PENICILLIN G SODIUM 10 M.U.

Israel - English - Ministry of Health

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Active ingredient:
BENZYLPENICILLIN SODIUM
Available from:
ABIC MARKETING LTD, ISRAEL
ATC code:
J01CE01
Pharmaceutical form:
POWDER FOR SOLUTION FOR INJECTION
Composition:
BENZYLPENICILLIN SODIUM 10 MU/VIAL
Administration route:
I.M, I.V
Prescription type:
Required
Manufactured by:
SANDOZ GmbH, AUSTRIA
Therapeutic group:
BENZYLPENICILLIN
Therapeutic area:
BENZYLPENICILLIN
Therapeutic indications:
Infections due to penicillin - sensitive microorganisms.
Authorization number:
137 28 21065 00
Authorization date:
2012-10-31

Penicillin G Sodium SPC - Notification – HS - 01/09/2019 - CLEAN

SUMMARY OF PRODUCT CHARACTERISTICS

Penicillin G Sodium 5 MU

Penicillin G Sodium 10 MU

Powder for solution for I.V. or I.M. injection

1.

NAME OF THE MEDICINAL PRODUCT

Penicillin G Sodium 5 MU

Penicillin G Sodium 10 MU

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Penicillin G Sodium 5 MU:

Each vail contains 2.994 g benzylpenicillin sodium, corresponding to 5,000,000 IU.

Penicillin G Sodium 10 MU:

Each vail contains 5.988 g benzylpenicillin sodium, corresponding to 10,000,000 IU.

3.

PHARMACEUTICAL FORM

White to whitish powder for solution for injection.

pH after reconstitution: 5.5 — 7.5

4.

CLINICAL PARTICULARS

4.1. Therapeutic indications

Infections due to penicillin - sensitive microorganisms.

4.2. Posology and method of administration

Parenteral drug products should be inspected visually for particulate matter and discoloration,

prior to administration, whenever solution and container permit.

Penicillin G should preferably be administered by intramuscular injection. However when

large doses are required, it may be advisable to administer Penicillin G by means of a

continuous intravenous drip.

Severe infections

A minimum of 5 MU daily is recommended for the treatment of severe infections due to

susceptible strains of Streptococci, Pneumococci and Staphylococci (bacteremia, empyema,

severe pneumonia, pericarditis, endocarditis, meningitis and other severe infections).

Anthrax

A minimum of 5 MU/ day in divided doses, until cure is achieved.

Actinomycosis

1-6 MU/ day for cervicofacial cases.

10-20 MU/ day for thoracic and abdominal disease.

Penicillin G Sodium SPC - Notification – HS - 01/09/2019 - CLEAN

Clostridial infections

20 MU per day (as adjunctive therapy to antitoxin).

Diphtheria

For prevention of the carrier state, 0.3-0.4 MU/ day in divided doses for 10-12 days.

Erysipeloid Endocarditis

2-20 MU/ day for 4-6 weeks.

Fusospirochetal Infections

5-10 MU/ day.

Gram-negative Bacteremia

20-80 MU/ day.

Listeria infections

In adults with meningitis, 15-20 MU/ day for 2 weeks.

In adults with endocarditis, 15-20 MU/ day for 4 weeks.

In neonates, 0.5-1.0 MU/ day.

Pasteurella infections

In bacteremia and meningitis: 4-6 MU/ day for 2 weeks.

Rat-bite fever

12-15 MU daily for 3-4 weeks.

Gonorrheal endocarditis and arthritis

A minimum of 5 MU daily.

Syphilis

Penicillin G may be used in the treatment of acquired and congenital syphilis but, because of

the necessity of frequent dosage, hospitalization is recommended.

Dosage and duration of therapy is determined by the age of the patient and the stage of the

disease.

Meningococcal Meningitis

1-2 MU intramuscularly every 2 hours, or continuous intravenous drip of 20-30 MU/ day.

4.3. Contraindications

Hypersensitivity to the active substance

History of hypersensitivity to penicillin

Past medical history of severe allergic hypersensitivity reaction (e.g. anaphylaxis) to

another beta-lactam antibiotic (e.g. cephalosporin, carbapenem, or monobactam)

4.4. Special warnings and precautions for use

In patients with cephalosporin hypersensitivity, cross allergy is possible (incidence according

to the literature is 5-10%).

A hypersensitivity test should be performed before commencing therapy. Patients should be

informed of the possible occurrence of a hypersensitivity reaction. Special caution is advised

in patients with allergic predisposition or bronchial asthma. Following administration of the

drug, patients should be observed for 30 minutes, and an adrenaline solution should be ready

for injection in case of emergency. If an allergic reaction occurs, discontinue therapy and, if

necessary, initiate symptomatic therapy.

