. In anephric patients, the average half-life of elimination is 7.5 days.

The total systemic and renal clearance of vancomycin may be reduced in the elderly due to the natural decrement of glomerular filtration.

Although no long term studies in animals have been performed to eva luate carcinogenic potential, no mutagenic potential of vancomycin was found in standard laboratory tests. No definitive fertility studies have been performed.

None.

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.

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 the administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less.

Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles. The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity.

2 years.

Before reconstitution: Do not store above 25°C.

After reconstitution: For single use only. Discard any unused portion.

When aseptically prepared, the solution may be stored for up to 24 hours in a refrigerator (2° - 8°C). The product contains no antimicrobial preservative. Therefore, if aseptic preparation cannot be ensured, the solution should be prepared immediately before use.

Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution or container permits.

Rubber-stoppered 10ml type 1 flint glass vials each containing chromatographically purified vancomycin hydrochloride, 525,000 IU, equivalent to 500mg vancomycin, as an off-white lyophilised plug.

One 10ml vial packaged in a cardboard carton.

Preparation of solution: At the time of use, add 10ml of Water for Injections PhEur to the vial. Vials reconstituted in this manner will give a solution of 50mg/ml.

FURTHER DILUTION IS REQUIRED. Read instructions which follow:

Intermittent infusion is the preferred method of administration. The above solution (containing 500mg vancomycin) can be added to 100-200ml Sodium Chloride Intravenous Infusion BP or 5% Dextrose Intravenous Infusion BP. The desired dose should be given by intravenous infusion over a period of at least 60 minutes. If administered over a shorter period of time or in higher concentrations, there is the possibility of inducing marked hypotension in addition to thrombophlebitis. Rapid administration may also produce flushing and a transient rash over the neck and shoulders.

Continuous infusion (should be used only when intermittent infusion is not feasible). Two to four vials (1-2g) can be added to a sufficiently large volume of Sodium Chloride Intravenous Infusion BP or 5% Dextrose Intravenous Infusion BP to permit the desired daily dose to be administered slowly by intravenous drip over a 24-hour period.

Oral Administration

The contents of the 500mg vial for parenteral administration may be used.

Common flavouring syrups may be added to the solution at the time of administration to improve the taste.

Capsules are also available.

Flynn Pharma Limited

Alton House

4 Herbert Street

Dublin 2

PA1226/5/3

8^th May 1981/ 8^th May 2006

August 2006