VANCOMYCIN MYLAN 500 MG

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה

ךיראת

/2017

3

/

8

םושירה רפסמו תילגנאב רישכתה םש

30297

-

63

-

123

–

Vancomycin Mylan 500 mg

30298

-

64

-

123

–

Vancomycin Mylan 1 g

םושירה לעב םש

:

Genmedix

! דבלב תורמחהה טורפל דעוימ הז ספוט

ה

תושקובמה תורמחה

ןולעב קרפ

טסקט שדח

טסקט יחכונ

4.1

Therapeutic

indications

Oral Therapy administration:

Vancomycin hydrochloride injection may be given orally for the

treatment of antibiotic- associated Pseudomembrannous colitis due

to Staphylococcus enterocolitis and Clostridium difficile.

Vancomycin hydrochloride is not effective orally when

administered for other types of infection.

Vancomycin is ineffective in these diseases if given parenterally

Oral Therapy Vancomycin hydrochloride injection may be given orally

for the treatment of antibiotic-associated Pseudomembrannous colitis

due to Staphylococcus enterocolitis and Clostridium difficile.

Vancomycin hydrochloride is not effective orally when administered

for other types of infection.

Consideration should be given to official guidance on the appropriate

use of antibacterial agents.

4.4 Special

warnings

and

precautions

for use

Nephrotoxicity:Some patients with inflammatory disorders of the

intestinal mucosa may have significant systemic absorption of oral

vancomycin must be used with cautionand, 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 failure asimpairment. It should be noted that the

possibilitytotal systemic and renal clearances of developing toxic

effects is much highervancomycin are reduced in the

Nephrotoxicity: vancomycin must be used with caution in patients with

renal failure as the possibility of developing toxic effects is much

higher in the presence of prolonged high blood concentrations. In the

treatment of these patients and in those who are receiving concomitant

treatment

with

other

nephrotoxic

active

substances

(i.e.

aminoglycosides), serial tests of renal function must be performed and

the appropriate dose regimens adhered to in order to reduce the risk of

nephrotoxicity to a minimum (see section 4.2).

10‏,lairA‏ לדחמ

תרירב ‏ ןפוג

בצועמ

תופשו‏תירבע‏רובע‏ןפוג‏ שגדומ

‏אל‏ קנ

תופשו‏

תירבע ‏ קנ

10‏,lairA‏ תורחא

תינמרג‏ תידועסה

ברע ‏תיברע‏ תורחא

הינמרג

תירבע‏רובע‏ןפוג‏ קנ

11‏ ןפוג

בצועמ

11‏,namoR‏weN‏semiT‏ תורחא

‏תופשו

ברע ‏תיברע‏ תורחא

‏תופשו‏

תירבע ‏ קנ

לא‏

הינטירב

‏תילגנא‏ תידועסה

קודקד‏וא‏תויא‏קודבת semiT‏ לדחמ

תרירב ‏ ןפוג

בצועמ

תירבע‏רובע‏ןפוג‏ קנ

11‏,namoR‏weN

11‏,namoR‏weN‏semiT‏ תורחא

‏תופשו

ברע ‏תיברע‏ תורחא

‏תופשו‏

תירבע ‏ קנ

ןמס‏ תידועסה

בצועמ

תופשו‏

תירבע ‏ קנ

11‏ ןפוג

בצועמ

תינמרג‏ תידועסה

ברע ‏תיברע‏ תורחא

ןמס‏

הינמרג

ןמס‏ קנ

11‏ ןפוג

בצועמ

בצועמ

בצועמ

ןמס‏ קנ

11‏ ןפוג

בצועמ

בצועמ

בצועמ

ןמס‏ קנ

11‏ ןפוג

בצועמ

בצועמ

בצועמ

ןמס‏ קנ

11‏ ןפוג

בצועמ

בצועמ

בצועמ

ןמס‏ קנ

11‏ ןפוג

בצועמ

בצועמ

presenceelderly.

4.6

Fertility,

Pregnancy

and lactation

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 nursing mother,

the decision should to stop breastfeeding should be considered.