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Caution is advised in patients with the following conditions:

allergic predispositioin (urticaria or hay fever) or bronchial asthma (increased risk of

hypersensitivity reactions)

severe heart disease or severe electrolyte disturbances of a different etiology (care

should be taken in this patient group for electrolyte intake, especially for potassium

intake)

kidney disease

liver injury

epilepsy, cerebral edema or meningitis (increased risk of seizures, especially at high

doses (> 20 MU) of penicillin G-Sodium; see section 4.8)

acute mononucleosis (increased risk of skin rash)

in the treatment of concomitant infections in patients with acute lymphoblastic

leukemia (increased risk of skin reactions)

dermatomycoses (para-allergic reactions are possible as there may be an antigenic

association between penicillins and dermatophyte metabolic products; see

section 4.8)

Rarely, prolonged prothrombin time has been reported in patients receiving penicillins.

Adequate monitoring should be performed in concomitant administration of anticoagulants.

The dose of oral anticoagulants may have to be adjusted in order to maintain the desired

level of anticoagulation (see sections 4.5 and 4.8).

It should be noted that the absorption of Penicillin G-Sodium is delayed following

intramuscular administration in patients with diabetes (see section 5.2).

In patients with venereal diseases, dark-field studies should be performed prior to the

initiation of treatment for suspected co-existing syphilis. In addition, follow-up serological tests

should be performed for at least 4 months.

Attention should be paid to the overgrowth of resistant germs during long-term therapy. If

secondary infections occur, appropriate measures should be taken.

severe

persistent

diarrhea,

antibiotic-related

pseudomembranous

colitis

should

considered (mucohemorrhagic, watery diarrhea; dull, diffuse to colicky abdominal pain; fever;

rarely tenesmus), which can be life-threatening. Therefore, Penicillin G-sodium should be

discontinued immediately in these cases, and a therapy targeting the identified pathogens

should be initiated. Anti-peristaltic agents are contraindicated.

During therapy of Lyme disease or syphilis, a Jarisch-Herxheimer reaction characterized by

fever, chills, general and focal symptoms (usually 2 to 12 hours after the administration of the

first dose) may occur as a consequence of the bactericidal action of penicillin on the

pathogens. Patients should be advised that this is a common transient consequence of

antibiotic therapy. Appropriate therapy should be initiated to suppress or alleviate the Jarisch-

Herxheimer reaction (see section 4.8).

In conditions such as severe pneumonia, empyema, sepsis, meningitis or peritonitis, which

require

higher

serum

penicillin

levels,

treatment

with

water-soluble

alkali

salt

benzylpenicillin should be commenced.

If neurological involvement in patients with congenital syphilis cannot be ruled out, penicillin

forms that achieve higher drug levels in the cerebrospinal fluid should be used.

Severe local reactions can occur in intramuscular administration to infants. If possible,

intravenous therapy should be performed.

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In the case of intravenous administration of very high doses (over 10 MU/ day), the site of

injection should be changed every other day to avoid superinfection and thrombophlebitis.

Infusions of more than 10 MU of Penicillin G-Sodium should be administered slowly due to

the risk of electrolyte disturbances, and infusions of more than 20 MU should be given slowly

due to the risk of seizures (see section 4.8).

In prolonged treatment (longer than 5 days) with high doses of penicillin, it is recommended

to monitor electrolytes, blood counts and kidney function tests.

Effect on diagnostic laboratory procedures:

A positive direct Coomb’s test often develops (

1% to < 10%) in patients receiving 10

million IU (equivalent to 6 g) of benzylpenicillin or more per day. The direct antiglobulin

test may still remain positive for 6 to 8 weeks after discontinuation of penicillin (see

sections 4.5 and 4.8).

Determination of urinary protein using the precipitation techniques (sulphosalicylic acid,

trichloroacetic acid), the Folin-Ciocalteu-Lowry method or the Biuret method may lead to

false positive results. Caution should therefore be exercised when interpreting the

results of such tests in patients receiving Penicillin G-Sodium. Protein determination

using test strips is not affected.

The amino acid determination in the urine by means of the ninhydrin method can also

lead to false positive results.

Penicillins bind to albumin. In electrophoretic methods for albumin determination, this

can simulate pseudobisalbuminemia.

During therapy with Penicillin G-Sodium, non-enzymatic urinary glucose detection and

urobilinogen detection may prove false-positive. In patients treated with Penicillin G-

Sodium, enzymatic urine glucose tests should be used as these are not affected by said

interaction.

