1 Name of Medicine
Vancomycin hydrochloride.
2 Qualitative and Quantitative Composition
Vancomycin BNM capsules contain either 125 mg or 250 mg of vancomycin (as hydrochloride) as the active ingredient.
Excipient(s) with known effect.
Tartrazine (125 mg capsules only). It may contain sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
Vancomycin BNM 125 mg capsules are size 2, hard gelatin capsules, with blue cap and yellow body, imprinted with "OP64" on the cap and the body in white ink.
Vancomycin BNM 250 mg capsules are size 0, hard gelatin capsules, with blue cap and dark-yellow body, imprinted with "OP65" on the cap and the body in white ink.
4.1 Therapeutic Indications
Vancomycin BNM capsules may be administered orally for the treatment of staphylococcal enterocolitis and antibiotic-associated pseudomembranous colitis produced by C. difficile. Parenteral administration of vancomycin is not effective for the above indications; therefore, Vancomycin BNM must be given orally. Vancomycin BNM is not effective by the oral route for other types of infection.
4.2 Dose and Method of Administration
Adults.
The usual daily dosage for staphylococcal enterocolitis and for antibiotic induced pseudomembranous colitis produced by C. difficile is 250 mg 6 hourly for 5-10 days. However, doses of 500 mg to 2 g orally administered in 3 or 4 divided doses for 7-10 days have been used for the treatment of antibiotic associated pseudomembranous colitis produced by C. difficile. Vancomycin is not effective by the oral route for other types of infections.
Children.
The usual daily dose is 20 mg/kg orally in 4 divided doses but doses of up to 40 mg/kg/day may be used. The total daily dose should not exceed 2 g.4.3 Contraindications
Vancomycin BNM is contraindicated in patients with known hypersensitivity to vancomycin or any of the excipients or other glycopeptides.
4.4 Special Warnings and Precautions for Use
General.
Patients with a creatinine clearance < 60 mL/minute and all elderly individuals 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.
Potential for systemic absorption.
Clinically significant serum concentrations have been reported in some patients who have taken multiple oral doses of vancomycin for active C. difficile-induced pseudomembranous colitis; therefore, monitoring of serum concentrations may be appropriate in these patients.
Significant systemic absorption of orally administered vancomycin has been reported in some patients with inflammatory disorders of the intestinal mucosa. Therefore, patients treated with Vancomycin BNM capsules may be at risk for the development of adverse reactions associated with the parenteral administration of vancomycin (see package insert accompanying the intravenous products). The risk is greater if renal impairment is present. It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly. The need for estimation of serum levels and dosage adjustment should be considered in such cases.
Hypersensitivity reactions.
Serious and occasionally fatal hypersensitivity reactions are possible (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). In case of hypersensitivity reactions, treatment with vancomycin must be discontinued immediately and the adequate emergency measures must be initiated.
Severe cutaneous adverse reactions.
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP) have been reported in association with vancomycin treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be advised to inform their doctor at the first appearance of rash or any other sign of hypersensitivity.
If a SCAR is suspected, the drug should be discontinued and specialist dermatological assessment should be carried out.
Ototoxicity.
Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive intravenous doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent such as an aminoglycoside or have impaired renal clearance of vancomycin (e.g. in the elderly). Serial tests of auditory function may be helpful in order to minimise the risk of ototoxicity and are recommended, particularly in patients at risk and those with other special sensory impairment (e.g. blindness). Vancomycin BNM capsules should be avoided in patients with previous hearing loss unless no other appropriate therapy is available. If it is used in such patients, the dose of vancomycin should be regulated by periodic determination of drug levels in the blood. Patients with renal insufficiency 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 hematologic studies, urinalyses, and liver and renal function tests.
Infusion reactions.
Rapid bolus administration of vancomycin (e.g. over several minutes) may be associated with exaggerated hypotension, including shock, and, rarely, cardiac arrest, histamine like responses and maculopapular or erythematous rash ("red neck").
For intravenous infusion, vancomycin should be administered in a dilute solution at a rate not exceeding 500 milligram/hour to avoid rapid infusion related reactions, e.g. hypotension, flushing, erythema, urticaria and pruritus. Stopping the infusion usually results in a prompt cessation of these reactions (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
When given intravenously, toxic serum levels can occur. Vancomycin is excreted fairly rapidly by the kidney and blood levels increase markedly with decreased renal clearance. During parenteral therapy, the risk of toxicity and nephrotoxicity appears appreciably increased by high blood concentrations or prolonged treatment.
Since vancomycin is irritating to tissue and causes drug fever, pain and possibly necrosis, it should never be injected intramuscularly; it must be administered intravenously.
Pain and thrombophlebitis occur in many patients receiving vancomycin and are occasionally severe. The frequency and severity of thrombophlebitis can be minimised if the drug is administered in a volume of at least 200 mL of glucose or saline solution and if the injection sites are rotated.