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 nursing mother, the

decision should to stop breastfeeding should be considered.

Usage in pregnancy:

It has been reported, however, that pregnant patients may require

significantly increased doses of vancomycin to achieve therapeutic

serum concentrations.

Usage in nursing mothers:

It is unlikely that a nursing infant can absorb a significant amount

of vancomycin from its gastro-intestinal tract.

4.8

Undesirable

effects

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

System Organ Class

Frequency grouping

Blood and lymphatic

system disorders

Rare

- thrombocytopenia

- neutropenia,

- agranulocytosis,

- eosinophilia.

Immune system

disorders

Rare

- anaphylactic reactions,

- hypersensitivity reactions.

תופשו‏

תירבע ‏ קנ

11‏ ןפוג

בצועמ

תינמרג‏ תידועסה

ברע ‏תיברע‏ תורחא

ןמס‏

הינמרג

ןמס‏ קנ

11‏ ןפוג

בצועמ

10‏,lairA‏ לדחמ

תרירב ‏ ןפוג

בצועמ

תירבע‏רובע‏ןפוג‏ רוחש

‏ ןפוג

‏עבצ‏ קנ

10‏,namoR‏weN‏semiT‏ תורחא

‏תופשו

ברע ‏תיברע‏ תורחא

‏תופשו‏

תירבע ‏ קנ

תידועסה

יקנ‏ תינבת

‏ ןימיל

‏לאמשמ בצועמ

ןבל

10‏,lairA‏ לדחמ

תרירב ‏ ןפוג

בצועמ

תירבע‏רובע‏ןפוג‏ רוחש

‏ ןפוג

‏עבצ‏ קנ

10‏,namoR‏weN‏semiT‏ תורחא

‏תופשו

ברע ‏תיברע‏ תורחא

‏תופשו‏

תירבע ‏ קנ

תידועסה

10‏,lairA‏ לדחמ

תרירב ‏ ןפוג

בצועמ

תירבע‏רובע‏ןפוג‏ רוחש

‏ ןפוג

‏עבצ‏ קנ

10‏,namoR‏weN‏semiT‏ תורחא

‏תופשו

ברע ‏תיברע‏ תורחא

‏תופשו‏

תירבע ‏ קנ

תידועסה

יקנ‏ תינבת

‏ ןימיל

‏לאמשמ בצועמ

ןבל

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, bradycardia,

cardiogenic shock 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 25 g. Neutropenia appears to be promptly

reversible when vancomycin is discontinued. Thrombocytopenia

has rarely been reported. Reversible agranulocytosis (less than 500

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)

and rare cases of vasculitis. Vancomycin has been associated with

the bullous eruption disorders, Stevens-Johnson syndrome, toxic

epidermal necrolysis and linear IgA bullous dermatosis. If a

bullous disorder is suspected, the drug should be discontinued and

specialist dermatological assessment should be carried out.

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.

Rare

- vasculitis.

Respiratory, thoracic and

mediastinal disorders

Common

- dyspnoea,

- stridor.

Gastrointestinal

disorders

Rare

- nausea

Very Rare

- - pseudomembranous

enterocolitis after intravenous

administration.

Skin and subcutaneous

tissue disorders

Common

- exanthema and mucosal

inflammation,

- pruritus,

- urticaria.

Very Rare

- exfoliative dermatitis,

- Stevens-Johnson syndrome,

- Lyell’s syndrome,

- IgA induced bullous dermatitis.

Renal and urinary

disorders

Common

- renal insufficiency manifested

primarily by increased serum

creatinine or serum urea

concentrations.

Rare

- interstitial nephritis,

- acute renal failure.

General disorders and

administration site

conditions

Common

- redness of the upper body and

the face,

- pain and spasm of the chest and

back muscles.

Rare

- drug fever,

- shivering.