In the determination of 17-ketosteroids in urine (using Zimmermann reaction), increased

levels may occur in patients on therapy with Penicillin G-Sodium.

This medicinal product contains 39 mg sodium per 1MU dose, equivalent to 2% of the WHO

recommended maximum daily intake for sodium.

Penicillin G Sodium is considered high in sodium. This should be particularly taken into

account for those on a low salt diet.

4.5. Interaction with other medicinal products and other forms of interaction

Simultaneous administration of Penicillin G -Sodium is not recommended for:

Based on the general principle of not combining bactericidal and bacteriostatic antibiotics,

Penicillin G-Sodium should not be used in combination with bacteriostatic antibiotics.

Mixed

syringes

or

infusions:

order

avoid

undesired

chemical

reactions,

administration of mixed syringes and infusions, as well as mixing with solutions containing

carbohydrates such as glucose, should be avoided (see section 6.2).

Caution should be exercised in concomitant administration with:

Probenecid:

Administration

probenecid

leads

inhibition

tubular

secretion

benzylpenicillin, thereby increasing serum concentration and prolonging the elimination half-

life. In addition, probenecid also inhibits penicillin transport from the cerebrospinal fluid, so

that

concomitant

administration

probenecid

further

reduces

already

poor

penetration of benzylpenicillin into brain tissue.

Antiphlogistics, anti-inflammatory agents and antipyretics: In co-administration of Penicillin G-

Sodium

with

antiphlogistics,

anti-inflammatory

agents

antipyretics:

(especially

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indomethacin, phenylbutazone, high doses of salicylates), competitive inhibition of excretion,

increasing serum levels and prolonging the elimination half-life, should be kept in mind.

Digoxin: In patients treated with digoxin, caution should be exercised with Penicillin G-Sodium

as there is a risk of bradycardia due to interactions.

Methotrexate: The excretion of methotrexate is reduced when co-administered with Penicillin

G-Sodium.

This

lead

increased

methotrexate

toxicity.

Concomitant

methotrexate and penicillin should be avoided whenever possible. If co-administration is

unavoidable, a reduction in methotrexate dose should be considered and methotrexate serum

levels monitored. The patient should be monitored for potential additional methotrexate side

effects, including leukopenia, thrombocytopenia and skin suppuration.

Oral anticoagulants: Oral anticoagulants and penicillin antibiotics have been used in practice

largely without interactions. However, the literature has reported an increased number of

patients who displayed an increased bleeding tendency if given acenocoumarol or warfarin

concomitantly with penicillin. If concomitant use is required, prothrombin time or other

appropriate coagulation parameters should be carefully monitored in additional administration

or discontinuation of penicillin. In addition, the oral dose of anticoagulants may have to be

adjusted (see sections 4.4 and 4.8).

Synergism between antibiotics:

Penicillin G-Sodium should only be used in combination with other antibiotics if synergism or

at least an additive effect is to be expected. The individual components of a combination are

generally given in a fully effective dose. (Exception: in cases of proven synergism, the dose of

the more toxic combination component can be reduced).

For a given indication, reference is made in particular to the possibility of combining Penicillin

G-Sodium with the following bactericidal antibiotics:

isoxazolylpenicillins (e.g. flucloxacillin and other narrow-spectrum beta lactams)

aminopenicillins

aminoglycosides

The penicillins mentioned are slowly injected intravenously before administering the Penicillin

G-Sodium

infusion,

possible,

aminoglycosides

should

given

separate

intramuscular application.

4.6. Fertility, pregnancy and breast-feeding

Pregnancy

Benzylpenicillin crosses the placenta. 1-2 hours after administration, levels comparable to

maternal serum levels are achieved in the fetal serum. Animal studies did not indicate any

direct or indirect harmful effects regarding reproductive toxicity.

The use of Penicillin G-Sodium during pregnancy is possible with appropriate indication and

benefit-risk consideration.

During pregnancy, Penicillin G-Sodium is not indicated for the treatment of syphilis.

Breast-feeding

Penicillins appear in small quantities in human breast milk.

Although no side effects have been reported in breast-fed infants to date, the possibility of

sensitization or alteration of intestinal flora must be considered.

Mothers of infants who also eat baby food should pump and discard breastmilk while

receiving Penicillin G-Sodium treatment. Breastfeeding can be resumed 24 hours after

treatment discontinuation.