Drug interactions with anti-motility agents and proton pump inhibitors.
Anti-motility agents should be avoided and proton pump inhibitor use should be reconsidered.
Cross-sensitivity reactions.
Vancomycin should be used with caution in patients with allergic reactions to teicoplanin, since cross hypersensitivity, including fatal anaphylactic shock, may occur.
Blood disorders.
Reversible neutropenia has been reported in patients receiving vancomycin hydrochloride (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients who will undergo prolonged therapy with vancomycin or those who are receiving concomitant medicines which may cause neutropenia should have periodic monitoring of the leukocyte count.
Use during anaesthesia.
In surgical patients, the administration of vancomycin should be carefully timed in relation to the induction of anaesthesia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Clostridioides difficile-associated disease.
In rare instances there have been reports of pseudomembranous colitis due to Clostridioides difficile developing in patients who received intravenous vancomycin. C. difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including vancomycin hydrochloride, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
Overgrowth of non-susceptible organisms.
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.
Use in renal impairment.
Because of its ototoxicity and nephrotoxicity, vancomycin should be used with care in patients with renal insufficiency. When treating patients with underlying renal dysfunction or those patients receiving concomitant therapy with an aminoglycoside or other nephrotoxic drugs, serial monitoring of renal function should be performed.
Haemorrhagic occlusive retinal vasculitis.
Haemorrhagic occlusive retinal vasculitis, including permanent loss of vision, can occur in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery. The safety and efficacy of vancomycin administered by the intracameral or the intravitreal route have not been established by adequate and well-controlled trials and these are not approved routes of administration for vancomycin. Vancomycin is not indicated for prophylaxis of endophthalmitis.
Other.
Concurrent and sequential use of other neurotoxic and/or nephrotoxic antibiotics, particularly etacrynic acid, neuromuscular blocking agents, aminoglycoside antibiotics, polymyxin B, colistin, viomycin and cisplatin requires careful monitoring.
Use in the elderly.
It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly. The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage is not adjusted. Vancomycin dosage schedules should be adjusted in elderly patients (see Section 4.2 Dose and Method of Administration).
Paediatric use.
In premature neonates, infants and children, it is appropriate to confirm vancomycin serum concentrations. Concomitant administration of vancomycin and anaesthetic agents has been associated with erythema and histamine like flushing in children (see Section 4.8 Adverse Effects (Undesirable Effects)).
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Concurrent administration with other neurotoxic (e.g. ototoxic) or nephrotoxic drugs, e.g. streptomycin, neomycin, gentamicin, kanamycin, amikacin, amphotericin B, bacitracin, tobramycin, polymyxin B, colistin, cisplatin or piperacillin/tazobactam, requires careful monitoring (see Section 4.4 Special Warnings and Precautions for Use).
In order to minimise the risk of nephrotoxicity when treating patients with underlying renal dysfunction or those patients receiving concomitant therapy with an aminoglycoside, serial monitoring of renal function should be performed and particular care should be taken in following appropriate dosing schedules (see Section 4.2 Dose and Method of Administration).
Diuretics such as etacrynic acid and furosemide (frusemide) may aggravate ototoxicity.
Colestyramine has been shown to bind vancomycin in vitro. Therefore, if oral vancomycin is used with colestyramine, the two medicines should be administered several hours apart.
Reversible neutropenia has been reported in patients receiving vancomycin hydrochloride (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients who are receiving concomitant medicines which may cause neutropenia should have periodic monitoring of the leukocyte count.
Vancomycin may enhance neuromuscular blockade produced by medicines such as suxamethonium or vecuronium.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No data available.
(Category B2)
Animal reproduction studies have not been conducted with vancomycin. It is also not known whether vancomycin can affect reproduction capacity. In a controlled clinical study vancomycin was administered intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse to evaluate potential ototoxic and nephrotoxic effects on the infant. Vancomycin 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 attributed to the administration of vancomycin. As only 10 patients were treated with vancomycin in this study, and administration was only in the second and third trimesters, it is not known whether vancomycin causes foetal harm. Vancomycin BNM capsules should be given to a pregnant woman only if clearly needed and blood levels should be monitored carefully to minimise fetal toxicity.
Vancomycin hydrochloride is excreted in human milk after intravenous administration. Caution should be exercised when vancomycin hydrochloride is administered to a lactating woman. Because of the potential for adverse events, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious, potentially life-threatening adverse drug reaction with distinct feature. Prompt recognition along with drug withdrawal is essential for improved prognosis. DRESS is characterised by severe drug eruption accompanied by high fever, erythematous rash and inflammation of internal organs.
