Benzylpenicillin sodium 600 mg powder for solution for injection or infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Benzylpenicillin sodium 600 mg powder for solution for injection or infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains benzylpenicillin sodium 600 mg.

3 PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

White crystalline, water-soluble sterile powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Benzylpenicillin is indicated for:

• most wound infections,
• pyogenic infections of the skin,
• soft tissue infections
• infections of the nose, throat, nasal sinuses, respiratory tract and middle ear, etc.

It is also indicated for the following infections caused by penicillin-sensitive microorganisms:

• Generalised infections, septicaemia and pyaemia from susceptible bacteria.
• Acute and chronic osteomyelitis, sub-acute bacterial endocarditis and meningitis caused by susceptible organisms.
• Suspected meningococcal disease.
• Gas gangrene, tetanus, actinomycosis, anthrax, leptospirosis, rat-bite fever, listeriosis, severe Lyme disease, and prevention of neonatal group B streptococcal infections.
• Complications secondary to gonorrhoea and syphilis (e.g. gonococcal arthritis or endocarditis, congenital syphilis and neurosyphilis).
• Diphtheria, brain abscesses and pasteurellosis.

Consideration should be given to official local guidance (e.g. national recommendations) on the appropriate use of antibacterial agents.

Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.

4.2 Posology and method of administration

Posology

The following dosages apply to both intramuscular and intravenous injection.

Alternate sites should be used for repeated injections.

Adults

600 to 3,600 mg (1 to 6 mega units) daily, divided into 4 to 6 doses, depending on the indication. Higher doses (up to 14.4 g/day (24 mega units) in divided doses) may be given in serious infections such as adult meningitis by the intravenous route.

In bacterial endocarditis, 7.2 to 12 g (12 to 20 mega units) or more may be given daily in divided doses by the intravenous route, often by infusion.

Doses up to 43.2 g (72 mega units) per day may be necessary for patients with rapidly spreading gas gangrene.

High doses should be administered by intravenous injection or infusion, with intravenous doses in excess of 1.2g (2 mega units) being given slowly, taking at least one minute for each 300 mg (0.5 mega unit) to avoid high levels causing irritation of the central nervous system and/or electrolyte imbalance.

For the prevention of Group B Streptococcal disease of the newborn, a 3 g (5 mega units) loading dose should be given to the mother initially, followed by 1.5 g (2.5 mega units) every 4 hours until delivery.

Paediatric patients

Pediatric doses are generally determined on a weight basis and should be calculated for each patient individually.

Children aged 1 month to 12 years

100 mg/kg/day in 4 divided doses; not exceeding 4 g/day.

Infants aged 1-4 weeks

75 mg/kg/day in 3 divided doses.

Newborn Infants

50 mg/kg/day in 2 divided doses.

Meningococcal disease

Children 1 month to 12 years: 180-300 mg/kg/day in 4-6 divided doses, not exceeding 12 g/day.

Infants 1-4 weeks: 150 mg/kg/day in 3 divided doses.

Newborn infants: 100 mg/kg/day in 2 divided doses.

Adults and children over 12 years: 2.4 g every 4 hours

Suspected meningococcal disease

If meningococcal disease is suspected general practitioners should give a single dose of benzylpenicillin sodium, before transferring the patient to hospital, as follows:

Adults and children over 10 years: 1,200 mg IV (or IM)

Children 1-9 years: 600 mg IV (or IM)

Children under 1 year: 300 mg IV (or IM)

Premature babies and neonates

Dosing should not be more frequent than every 8 or 12 hours in this age group, since renal clearance is reduced at this age and the mean half-life of benzylpenicillin may be as long as 3 hours.

Since infants have been found to develop severe local reactions to intramuscular injections, intravenous treatment should preferably be used.

Special populations

Patients with renal insufficiency

For doses of 0.6-1.2 g (1-2 mega units) the dosing interval should be no more frequent than every 8-10 hours.

For high doses e.g. 14.4 g (24 mega units) required for the treatment of serious infections such as meningitis, the dosage and dose interval of benzylpenicillin sodium should be adjusted in accordance with the following schedule:

The dose in the above table should be further reduced to 300 mg (0.5 mega units) 8 hourly if advanced liver disease is associated with severe renal failure.