During or shortly after rapid infusion anaphylactic reactions

may occur, including hypotension, dyspnea, urticaria or

pruritus. The reactions abate when administration is stopped,

generally between 20 minutes and 2 hours after having

stopped administration

Ototoxicity has primarily been reported in patients given high

doses, or concomitant treatment with other ototoxic medicinal

products, or with pre-existing reduction in kidney function or

hearing

After oral administration, as vancomycine could be absorbed

in case of digestive lesion, the risk of the above mentioned

undesirable effects described cannot be eliminated.

4.9 Overdose

Toxicity due to overdose has been reported. 500 mg IV to a child,

2 year of age, resulted in lethal intoxication.

Administration of a total of 56 g 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 antidoteSupportive care is not known.

Symptomatic

treatment

while

maintaining

renal

function

required.

advised, with maintenance of glomerular filtration. Vancomycin is

poorly removed from the blood by haemodialysis or peritoneal

dialysis. Haemofiltration or Haemoperfusion with polysulfone

resins haveAmberlite resin XAD-4 has been usedreported to

reduce serum concentrationsbe of vancomycinlimited benefit.

Toxicity due to overdose has been reported. 500 mg IV to a child, 2

year of age, resulted in lethal intoxication.

Administration of a total of 56 g 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.

Symptomatic

treatment

while

maintaining

renal

function

required.

Vancomycin is poorly removed from the blood by haemodialysis or

peritoneal

dialysis.

Haemofiltration

haemoperfusion

with

polysulfone resins have been used to reduce serum concentrations of

vancomycin.

6.2

Incompatibili

ties

Vancomycin solutions must basically be administered separately

unless chemicophysical tolerability with other infusion solutions

has been proven.

Combination therapy

In the event of combination therapy with vancomycin and other

antibiotics / chemotherapeutic agents, they must be administered

separately.

ב"צמ נמוסמ ובש ,ןולעה תו

תורמחהה שקובמה תו בוהצ עקר לע

.

