PENICILLIN G SODIUM 10 M.U.

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.

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

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.

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

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

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

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

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

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.