Vancomycin (as hydrochloride)

Transcription

1 Vancomycin (as hydrochloride) Vancocin CP 500mg Powder for Injection (I.V.) PRODUCT DESCRIPTION Vancomycin hydrochloride, 500 mg, lyophilisate for solution for infusion: Each vial contains vancomycin 500 mg (equivalent to 525,000 IU) as vancomycin hydrochloride. It is a white to off white lyophilised powder. PHARMACOLOGIC PROPERTIES Pharmacodynamics 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 bactericidal for dividing microorganisms. Pharmacodynamic effects 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. Crossresistance 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. Commonly susceptible species Gram positive Enterococcus faecalis Staphylococcus aureus Staphylococcus coagulase negative Streptococcus spp. Streptococcus pneumoniae Clostridium spp. Species for which acquired resistance may be a problem Enterococcus faecium Inherently resistant Gram-negative bacteria Chlamydia spp. Mycobacteria Mycoplasma spp. Rickettsia spp.

2 Pharmacokinetics Absorption and Distribution In subjects with normal renal function, multiple intravenous dosing of 1 g of vancomycin (15 mg/kg) infused over 60 minutes produces mean plasma concentrations of approximately 63 mg/l immediately after the completion of infusion and mean plasma concentrations of approximately 23 mg/l 2 hours after infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mg/l at the completion of infusion, mean plasma concentrations of about 19 mg/l 2 hours after infusion, and mean plasma concentrations of about 10 mg/l 6 hours after infusion. The plasma concentrations during multiple dosing are similar to those after a single dose. Metabolism and Elimination 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 L/kg/h, and mean renal clearance is about L/kg/h. Renal vancomycin clearance is fairly constant and accounts for 70% to 80% of vancomycin elimination. The volume of distribution ranges from 0.39 to 0.97 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. Special patient populations Renal impairment 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. Clinical Studies Not relevant for this product. NON-CLINICAL INFORMATION 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. INDICATIONS Vancomycin hydrochloride is used for the treatment of potentially life-threatening infections due to susceptible Gram-positive organisms which cannot be treated with other effective, less toxic antimicrobial drugs, including the penicillins and cephalosporins: 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. Endocarditis and as prophylaxis against endocarditis in patients at risk from dental or surgical procedures. Other infections due to staphylococci, including osteomyelitis, pneumonia, septicaemia and soft tissue infections. Consideration should be given to official guidance on the appropriate use of antibacterial agents. DOSAGE AND ADMINISTRATION Infusion-related events are related to both concentration and rate of administration of vancomycin. Concentrations of no more than 5 mg/ml and rates of no more than 10 mg/min are recommended in adults (see also age-specific recommendations). In selected patients in need of fluid restriction, a concentration up to 10 mg/ml may be used; use of such higher concentrations may increase the risk of infusion-related events. Infusion-related events may occur, however, at any rate or concentration. Route of Administration For intravenous use. Adults The usual daily intravenous dose is 2 g divided either as 500 mg every six hours or 1 g every 12 hours. Each dose should be administered at no more than 10 mg/min, or over a period of at least 60 minutes, whichever is longer. Other patient factors, such as age or obesity, may call for modification of the usual daily dose. 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. Children The usual intravenous dosage of vancomycin is 10 mg/kg per dose given every six hours. Each dose should be administered over a period of at least 60 minutes.

3 Infants and Neonates In neonates and young infants, the total daily intravenous dosage may be lower. In both neonates and infants, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the first week of life and thereafter every eight hours up to the age of one month. Each dose should be administered over 60 minutes. Close monitoring of serum concentrations of vancomycin may be warranted in these patients. Dosing recommendations for neonates is depending on post-conception age: Vancomycin Dosage Guideline for Neonates (based on Gabriel MH, Kildod CW, Gennrich JL et al.: Prospective evaluation of a vancomycin dosing guidelines for neonates. Clin Pharm 1991, 10, ) a PCA (Weeks) <30 7 > > 14 >36 7 >7 Chronological Age (Days) Serum Concentration (mg/dl) b c 1.2 c c Creatinine Dosage (mg/kg) 15 every 24 hr 10 every 8 hr 10 every 8 hr a PCA = postconceptual age (gestational age at birth plus chronological age) b If the serum creatinine concentration is >1.2 mg/dl, use an initial dosage of 15 mg/kg every 24 hours c Serum creatinine concentration is not used to determine the dosage for this type of patient because of its lack of reliability or because of the lack of information. Elderly and Renal impairment Dosage adjustment must be made in patients with impaired renal function. 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 can be determined by use of microbiologic assay, radioimmunoassay, fluorescence immunoassay (including polarization), or high-pressure liquid chromatography. Dosage table for treatment of patients with impaired renal function: Creatinine clearance ml/minute Dose of vancomycin mg/24 hours These figures do not apply to anephric patients, where an initial dose of 15 mg/kg should usually be given for the rapid achievement of therapeutic serum concentration; the dose needed to maintain a constant level is 1.9 mg/kg for 24 hours. In patients with marked renal impairment,, it is possible to administer a maintenance dose of 250 mg to 1 g once every few days. In the case of anuria, 1 g of vancomycin is usually administered every 7 10 days (see Section Pharmacokinetics). Hepatic impairment There are no relevant data available. CONTRAINDICATIONS Vancomycin hydrochloride is contraindicated in: Hypersensitivity to vancomycin hydrochloride or to any excipients of the product.