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב(

מב םייוניש אלו יתוהמ ןכות קר ןמסל שי .הנוש עבצב .טסקטה םוקי

ךיראתב ינורטקלא ראודב רבעוה

/2017

3

/

8

10‏,lairA‏ לדחמ

תרירב ‏ ןפוג

בצועמ

תירבע‏רובע‏ןפוג‏ רוחש

‏ ןפוג

‏עבצ‏ קנ

10‏,namoR‏weN‏semiT‏ תורחא

‏תופשו

ברע ‏תיברע‏ תורחא

‏תופשו‏

תירבע ‏ קנ

תידועסה

יקנ‏ תינבת

‏ ןימיל

‏לאמשמ בצועמ

ןבל

רוחש

‏ ןפוג

‏עבצ‏ קנ

11‏ ןפוג

בצועמ

semiT‏ תורחא

‏תופשו‏תירבע‏רובע‏ןפוג תופשו‏

תירבע ‏ קנ

11‏,namoR‏weN

תידועסה

ברע ‏תיברע‏ תורחא

הנש‏ ןימיל

‏לאמשמ‏ לאמש

בצועמ

הנש‏ יתאיסאל

‏יניטל‏טסקט‏ןיב‏חוור םירפסמל

‏יתאיסא‏טסקט‏ןיב‏חוור

ןבל

‏יקנ‏ תינבת

רוחש

‏ ןפוג

‏עבצ‏ קנ

11‏ ןפוג

בצועמ

semiT‏ תורחא

‏תופשו‏תירבע‏רובע‏ןפוג תופשו‏

תירבע ‏ קנ

11‏,namoR‏weN

תידועסה

ברע ‏תיברע‏ תורחא

רוחש

‏ ןפוג

‏עבצ‏ קנ

11‏ ןפוג

בצועמ

semiT‏ תורחא

‏תופשו‏תירבע‏רובע‏ןפוג תופשו‏

תירבע ‏ קנ

11‏,namoR‏weN

ןמס‏,‏ תידועסה

ברע ‏תיברע‏ תורחא

רוחש

‏ ןפוג

‏עבצ‏ קנ

11‏ ןפוג

בצועמ

semiT‏ תורחא

‏תופשו‏תירבע‏רובע‏ןפוג תופשו‏

תירבע ‏ קנ

11‏,namoR‏weN

ןמס‏,‏ תידועסה

ברע ‏תיברע‏ תורחא

בצועמ

בצועמ

בצועמ

בצועמ

בצועמ

בצועמ

בצועמ

בצועמ

בצועמ

page 1 of 11

W12-037-293-003

September 2015

1. NAME OF THE MEDICINAL PRODUCT

ANCOMYCIN

Mylan 500 mg, lyophilized powder for for concentrated solution

ANCOMYCIN

Mylan 1G, lyophilized powder for for concentrated solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Vancomycin 500 mg lyophilized powder for injection

Each vial contains 500 mg Vancomycin (as hydrochloride), equivalent to 500,000 IU.

When reconstituted with 10 ml of water for injections, the solution contains 50mg/ml vancomycin.

Vancomycin 1 g lyophilized powder for injection

Each vial contains 1 g Vancomycin (as hydrochloride), equivalent to 1,000,000 IU.

When reconstituted with 20 ml of water for injections, the solution contains 50mg/ml vancomycin.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

lyophilized powder

for concentrated solution

White to almost white powder.

After reconstitution, the pH of the solution is between 2.8 and 4.5.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Intravenous infusion:

Vancomycin hydrochloride is indicated for the treatment of severe or serious infections due to

susceptible strains of methicillin - resistant (beta-Iactam-resistant) staphylococci.

It is also indicated for administration to penicillin-allergic patients as well patients who have failed to

respond to or who cannot receive other drugs including cephalosporins or penicillins and for

infections due to vancomycin-susceptible organisms that are resistant to other antimicrobial drugs.

Vancomycin hydrochloride is indicated for first-line therapy when methicillin-resistant staphylococci

are suspected but when susceptibility data become available appropriate therapy should be instituted.

Vancomycin hydrochloride is effective in the treatment of staphylococcal endocarditis as well as in

other infections due to staphylococci including lower respiratory tract infections septicemia skin and

skin - structure infection and bone infections.

Antibiotic therapy is as an adjunct to appropriate surgical measures when staphylococcal infections

are purulent and localized.

For endocarditis due to Streptococcus viridans or Streptococcus bovis vancomycin hydrochloride has

been shown to be effective in combination with an aminoglycoside.

Vancomycin hydrochloride has been shown to be effective only in combination with an

aminoglycoside for endocarditis due to enterococci (eg Enterococcus fecalis).

Vancomycin hydrochloride has been shown to be effective for the treatment of diphtheroid

endocareditis. In early-onset prosthetic valve endocarditis caused by Staphylococcus epidermidis or

Page 2 of 11

diptheroids vancomycin hydrochloride has been administered successfully in combination with either

rifampin an aminoglycoside or combined with both drugs.

Bacteriologic cultures of specimens should be obtained for isolation and identification of causative

organisms and determination of susceptibilities to vancomycin hydrochloride.

Oral administration:

Vancomycin hydrochloride injection may be given orally for the treatment of antibiotic- associated

Pseudomembrannous colitis due to Staphylococcus enterocolitis and Clostridium difficile.

Vancomycin hydrochloride is not effective orally when administered for other types of infection.

Vancomycin is ineffective in these diseases if given parenterally

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

4.2 Posology and method of administration

Therapeutic indications for intravenous and oral administration are different. Both administration

routes could not be commuted.

Intravenous administration

Solution concentrations of no more than 5 mg/ml are recommended. In selected patients in need of

fluid restriction, solution concentration up to 10 mg/ml may be used; use of such higher

concentrations may increase the risk of infusion-related events (see section 6.6).

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 adverse events are

related to both concentration and rate of administration of vancomycin.

The duration of treatment is guided by the severity of the infection and its clinical and bacteriological

progression.

Patients with normal renal and hepatic functions

Adult and adolescents above 12 years of age:

The recommended daily intravenous dose is 2000 mg (2g), divided into doses of 500mg every 6 hours

or 1000mg every 12 hours.