If haemodialysis is required, an additional dose of 300 mg (0.5 mega units) should be given 6 hourly during the procedure.

Elderly patients

Elimination may be delayed in elderly patients and dose reduction may be necessary.

Method of administration

For intramuscular and/or intravenous use.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

• Hypersensitivity to penicillins or any of the excipients.
• History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta lactam agent (e.g. a cephalosporin, carbapenem or monobactam).

4.4 Special warnings and precautions for use

Massive doses of benzylpenicillin sodium can cause hypokalaemia and sometimes hypernatraemia. Use of a potassium-sparing diuretic may be helpful. In patients undergoing high-dose treatment for more than 5 days, electrolyte balance, blood counts and renal functions should be monitored.

In the presence of impaired renal function, large doses of penicillin can cause cerebral irritation, convulsions and coma.

Skin sensitisation may occur in persons handling the antibiotic and care should be taken to avoid contact with the substance.

It should be recognised that any patient with a history of allergy, especially to drugs, is more likely to develop a hypersensitivity reaction to penicillin. Patients should be observed for 30 minutes after administration and if an allergic reaction occurs the drug should be withdrawn and appropriate treatment given.

Delayed absorption from the intramuscular depot may occur in diabetics.

Prolonged use of benzylpenicillin may occasionally result in an overgrowth of non-susceptible organisms or yeast and patients should be observed carefully for superinfections.

Pseudomembranous colitis should be considered in patients who develop severe and persistent diarrhoea during or after receiving benzylpenicillin. In this situation, even if Clostridium difficile is only suspected, administration of benzylpenicillin should be discontinued and appropriate treatment given.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in association with beta-lactam antibiotics (including penicillins) treatment.

Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibacterials may also be hypersensitive to benzylpenicillin (see section 4.3). Benzylpenicillin should be used with caution in patients with a history of non-severe hypersensitivity reactions to any other beta-lactam antibiotics (e.g. cephalosporins or carbapenems) and not at all in patients with history of severe hypersensitivity reactions. If a severe allergic reaction or SCAR occurs during treatment with benzylpenicillin, treatment with the medicinal product should be discontinued and appropriate measures taken.

Sodium overload and/or heart failure may occur if benzylpenicillin sodium is administered in sodium-containing solvents to patients who suffer from renal failure and/or heart failure. Therefore, for such patients, benzylpenicillin sodium should not be reconstituted in sodium-containing liquids such as Sodium Chloride Injection BP or Ringer's solution.

Benzylpenicillin sodium 600 mg contains 38.7mg (1.68 mmol) of sodium (main component of cooking/table salt) in each dosage unit. This is equivalent to 1.93% of the recommended maximum daily dietary intake of sodium for an adult. 10 dosage units (6g) reflects the lowest number of dosage units for which the threshold of 17mmol (391mg) of sodium is reached. This should be particularly taken into account for those on a low salt (sodium) diet.

4.5 Interaction with other medicinal products and other forms of interaction

There is reduced excretion of methotrexate (and therefore increased risk of methotrexate toxicity) when used with benzylpenicillin sodium.

Probenecid inhibits tubular secretion of benzylpenicillin sodium and so may be given to increase the plasma concentrations.

Penicillins may interfere with:

• Urinary glucose test
• Coomb's tests
• Tests for urinary or serum proteins
• Tests which use bacteria e.g. Guthrie test.

4.6 Fertility, pregnancy and lactation

Pregnancy

Benzylpenicillin sodium has been taken by a large number of pregnant women and women of childbearing age without an increase in malformations or other direct or indirect harmful effects on the foetus having been observed.

Breast-feeding

Although it is not known if benzylpenicillin sodium may be excreted into the breast milk of nursing mothers, it is actively transported from the blood to milk in animals and trace amounts of other penicillins in human milk have been detected.

Fertility

Reproduction studies in mice, rats and rabbits have not produced evidence of any negative effects on male and female fertility.

4.7 Effects on ability to drive and use machines

None

4.8 Undesirable effects

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000), Not known (cannot be estimated from the available data).

Blood and Lymphatic System Disorders

Rare (0.01% - 0.1%)

Granulocytopenia (neutropenia), agranulocytosis and leucopenia have been reported in patients receiving prolonged high doses of benzylpenicillin sodium (eg. Subacute bacterial endocarditis). Diarrhoea caused by Clostridium difficile.