4 WARNINGS AND PRECAUTIONS Method of administration. 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 infusionrelated reactions. Stopping the infusion usually results in a prompt cessation of these reactions (see Section Adverse reactions). Injection site reactions 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. Ototoxicity and nephrotoxicity 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. Use in pediatrics 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. Use in elderly The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage is not adjusted (see Section Dosage and administration) Long term use and renal impairment 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. 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. Periodic tests All patients receiving the drug should have periodic haematological studies, urine analysis and renal function tests. Prolonged use and 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. Pseudomembranous colitis In rare instances, there have been reports of pseudomembranous colitis, due to C. difficile, developing in patients who received intravenous vancomycin. Cross hypersensitivity As cases of cross hypersensitivity has been reported, Vancomycin must be administered with care in patients with known hypersensitivity to teicoplanin. Ability to perform tasks that require judgement, motor or cognitive skills Vancomycin has negligible influence on the ability to drive and the use of machines. DRUG INTERACTIONS Anaesthetic agents 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.

5 Ototoxic, neurotoxic, or nephrotoxic drugs 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, when indicated, requires careful monitoring. Neuromuscular blocking agents There is an increased potential of neuromuscular blockade with concomitant administration of vancomycin and neuromuscular blocking agents. PREGNANCY AND LACTATION Fertility There are no relevant data available. Pregnancy Vancomycin should be given in pregnancy only if clearly needed and after a careful risk/benefit evaluation. 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 However, vancomycin penetrates the placenta and a potential risk of embryonal and neonatal ototoxicity and nephrotoxicity cannot be excluded. Lactation 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 the nursing mother, the decision to stop breastfeeding should be considered. ADVERSE EFFECTS The most common adverse reactions are phlebitis and pseudo-allergic reactions in connection with too rapid intravenous infusion of vancomycin. 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 Warnings and Precautions). 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. Clinical Trial Data and Post Marketing Data Adverse reactions are ranked under headings of frequency using the following convention: Very common 1/10 Common 1/100 to <1/10 Uncommon 1/1000 to <1/100 Rare 1/10000 to <1/1000 Very rare <1/10000 Not known (cannot be estimated from the available data). Immune system disorders Rare: anaphylactic reactions, hypersensitivity reactions Blood and lymphatic system disorders Rare: thrombocytopenia, neutropenia, agranulocytoses, eosinophilia 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 Rare: vasculitis Respiratory, thoracic and mediastinal disorders Common: dyspnoea, stridor Gastrointestinal disorders Rare: nausea Very rare: pseudomembranous enterocolitis (see Section Warnings and Precautions)

6 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 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 (see Section Warnings and Precautions), redness of the upper body and the face Rare: drug fever, shivering, pain in the chest and back muscles OVERDOSAGE AND TREATMENT 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. STORAGE CONDITIONS Prior to reconstitution, vials should be stored at temperature not exceeding 25ºC. Reconstituted solution should be stored between 2ºC to 8ºC. INSTRUCTIONS FOR USE / HANDLING At the time of use, add 10 ml of sterile Water for Injections to a 500mg vial Similarly, add 20 ml of sterile Water for Injections to a 1 g vial. Vials reconstituted in this manner will give a solution of 50 mg/ml FURTHER DILUTION IS REQUIRED. Read instructions below: 1. Intermittent infusion is the preferred method of administration. Reconstituted solutions containing 500 mg vancomycin must be diluted with at least 100 ml diluent. Reconstituted solutions containing 1g vancomycin must be diluted with at least 200 ml diluent. 0.9% Sodium Chloride Intravenous Infusion, 5% Dextrose Intravenous Infusion or Ringer acetate solution are suitable diluents. The desired dose should be given by intravenous infusion over a period of at least 60 minutes. 2. Continuous infusion (should be used only when intermittent infusion is not feasible). 1-2 g of vancomycin can be added to a sufficiently large volume of 0.9% Sodium Chloride Intravenous Infusion, 5% Dextrose Intravenous Infusion or Ringer acetate solution, to permit the desired daily dose to be administered slowly by intravenous drip over a 24 hour period. For single use only. Discard any unused contents. 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. 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 Use and Handling. AVAILABILITY Vancomycin hydrochloride (Vancocin CP) Powder for Injection (I.V.): Packaging of 500mg (Box of 1 vial) CAUTION Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription. Keep all medicines out of reach of children. VANCOCIN is a registered trademark of the GlaxoSmithKline group of companies 2011, GlaxoSmithKline. All rights reserved. Version number: NCDS v.02 Revision date: 24 November 2011

7 Imported by: GlaxoSmithKline Philippines Inc 2266 Chino Roces Avenue, City of Makati Tel. No Manufactured by: Vianex S.A. Pallini, Attica, Greece I-VNC-1