For bacterial endocarditis, the generally accepted regimen is 1000 mg of vancomycin intravenously

every 12 hours for 4 weeks either alone or in combination with other antibiotics (gentamicin plus

rifampin, gentamicin, streptomycin).

Enterococcal endocarditis is treated for 6 weeks with vancomycin in combination with an

aminoglycoside

– according to national recommendations.

Children 1 month to 12 years of age:

The recommended intravenous dose is 10mg/kg, every 6 hours.

Infants and newborn:

The recommended initial dose is 15 mg/kg, followed by 10 mg/kg every 12 hours during the first

week of life and every 8 hours after that age and up to 1 month of age. Careful monitoring of serum

concentration of vancomycin is recommended (see below).

Elderly patients:

Lower maintenance doses may be required due to the age –related reduction in renal function.

Page 3 of 11

Obese patients:

Modification of the usual daily doses may be required.

Patients with impaired hepatic function

There is no evidence that the dose has to be reduced in patients with impaired hepatic function.

Patients with impaired renal function

The dose must be adjusted in patients with impaired renal function and the following nomogram can

serve as guidance. Careful monitoring of serum concentration of vancomycin is recommended (see

below)

If the creatine clearance is not available, the following formula may be applied to calculate the

creatinine clearance from the patients age, sex and serum creatinine:

Men:

Weight [kg] x (140 - age [years])

72 x serum creatinine [mg/100 ml]

Women: 0.85 x value calculated by the above formula.

Where possible, the creatinine clearance should always be determined.

In patients with mild or moderate renal failure, the starting dose must not be less than 15 mg/kg. In

patients with severe renal failure, it is preferable to administer a maintenance dose between 250 mg

and 1000 mg at a spacing of several days rather than administer lower daily doses.

Patients with anuria (with practically no renal function) should receive a dose of 15 mg/kg body

weight until the therapeutic serum concentration is reached. The maintenance doses are 1.9 mg/kg

body weight per 24 hours.

In order to facilitate the procedure, adult patients with strongly impaired renal function may obtain a

maintenance dose of 250 - 1000 mg at intervals of several days instead of a daily dose.

Dosage in case of haemodialysis

Page 4 of 11

For patients without any renal function, even under regular hemodialysis, the following dosage is also

possible: Saturating dose 1000 mg, maintenance dose 1000 mg every 7 - 10 days.

If polysulfone membranes are used in haemodialysis (high flux dialysis), the half-life of vancomycin

is reduced. An additional maintenance dose may be necessary in patients on regular haemodialysis.

Monitoring of vancomycin serum concentrations:

The serum concentration of vancomycin should be monitored at the second day of treatment

immediately prior to the next dose, and one hour post infusion. Therapeutic vancomycin blood levels

should be between 30 and 40 mg/l (maximum 50 mg/l) one hour after the end of the infusion, the

minimum level (short prior to the next administration) between 5 and 10 mg/l.

The concentrations should normally be monitored twice or three times per week.

Oral administration

Treatment of colitis due to C. difficile

Adults: The usual daily dose is 0,5g to 2 g given in 4 divided doses (125 mg to 500 mg per dose) for 7

to 10 days.

Children: The usual daily dose is 40 mg/kg/day given in 4 divided doses, up to a maximum

of 250 mg/dose, for 7 to 10 days.

Method of Administration

For intravenous infusion only, and not for intramuscular administration.

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 500 mg/100ml or at least

1000mg/200 ml).

Patients requiring fluid restriction can receive a solution of 500 mg /50 ml or 1000 mg /100 ml. With

these higher concentrations the risk for infusion related side effects can be increased

Oral administration:

For information about the preparation of the solution, please refer to section 6.6 special precautions

for disposal and other handling.

4.3 Contraindications

Vancomycin is contraindicated in patients with known hypersensitivity to this drug.

4.4 Special warnings and precautions for use

Warnings

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.

Page 5 of 11

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.

Vancomycin should be administered with caution in patients allergic to teicoplanin, since allergic

cross reactions between vancomycin and teicoplanin have been reported.