Penicillin G Sodium SPC - Notification – HS - 01/09/2019 - CLEAN

Fertility

No studies have been conducted to investigate the effects of Penicillin G-Sodium on fertility.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Due

to possible serious undesirable effects (e.g. anaphylactic shock with loss of conscience, and

anaphylactic reactions, see also section 4.8), Penicillin G-Sodium may affect the ability to

drive and use machines.

4.8. Undesirable effects

The side effects are classified based on body systems and their frequency according to the

following classification:

Very common (

1/10)

Common (

1/100, <1/10)

Uncommon (

1/1,000, <1/100)

Rare (

1/10,000, <1/1,000)

Very rare (<1/10,000)

Not known (frequency cannot be estimated from available data)

Blood and lymphatic system disorders

Very rare:

Eosinophilia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, agranulocytosis,

pancytopenia, hemolytic anemia, blood coagulation disturbances

Frequency not known:

Prolongation of bleeding time and prothrombin time (see section 4.4)

Immune system disorders

Uncommon:

Allergic reactions: urticaria, angioneurotic edema, erythema multiforme, exfoliative dermatitis,

fever, joint pain, anaphylaxis or anaphylactoid reactions (asthma, purpura, gastrointestinal

manifestations). In patients with dermatomycoses, there may be para-allergic reactions as

there may be antigenic association between penicillins and dermatophyte metabolites.

Frequency not known:

Serum disease, Jarisch-Herxheimer reaction associated with spirochete infections (syphilis

and Lyme disease)

Metabolism and nutrition disorders

Rare:

Rapid infusion of more than 10 MU may cause electrolyte imbalances.

Nervous system disorders

Rare:

Neuropathy. A high-dose infusion (over 20 MU in adults) may cause seizures. Special care

should be taken in patients with severe renal impairment, epilepsy, meningitis, cerebral

edema or cardiopulmonary bypass.

Gastrointestinal disorders

Uncommon:

Stomatitis, glossitis, black hairy tongue (lingua villosa nigra), nausea, vomiting

If diarrhea occurs during therapy, the possibility of pseudomembranous colitis should be

considered (see section 4.4).

Penicillin G Sodium SPC - Notification – HS - 01/09/2019 - CLEAN

Hepato biliary disorders

Not known:

Hepatitis, cholestasis

Skin and subcutaneous tissue disorders

Frequency not known: Pemphigoid

Renal and urinary disorders

Rare:

Nephropathy (after intravenous administration of more than 10 MU Penicillin G-Sodium),

albuminuria, cylindruria and hematuria

Oliguria or anuria that rarely occurs during high-dose penicillin therapy usually disappears 48

hours after discontinuation of therapy. Diuresis can also be initiated by 10% mannitol solution.

General disorders and administration site conditions

Rare:

Severe local reactions may be associated with intramuscular administration to infants.

Examinations

Common:

Positive direct Coomb's test

False-positive protein determination in urine by means of precipitation methods (Folin-

Ciocalteu-Lowry method, Biuret method)

False-positive amino acid determination in urine (ninhydrin method)

Simulation of pseudobisalbuminemia in electrophoretic methods for albumin

determination

False-positive non-enzymatic urine sugar detection and urobilinogen detection

Elevated levels in the determination of 17-ketosteroids in urine (using the Zimmermann

reaction) (see section 4.5)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 https://sideeffects.health.gov.il/

4.9. Overdose

In case of overdose, increased neuromuscular excitability or cerebral seizures are expected.

Countermeasures:

Discontinuation,

clinical

monitoring

symptomatic

treatment

necessary. Penicillin G-Sodium can be removed by hemodialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group

Benzylpenicillin (Penicillin G) is a semi-synthetic beta-lactam antibiotic, inactivated by beta-

lactamase.

ATC code: JO10E01

Mechanism of action

Penicillin G Sodium SPC - Notification – HS - 01/09/2019 - CLEAN

The mechanism of action of benzylpenicillin is based on inhibition of bacterial cell wall

synthesis (during the growth phase) by blocking the penicillin-binding proteins (PBPs) such

as transpeptidases. This has a bactericidal effect.

Relationship between pharmacokinetics and pharmacodynamics

The efficacy depends essentially on the length of time during which the active ingredient

levels are above the MIC of the pathogen.

Resistance mechanisms

Resistance to benzylpenicillin may be due to the following mechanisms:

Inactivation by beta-lactamases: Benzylpenicillin can be inactivated by beta-lactamase

therefore

effective

against

beta-lactamase-producing

bacteria

(e.g.

staphylococci or gonococci).

