Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8).
In case of hypersensitivity reactions, treatment with vancomycin must be discontinued immediately and the adequate emergency measures must be initiated.

In patients receiving vancomycin over a longer-term period or concurrently with other medications which may cause neutropenia or agranulocytosis, the leukocyte count should be monitored at regular intervals. All patients receiving vancomycin should have periodic haematologic studies, urine analysis, liver and renal function tests.

Vancomycin should be used with caution in patients with allergic reactions to teicoplanin, since cross hypersensitivity, including fatal anaphylactic shock, may occur.

Spectrum of antibacterial activity

Vancomycin has a spectrum of antibacterial activity limited to Gram-positive organisms. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a high suspicion that the most likely pathogen(s) would be suitable for treatment with vancomycin.

The rational use of vancomycin should take into account the bacterial spectrum of activity, the safety profile and the suitability of standard antibacterial therapy to treat the individual patient.

Ototoxicity
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.
Vancomycin should also be avoided in patients with previous hearing loss. 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.
The elderly are particularly susceptible to auditory damage. Monitoring of vestibular and auditory function in the elderly should be carried out during and after treatment. Concurrent or sequential use of other ototoxic substances should be avoided.

Infusion-related reactions

Rapid bolus administration (e.g., over several minutes) may be associated with exaggerated hypotension, shock and, rarely, cardiac arrest (see section 4.8 Adverse reactions) histamine like responses and maculopapular or erythematous rash (“red man’s syndrome” or “red neck syndrome”). So vancomycin should be infused slowly in a diluted solution (2.5 to 5.0mg/ml) at a rate not greater than 10 mg/min and 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.


The frequency of infusion-related reactions (including hypotension, flushing, erythema, urticaria and pruritus) increases with the concomitant administration of anaesthetic agents (see section 4.5). This may be reduced by administering vancomycin by infusion over at least 60 minutes,
before anaesthetic induction.
Severe cutaneous adverse reactions (SCARs)
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with vancomycin treatment (see section 4.8). Most of these reactions occurred within a few days and up to eight weeks after commencing treatment with vancomycin.
At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, vancomycin should be withdrawn immediately and an alternative treatment considered. If the patient has developed a SCAR with the use of vancomycin, treatment with vancomycin must not be restarted at any time.

Administration site related reactions
Pain and thrombophlebitis may occur in many patients receiving intravenous vancomycin and are occasionally severe. The frequency and severity of thrombophlebitis can be minimized by administering the medicinal product slowly as a dilute solution (see section 6.6) and by changing the sites of infusion regularly.


The efficacy and safety of vancomycin has not been established for the intrathecal, intralumbar and intraventricular routes of administration

The administration of vancomycin by intraperitoneal injection during continuous ambulatory peritoneal dialysis has been associated with a syndrome of chemical peritonitis.

Nephrotoxicity
Vancomycin should be used with care in patients with renal insufficiency, including anuria, as the possibility of developing toxic effects is much higher in the presence of prolonged high blood concentrations. The risk of toxicity is increased by high blood concentrations or prolonged therapy.
Regular monitoring of the blood levels of vancomycin is indicated in high dose therapy and 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 (see sections 4.2 and 4.5).


Eye disorders
Vancomycin is not authorized for intracameral or intravitreal use, including prophylaxis of endophthalmitis.
Hemorrhagic occlusive retinal vasculitis (HORV), including permanent loss of vision, have been observed in individual cases following intracameral or intravitreal use of vancomycin during or after cataract surgery.


Paediatric population
The current intravenous dosing recommendations for the paediatric population, in particular for children below 12 years of age, may lead to sub-therapeutic vancomycin levels in a substantial number of children. However, the safety of increased vancomycin 

dosing has not been properly assessed and higher doses than 60 mg/kg/day cannot be generally recommended.
Vancomycin should be used with particular care in premature neonates and young infants, because of their renal immaturity and the possible increase in the serum concentration of vancomycin. The blood concentrations of vancomycin should therefore be monitored carefully in these children. Concomitant administration of vancomycin and anaesthetic agents has been associated with erythema and histamine-like flushing in children and anaphylactoid reactions . If vancomycin has to be administered in surgical prophylaxis, it is recommended that the anaesthetic agents be administered after the vancomycin infusion has been completed (see section 4.8 Adverse reactions).
. Similarly, concomitant use with nephrotoxic agents such as aminoglycoside antibiotics, NSAIDs (e.g., ibuprofen for closure of patent ductus arteriosus) or amphotericin B is associated with an increased risk of nephrotoxicity (see section 4.5) and therefore more frequent monitoring of vancomycin serum levels and renal function is indicated.

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).


Drug interactions with anaesthetic agents
Anaesthetic induced myocardial depression may be enhanced by vancomycin. During anaesthesia, doses must be well diluted and administered slowly with close cardiac monitoring. Position changes should be delayed until the infusion is completed to allow for postural adjustment (see section 4.5).

Pseudomembranous enterocolitis
In case of severe persistent diarrhoea the possibility of pseudomembranous enterocolitis that might be life-threatening has to be taken into account (see section 4.8). Anti-diarrhoeic medicinal products must not be given.

Superinfection
Prolonged use of vancomycin may result in the overgrowth of nonsusceptible microorganisms, principally fungi. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Reversible neutropenia has been reported (see section 4.8 Adverse reactions). Patients undergoing prolonged therapy with vancomycin or those who are receiving concomitant drugs that may cause neutropenia should have periodic monitoring of the leukocyte count.

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