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').

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 5.0 g/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.

4.5 Interaction with other medicinal products and other forms of interaction

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 minmised 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.

4.6

Pregnancy and lactation

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 evaluated 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

Page 6 of 11

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.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

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, bradycardia, cardiogenic shock 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 25 g. Neutropenia appears to be promptly reversible when

vancomycin is discontinued. Thrombocytopenia has rarely been reported. Reversible agranulocytosis

(less than 500 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) and rare cases of vasculitis. Vancomycin has been associated with

the bullous eruption disorders, Stevens-Johnson syndrome, toxic epidermal necrolysis and linear IgA

bullous dermatosis. If a bullous disorder is suspected, the drug should be discontinued and specialist

dermatological assessment should be carried out.

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go

v.il

and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com

Page 7 of 11

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: J01 XA01 for intravenous use and A07 AA09 for oral use.

Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis. The primary

mode of action of vancomycin is inhibition of cell-wall synthesis. In addition, vancomycin may alter

bacterial cell membrane permeability and RNA synthesis.There is no cross-resistance between

vancomycin and other classes of antibiotics.

EUCAST Clinical MIC Breakpoints

EUCAST Clinical MIC (version 6.0, valid from 2016-01-01)

Microorganism

Breakpoints (mg/L)

Susceptible

Resistant

Staphylococcus spp. (S. aureus)

≤ 2

> 2

Coagulase-negative staphylococcus

≤ 4

> 4

Enterococcus spp.

≤ 4

> 4

Streptococcus ABCG

≤ 2

> 2

Streptococcus pneumoniae

≤ 2

> 2

Viridans group streptococci

≤ 2

> 2

Gram-positive anaerobes

≤ 2

> 2

Clostridium difficile

≤ 2

> 2

Corynebacterium spp.

≤ 2

> 2

Non-susceptible isolates are rare or not yet reported. The identification and antimicrobial

susceptibility test result on any such isolate must be confirmed and the isolate sent to a reference

laboratory.

The breakpoints are based on epidemiological cut off values (ECOFFs), which distinguish wild type

isolates from those with reduced susceptibility.

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.

Commonly susceptible species:

Gram-positive aerobes

Enterococcus faecalis

Staphylococcus aureus

Coagulase-negative staphyloccoci

Streptococcus group B

Streptococcus group C

Streptococcus group G

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans streptococci

Page 8 of 11

Species for which acquired resistance may be a problem:

Gram-positive aerobes

Enterococcus faecium

Clostridium difficile (e.g. toxigenic strains implicated in pseudomembranous colitis) is a target

species for oral use where high intraluminal concentrations of vancomycin are achieved.

5.2 Pharmacokinetic properties

Vancomycin is given intravenously for therapy of systemic infections.

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, 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.

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 0.39 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.

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.

Vancomycin is not significantly absorbed from the normal gastro-intestinal tract and is therefore not

effective by the oral

route for infections other than staphylococcal enterocolitis and

pseudomembranous colitis due to Clostridium difficile.

Orally administered vancomycin does not usually enter the systemic circulation even when

inflammatory lesions are present. Measurable serum concentrations may occur infrequently in

patients with active C. difficile-induced pseudomembranous colitis and, in the presence of renal

impairment, the possibility of accumulation exists.

Administration of vancomycin oral solution, 2 g daily for 16 days to anephric patients with no

inflammatory bowel disease, gave serum levels of <0.66 μg/ml. With doses of 2 g daily, concentration

of 3,100 mg/kg can be found in the faeces and levels of <1 μg/ml can be found in the serum of

patients with normal renal function who have pseudomembranous colitis.

5.3 Preclinical safety data

Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no

mutagenic potential of vancomycin was found in standard laboratory tests. No definitive fertility

studies have been performed.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydrochloric acid (pH adjustment)

Page 9 of 11

Water for injections

6.2 Incompatibilities

Vancomycin solutions have a low pH, possibly leading to chemical or physical instability if they are

mixed with other substances. Each parenteral solution should therefore be checked visually prior to

use for precipitates and discolouration. Mixing with alkaline solutions should be avoided. This

medicinal product must not be mixed with other medicinal products except those mentioned in section

6.6.