Reduced affinity of PBPs for benzylpenicillin: The acquired resistance of pneumococci

and some other streptococci to benzylpenicillin is due to modifications of existing PBPs as

a result of a mutation. By contrast, the resistance of methicillin (oxacillin)-resistant

staphylococci is caused by the formation of an additional PBP with reduced affinity to

benzylpenicillin.

Inadequate penetration of benzylpenicillin through the outer cell wall may result in Gram-

negative bacteria not sufficiently inhibiting PBPs.

Efflux pumps can actively transport benzylpenicillin out of the cell.

There is a partial or complete cross-resistance of benzylpenicillin with other penicillins and

cephalosporins.

Limit values

Testing of benzylpenicillin is carried out using the usual dilution series. The results are

assessed on the basis of the limit values for benzylpenicillin. The following minimal inhibitory

concentrations for susceptible and resistant germs have been determined:

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Limit Values

PATHOGEN

SUSCEPTIBLE

RESISTANT

Staphylococcus spp.

0.12 mg/L

> 0.12 mg/L

Streptococcus spp.

(Groups A, B, C, G)

0.25 mg/L

> 0.25 mg/L

Streptococcus pneumoniae

0.06 mg/L

> 2 mg/L

Streptococci of the "viridans"

group

0.25 mg/L

> 2 mg/L

Neisseria meningitidis

0.06 mg/L

> 0.25 mg/L

Neisseria gonorrhoeae

0.06 mg/L

> 1 mg/L

Gram-negative anaerobes

0.25 mg/L

> 0.5 mg/L

Gram-positive anaerobes

0.25 mg/L

> 0.5 mg/L

Non-species specific limits*

0.25 mg/L

> 2 mg/L

Based mainly on serum pharmacokinetics

Prevalence of acquired resistance

The prevalence of acquired resistance of individual species can vary from place to place and

in the course of time. For this reason, and especially for the adequate treatment of severe

infections,

local

information

resistance

patterns

required.

effectiveness

benzylpenicillin is called into question due to the local resistance patterns, expert advice

should

sought.

Particularly

case

serious

infections

treatment

failures,

microbiological

diagnosis

with

pathogen

identification

susceptibility

testing

benzylpenicillin is indicated.

Prevalence of acquired resistance based on data from the last 5 years from national

resistance surveillance projects and studies (as of January 2015):

Usually susceptible species

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Aerobic Gram-positive microorganisms

Actinomyces israeli °

Corynebacterium diphtheriae °

Erysipelothrix rusiopathiae °

Gardnerella vaginalis °

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Streptococcus dysgalactiae subsp. equisimilis

(group C & G streptococci)

Streptococci of the “viridians” group °

Aerobic Gram-negative microorganisms

Borrelia burgdorferi

°

Eikenella corrodens

°

$

Haemophilus influenzae °

$

Neisseria meningitidis °

Anaerobic microorganisms

Clostridium perfringens °

Clostridium tetani °

Fusobacterium

spp.

°

Peptoniphilus

spp.

°

Peptostreptococcus

spp. °

Veillonella parvula °

Other microorganisms

Treponema pallidum °

Species in which acquired resistance can present a problem for use

Aerobic Gram-positive microorganisms

Enterococcus faecalis

$

Staphylococcus aureus

+

Staphylococcus epidermidis

+

Staphylococcus haemolyticus

+

Staphylococcus hominis

+

Aerobic Gram-negative microorganisms

Neisseria gonorrhoeae

$

Naturally resistant species

Aerobic Gram-positive microorganisms

Enterococcus faecium

Nocardia asteroides

Aerobic Gram-negative microorganisms

All Enterobacteriaceae species

Legionella pneumophila

Moraxella catarrhalis

Pseudomonas aeruginosa

Anaerobic microorganisms

Bacteroides

spp.

Other microorganisms

Chlamydia

spp.

Chlamydophila

spp.

Mycoplasma

spp.

°

No updated data are available at the time of publication of the table. In the primary

literature, standard reference works and recommendations for treatment, susceptibility is

assumed.

The natural sensitivity of most isolates lies in the intermediate range.

In at least one region, the resistance rate is more than 50%.

Penicillin G Sodium SPC - Notification – HS - 01/09/2019 - CLEAN

Umbrella term for a heterogeneous group of streptococcal species. Resistance rate may

vary depending on the streptococcal species in question.

5.2. Pharmacokinetic properties

Absorption

Benzylpenicillin is not acid-stable and is therefore only indicated for parenteral administration.

The alkali salts of benzylpenicillin are rapidly and almost completely absorbed after i.m.

injection

Plasma peak values of 150-200 1U/mL are achieved 15 - 30 min. after i.m. injection of 10 MU

of Penicillin G-Sodium. Peak values of up to 500 IU/mL can be achieved after a short infusion

(30 min.). Approximately 55% of the administered dose is bound to plasma proteins.