Vancomycin capsules may cause indigestion, stomach ache, nausea, chills, diarrhoea, pseudomembranous enterocolitis, and occasionally vomiting. Because oral vancomycin may be absorbed in some patients, the possibility of other adverse effects normally associated with parenteral administration (see below) should be borne in mind.
Nephrotoxicity.
Cases of increased serum creatinine or BUN concentrations and rare cases of interstitial nephritis in patients given intravenously administered vancomycin have been reported. Most of these have occurred in patients who were given aminoglycosides concomitantly or who had pre-existing kidney dysfunction. When vancomycin was discontinued, azotemia resolved in most patients. Transient elevations of urea and granular casts in the urine occasionally occur.
Vascular disorders.
Phlebitis and vasculitis have been reported in patients given vancomycin intravenous therapy.
Ototoxicity.
Cases of hearing loss associated with intravenously administered vancomycin have 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.
Haematological.
Patients have been reported to have developed reversible neutropenia, usually starting one week or more after onset of intravenous therapy with vancomycin or after a total dose of more than 25 g. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has rarely been reported. Eosinophilia has also been reported.
Although a causal relationship has not been established, reversible agranulocytosis (granulocyte count less than 500/mm3) has been reported rarely.
Liver function.
Elevation of liver transaminases.
Sensitivity reactions.
Infrequently, patients have been reported to have anaphylaxis, urticaria, pruritus, drug fever, hypotension, wheezing, dyspnoea, flushing of the upper body ("red neck"), pain and muscle spasm of the chest and back, and rashes including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and rare cases of vasculitis in association with vancomycin.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed by dialysis. Haemoperfusion with Amberlite resin XAD-4 has been reported to be of limited benefit. Haemofiltration and haemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance.
In managing overdosage, consider the possibility of multiple drug overdoses, interaction among medicines, and unusual drug kinetics in your patient.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics.
Vancomycin is active against C. difficile (e.g. toxigenic strains implicated in pseudomembranous enterocolitis). It is also active against staphylococci, including Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains).
Many strains of streptococci and C. difficile, are susceptible in vitro to concentrations of less than 5 mg/L. A small proportion of S. aureus strains require 10 to 20 mg/L for inhibition.
Vancomycin is not active in vitro against Gram-negative bacilli, mycobacteria or fungi.
Disc susceptibility tests.
Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure has been recommended for use with discs for testing susceptibility to vancomycin. Interpretations correlate zone diameters of the disc test with minimum inhibitory concentrations (MIC) values for vancomycin. With the procedure, a report from the laboratory of "resistant" indicates that the infecting organism is not likely to respond to therapy. A report of "intermediate susceptibility" suggests that the organism would be susceptible if the infection is confined to the urine, in which high antibiotic levels can be obtained, or if high dosage is used in other types of infection.
If the Bauer-Kirby method* of disc susceptibility testing is used, a 30 microgram disc of vancomycin should produce a zone of more than 11 mm when tested against a vancomycin-susceptible bacterial strain.
*Bauer AW, Kirby WM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966 Apr;45(4):493-6.; Standardized disk susceptibility test. Federal Register 1974;39:19182-19184.
Clinical trials.
No data available.
5.2 Pharmacokinetic Properties
Absorption and Excretion.
Vancomycin is poorly absorbed after oral administration. In a comparative bioavailability study of the capsule dosage form and the oral solution dosage form, there were no significant differences in serum or faecal concentrations. During multiple dosing of 250 mg every 8 hours for seven doses, faecal concentrations of vancomycin in volunteers exceeded 100 mg/kg in the majority of samples. No blood levels were detected and urinary recovery did not exceed 0.76%.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
No data available.6 Pharmaceutical Particulars
6.1 List of Excipients
Vancomycin BNM contains macrogol 6000, gelatin, titanium dioxide, sodium lauryl sulfate, brilliant blue FCF, iron oxide yellow (250 mg capsules only), tartrazine (125 mg capsules only), carnauba wax, white shellac and glyceryl monooleate.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C. Protect from moisture.
6.5 Nature and Contents of Container
Vancomycin BNM capsules 125 mg and 250 mg are supplied in PVC/PVDC/Alu blisters of 20 capsules.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Vancomycin hydrochloride is a mixture of related glycopeptides, consisting principally of vancomycin B, a substance produced by certain strains of Amycolatopsis orientalis or obtained by any other means. It is a white or almost white, hygroscopic powder; freely soluble in water; slightly soluble in alcohol. A 5% solution in water has a pH of 2.5 to 4.5.
Chemical structure.
The following structure of vancomycin hydrochloride has been confirmed by X-ray diffraction:
Molecular formula: C66H75Cl2N9O24.HCl.
Molecular weight: 1486; 500 mg of the base is equivalent to 0.34 mmol.
CAS number.
1404-93-9.7 Medicine Schedule (Poisons Standard)
Schedule 4 - Prescription Only Medicine.