Vancomycin solutions must basically be administered separately unless chemicophysical tolerability

with other infusion solutions has been proven.

Combination therapy

In the event of combination therapy with vancomycin and other antibiotics / chemotherapeutic agents,

they must be administered separately.

6.3

Shelf life

The expiry date of the product is indicated on the label and packaging.

Vancomycin Mylan 500 mg:

The solution reconstituted in water for injections may be stored for 24 hours between 2°C and 8°C.

The solution diluted using 0.9 % NaCl or 5 % glucose solution may be stored for 24 hours at

between 2°C and 8°C.

NOTE: The maximum storage time of the reconstituted and diluted solution is 24 hours.

Vancomycin Mylan 1 G:

The solution reconstituted in water for injections may be stored for 96 hours at temperatures

between 2°C and 8°C.

The solution diluted using 0.9 % NaCl or 5 % glucose solution may be stored for 96 hours at

between 2°C and 8°C.

NOTE: The maximum storage time of the reconstituted and diluted solution is 96 hours.

From a microbiological point of view, the prepared solution for infusion should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

Shelf life of the reconstituted solution for oral use: the reconstituted solution should be used

immediately.

6.4. Special precautions for storage

Store below 25°C

6.5 Nature and contents of container

Type II colourless glass vial, with a bromobutyl rubber stopper and an aluminium/plastic tear-off cap.

Pack size: 1 vial.

6.6 Special precautions for disposal and other handling

Preparation of the solution for infusion

The product must be reconstituted and the resulting concentrate must then be diluted prior to use.

Vancomycin 500 mg: dissolve the contents of one vial in 10 ml of water for injections.

For Vancomycin 1 g: dissolve the contents of one vial in 20 ml of water for injections.

The reconstituted solution should be a clear colourless to slightly yellowish solution, without visible

particles.

Page 10 of 11

One ml of reconstituted solution contains 50 mg of vancomycin.

For storage conditions of the reconstituted product see section 6.3.

Suitable diluents for further dilution are water for injections, 5% glucose solution or 0.9% sodium

chloride solution.

Different dilution is required depending on method of administration.

Intermittent infusion:

Vancomycin 500 mg:

Reconstituted solutions containing 500 mg vancomycin must be diluted with at least 100 ml diluent.

The desired dose should be administered by intravenous infusion at a rate of no more than 10 mg/min,

over at least 60 minutes.

Vancomycin 1 g:

Reconstituted solutions containing 1 g vancomycin must be diluted with at least 200 ml diluent. The

desired dose should be administered by intravenous infusion at a rate of no more than 10 mg/min,

over at least 60 minutes.

Continuous infusion:

This should be used only if treatment with an intermittent infusion is not possible.

1 g or 2 g of vancomycin, corresponding to 2 to 4 vials of reconstituted solution, may be added to a

sufficiently large volume of the above suitable diluent to permit the desired daily dose to be infused

over twenty-four hours.

For storage conditions of the diluted product see section 6.3.

Before

administration, the reconstituted and diluted solutions should be inspected visually for

particulate matter and discoloration. Only clear and colourless to pale yellow solution free from

particles should be used.

Preparation of the oral solution

After initial reconstitution of the vial, the selected dose may be diluted in 30 ml of water and given to

the patient to drink or the diluted material may be administered by a nasogastric tube.

Disposal

Vials are for single use only. Unused medicinal products must be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. MANUFACTURER

Mylan S.A.S., France

8. REGISTRATION HOLDER

:

Genmedix, 12 Beit Harishonim St., Emek Heffer

9. Israeli Drug License number(S):

VANCOMYCIN MYLAN 500 MG: 123.63.30297

VANCOMYCIN MYLAN 1 G: 123.64.30298

Page 11 of 11

The format of this leaflet has been determined by the Ministry of Health and its content has been

examined and approved on May 2017.