Distribution

When using

high-dose

penicillin

therapy,

therapeutically

effective

concentrations

reached even in poorly accessible tissues such as heart valves, bones, and in cerebrospinal

fluid or in empyema, etc.

Benzylpenicillin crosses the placenta. 10-30% of maternal plasma concentrations are found in

the fetal circulation. High concentrations are also achieved in the amniotic fluid. In contrast,

only minimal amounts are excreted into human breast milk. The volume of distribution is

about 0.3-0.4 L/kg, in children about 0.75 L/kg. The plasma protein binding is about 55%.

Biotransformation and elimination

Elimination occurs largely (50–80%) as unchanged substance via the kidneys (85–95%) and,

to a lesser degree, in active form with the bile (approximately 5%).

The plasma half-life is approximately 30 minutes in adults with healthy kidneys.

Kinetics of special patient groups

Diabetics: In diabetic patients, delayed absorption from the intramuscular depot is

expected.

Pre-term babies and newborns: Due to the immaturity of kidney and liver at this age,

serum half-life is up to three hours (and longer).

Therefore, the

intervals between

individual administrations should not be less than 8–12 hours (depending on the degree

of maturity).

Elderly: In advanced age, the elimination processes may be delayed as well, so the

dosage should be adjusted for the respective kidney function.

5.3. Preclinical safety data

Reproduction studies in mice, rats and rabbits have not shown any negative effects on fertility

or fetuses. Long-term studies on laboratory animals for carcinogenesis, mutagenicity and

fertility are not available.

6.

PHARMACEUTICAL PARTICULARS

6.1. List of excipients

None.

6.2. Incompatibilities

The contents of the vial should only be used in a solution containing water for injection, 5%

glucose solution or 0.9% saline in order to avoid incompatibilities.

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ךיראת

____________________

September 2, 2012

___

םש

רישכת

___תילגנאב

PENICILLIN G SODIUM 5 MU, 10 MU

_

רפסמ

____םושיר

5

MU: 024 73 21066 00, 10 MU: 025 45 21065 00

םש

לעב

םושירה

Salomon, Levin, & Elstein Ltd., P.O.Box 3696, Petach-Tikva

םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Warnings

Therefore, before initiating therapy with

this drug, careful inquiry should be made

concerning

previous

hypersensitivity

reactions to penicillins, cephalosporins, or

other allergens, because of the risk of

anaphylactoid reactions

If an allergic

reaction

occurs,

drug

should

discontinued

appropriate

therapy

instituted.

Serious anaphylactoid reactions require

immediate

emergency

treatment

with

adrenaline. Oxygen, intravenous steroids,

airway

management

including

intubation, should also be administered as

indicated.

Pseudomembranous colitis has been

reported

with

nearly

antibacterial

agents, including Penicillin G, and may

range in severity from mild to life-

threatening. Therefore, it is important to

consider this diagnosis in patients who

present with diarrhea subsequent to the

administration of antibacterial agents.

Use in Breastfeeding

Since penicillins are excreted in breast

milk, administration of this drug to nursing

mothers

lead

sensitization,

diarrhea, candidiasis and skin rash in

infants.

Therefore,

taking

into

account

importance of the drug to the mother,

either discontinue nursing, or discontinue

the drug.

Use in Infants

Penicillins

excreted

largely

unchanged by the kidney. Because renal

function is incompletely developed in

infants, the rate of elimination of the drug

tends to be slow. Penicillin-type drugs

should therefore be administered with

caution,

particularly in neonates, and

organ

system

function

should

evaluated frequently.

Therefore, before initiating therapy with this drug, careful inquiry

should be made concerning previous hypersensitivity reactions to

penicillins, cephalosporins, or other allergens, because of the risk

of anaphylactoid reactions (asthma, purpura, gastrointestinal

symptoms) (1). Patients should be observed for 30 minutes after

medicine administration and adrenaline or epinephrine should be

made immediately available for injection (1) . If an allergic

reaction occurs, the drug should be discontinued and appropriate

therapy instituted.

Serious anaphylactoid reactions require immediate emergency

treatment with adrenaline. Oxygen, intravenous steroids, and

airway management including intubation, should also be

administered as indicated.

If high-dose penicillin treatment is continued for more than 5

days, electrolyte balance, blood counts and renal function should

be monitored (1).

In patients receiving very high intravenous doses (more than 10

million IU daily) injection sites should be alternated every 2 days

to prevent superinfections and thrombophlebitis (1).

Pseudomembranous colitis/Clostridium difficile-associated

diarrhea (CDAD) (2)

has been reported with nearly all

antibacterial agents, including Penicillin G, and may range in

severity from mild to life-threatening. 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 diarrhea following

antibiotic use. Careful medical history is necessary since CDAD

has been reported to occur over two months after the

administration of antibacterial agents.

(2).

Therefore, it is

important to consider this diagnosis in patients who present with

diarrhea subsequent to the administration of antibacterial agents.

Use in Breastfeeding

Since penicillins are excreted in breast milk, administration of

this drug to nursing mothers may lead to sensitization, diarrhea,

candidiasis and skin rash in infants.

Residual benzylpenicillin may be present in breast milk at levels

corresponding to approximately 0.8% of the maternal dose (1)

Therefore, taking into account the importance of the drug to the

mother, either discontinue nursing, or discontinue the drug.

Use in Pediatrics Infants

Penicillins are excreted largely unchanged by the kidney.

Because renal function is incompletely developed in infants, the

rate of elimination of the drug tends to be slow. Penicillin-type

drugs should therefore be administered with caution, appropriate

reductions in the dosage and frequency of administration should

be made in these patients (2), particularly in neonates, and organ

system function should be evaluated frequently.

As infants have been found to develop severe local reactions to

intramuscular

injections,

treatment

should

preferably

intravenous (1)

Use in Geriatrics (2)

Clinical studies of Penicillin G Injection did not include

sufficient numbers of subjects aged 65 and over to determine

whether they respond differently from younger subjects. Other

reported clinical

experience has not identified differences in

responses between the elderly and younger patients. In general,

dose selection for an elderly patient should be cautious, usually

starting at the low end of the dosing range, reflecting the greater

frequency of decreased hepatic, renal, or cardiac function, and of

concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney,

and the risk of toxic reactions to this drug may be greater in

patients with impaired renal function. Because elderly patients

are more likely to have decreased renal function, care should be

taken in dose selection, and it may be useful to monitor renal

function.

Precautions

Other Precautions (1)

Particular caution should be exercised when treating patients

with an allergic diathesis such as urticaria or hay fever or with

bronchial asthma

Caution is also necessary when treating newborns, patients with

severe

cardiopathies

other

serious

heart

disease,

hypovolaemia, epilepsy and renal or hepatic damage

Caution is required when treating concurrent infections in

patients

presenting

mononucleosis

acute

lymphatic

leukaemia due to the increased risk of skin reactions.

Contraindications

Cross allergenicity to cephalosporins, with a reported incidence,

of 5 to 10%, is possible, and should be considered when treating

patients known to be hypersensitive to these medicines. (1)

Adverse events

Immediate reactions usually occur within

20 minutes of administration and range in

severity from urticaria and pruritus to

angloneurotic

edema,

laryngospasm,

bronchospasm,

hypotension,

vascular

collapse and death (see Warnings). Such

immediate anaphylactic reactions are very

rare and usually occur after parenteral

therapy, but a few cases of anaphylaxis

have been reported following oral therapy.

Another type of immediate reaction, an

accelerated reaction, may occur between

20 minutes

hours

after

administration and may include urticaria,

pruritus, fever and, occasionally, laryngeal

edema.

The reported incidence of allergic reactions to all penicillins

ranges from 0.7 to 10% percent in different studies. Sensitization

is usually the result of previous treatment with a penicillin, but

some individuals have had immediate reactions when first

treated. In such cases, it is postulated that prior exposure to

penicillin may have occurred via trace amounts present in milk or

vaccines (2).

Immediate reactions usually occur within 20 minutes of

administration and range in severity from urticaria and pruritus to

angloneurotic edema, laryngospasm, bronchospasm, hypotension,

vascular collapse and death (see Warnings). Such immediate

anaphylactic reactions are very rare and usually occur after

parenteral therapy, but a few cases of anaphylaxis have been

reported following oral therapy. Another type of immediate

reaction, an accelerated reaction, may occur between 20 minutes

and 45 hours after administration and may include urticaria,

pruritus, fever and, angioneurotic edema, erythema multiforme,

joint pain (1) occasionally, laryngeal edema.

Gastrointestinal system

Pseudomembranous colitis has been

reported with the onset occurring during or

after

Penicillin

treatment.

Nausea,

vomiting, stomatitis, black or hairy tongue,

and other symptoms of gastrointestinal

irritation may occur, especially during oral

therapy.

Hematological

Hematological

reactions

including

hemolytic

anemia,

granulocytopenia

(neutropenia),

thrombocytopenia,

thrombocytopenic purpura, eosinophilia,

leukopenia, and agranulocytosis have been

observed in patients receiving prolonged

high doses of Penicillin G (e.g. bacterial

endocarditis). These are believed to be

hypersensitivity

phenomena

usually reversible upon discontinuation of

therapy.

Urogenital system

Renal tubular damage and interstitial

nephritis have been associated with large

intravenous

doses

Penicillin

Manifestations

this

reaction

include

fever,

rash,

eosinophilia,

proteinuria, eosinophiluria, hematuria and

rise

serum

urea

nitrogen.

Discontinuation of Penicillin G results in

resolution in the majority of patients.

Local reactions

Phlebitis and thrombophlebitis may occur

with intravenous administration.

Gastrointestinal system

Pseudomembranous colitis has been reported with the onset

occurring during or after Penicillin G treatment. Nausea,

vomiting, stomatitis, glossitis (1) , black or hairy tongue, and

other

symptoms

gastrointestinal

irritation

occur,

especially during oral therapy.

If diarrhoea develops during treatment, the possibility of

pseudomembranous colitis should be excluded (1)

Hematological

Hematological

reactions

including

hemolytic

anemia,

granulocytopenia (neutropenia), thrombocytopenia, pancytopenia

(1) , thrombocytopenic purpura, eosinophilia, leukopenia, and

agranulocytosis have been observed in patients receiving

prolonged high doses of Penicillin G (e.g. bacterial endocarditis).

These are believed to be hypersensitivity phenomena and are

usually reversible upon discontinuation of therapy.

Hepatobiliary disorders (1)

Isolated cases

Hepatitis, cholestasis

Urogenital system

Renal tubular damage and interstitial nephritis have been

associated with large intravenous doses of Penicillin G.

Manifestations of this reaction may include fever, rash,

eosinophilia, proteinuria, eosinophiluria, hematuria and a rise in

serum urea nitrogen. Discontinuation of Penicillin G results in

resolution in the majority of patients.

Oliguria and anuria occur rarely during high-dose penicillin

therapy and usually disappear within 48 hours after discontinuing

treatment. Diuresis can also be stimulated with 10% mannitol

solution (1).

Local reactions

Rare

Severe local reactions on intramuscular administration to infants

(1).

Phlebitis and thrombophlebitis may occur with intravenous

administration.

Drug Interactions

Penicillins/Other Drugs that compete

with Renal Tubular Secretion: Other

drugs may compete with Penicillin G for

renal tubular secretion and thus prolong

the serum half-life of penicillin. These

drugs include: aspirin/, phenylbutazone,

sulfonamides,

indomethacin

thiazide

diuretics, furosemide and ethacrynic acid.

As penicillins are only active against proliferating micro-

organisms, Penicillin G sodium should not be combined with

bacteriostatic antibiotics. Combinations with other antibiotics

should only be considered if their effects can be expected to be

synergistic or at least additive. In general, each component in the

combination should be given at the individually effective dose for

monotherapy. However for combinations with proven synergistic

action, the dose of the more toxic component in the combination

may be reduced.)

If indicated, bactericidal antibiotic candidates for combination

with Penicillin G sodium include isoxazolyl penicillins such as

flucloxacillin and other narrow-spectrum beta-lactam antibiotics,

aminopenicillins, aminoglycosides. These should be administered

by slow IV injection prior to Penicillin G sodium infusions.

Wherever possible, aminoglycosides should be administered

separately by IM injection (1).

Penicillins/Other Drugs that compete with Renal Tubular

Secretion: Other drugs may compete with Penicillin G for renal

tubular secretion and thus prolong the serum half-life of

penicillin. These drugs include: aspirin/salicylates (in high doses)

(1),,

phenylbutazone,

sulfonamides,

indomethacin

thiazide

diuretics, furosemide and ethacrynic acid.

Laboratory Tests

Laboratory Tests (see also Precautions) (2)

Periodic assessment of organ system function, including

frequent evaluation of electrolyte balance, hepatic, renal and

hematopoietic systems, and cardiac and vascular status should be

performed during prolonged therapy with high doses of

intravenous penicillin G. If any impairment of function is

suspected or known to exist, a reduction in the total dosage

should be considered. In suspected staphylococcal infections,

proper laboratory studies, including susceptibility tests should be

performed. All infections due to Group A beta-hemolytic

streptococci should be treated for at least 10 days.

Patients being treated for gonococcal infection should have a

serologic test for syphilis before receiving penicillin. All cases of

penicillin treated syphilis should receive adequate follow

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