Not known

Anaemia, thrombocytopenia.

Immune System Disorders

Very Common (>10%)

Patients undergoing treatment for syphilis or neurosyphilis with benzylpenicillin may develop a Jarisch-Herxheimer reaction.

Common (1-10%)

Hypersensitivity to penicillin in the form of rashes (all types), fever, and serum sickness may occur (1-10% treated patients). These may be treated with antihistamine drugs.

Rare (0.01%-0.1%)

More rarely, anaphylactic reactions have been reported (<0.05% treated patients).

Not known

Angioedema.

Nervous System Disorders

Rare (0.01%-.01%)

Central nervous system toxicity, including convulsions, has been reported with massive doses over 60 g per day and in patients with severe renal impairment.

Not known

Metabolic encephalopathy.

Renal and Urinary Disorders

Rare (0.01%-0.1%)

Interstitial nephritis has been reported after intravenous benzylpenicillin sodium at doses of more than 12 g per day.

Skin and subcutaneous tissue disorders

Not known

Acute Generalised Exanthematous Pustulosis (AGEP), pruritus, maculo-papular rash, rash morbilliform, erythema.

Severe Cutaneous Adverse Reactions SCARs (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalised exanthematous pustulosis) have been reported with beta-lactam antibiotics, including penicillins (see section 4.4).

Reporting of suspected adverse reactions

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Excessive blood levels of benzylpenicillin sodium can be corrected by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta-lactamase sensitive penicillins.

ATC code: J01 CE01.

Mechanism of action

Benzylpenicillin sodium is a beta-lactam antibiotic. It is bacteriocidal by inhibiting bacterial cell wall biosynthesis.

Breakpoints:

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints (version 10.0)

Prevalence of acquired resistance

The prevalence of acquired resistance in individual species may vary geographically and over time. Thus, local information on the resistance situation is required, particularly for the adequate treatment of severe infections. If, based on the local resistance situation, the efficacy of benzylpenicillin is questionable, expert therapeutic advice should be sought. Particularly in cases of serious infection or unsuccessful therapy, a microbiological diagnosis should be sought, with the detection of the pathogen and its susceptibility to benzylpenicillin.

Prevalence of acquired resistance based on data from the past 5 years from national resistance monitoring projects and studies (version: April 2019):

Commonly susceptible species

Aerobic Gram-positive micro-organisms

Actinomyces israelii °

Corynebacterium diphtheriae °

Erysipelothrix rhusiopathiae °

Gardnerella vaginalis °

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Streptococcus dysgalactiae subsp. equisimilis

(Group C & G streptococci )

Streptococci of the “Viridans” group ° ^{^}

Aerobic Gram-negative micro-organisms

Borrelia burgdorferi °

Eikenella corrodens ° ^$

Haemophilus influenzae ° ^$

Neisseria meningitidis °

Anaerobic micro-organisms

Clostridium perfringens °

Clostridium tetani °

Fusobacterium spp. °

Peptoniphilus spp. °

Peptostreptococcus spp. °

Veillonella parvula °

Other micro-organisms

Treponema pallidum °

Species in which acquired resistance may pose a problem during use

Aerobic Gram-positive micro-organisms

Enterococcus faecalis ^$

Staphylococcus aureus ⁺

Staphylococcus epidermidis ⁺

Staphylococcus haemolyticus ⁺

Staphylococcus hominis ⁺

Aerobic Gram-negative micro-organisms

Neisseria gonorrhoeae ^$

Naturally resistant species

Aerobic Gram-positive micro-organisms

Enterococcus faecium

Nocardia asteroides

Aerobic Gram-negative micro-organisms

All Enterobacterales species

Legionella pneumophila

Moraxella catarrhalis

Pseudomonas aeruginosa

Anaerobic micro-organisms

Bacteroides spp.

Other micro-organisms

Chlamydia spp.

Chlamydophila spp.

Mycoplasma spp.

° At the time of the publishing of the table, no current data were available. Susceptibility is assumed in the primary literature, standard works and therapeutic recommendations.

$ The natural susceptibility of most isolates is within the intermediate range.

+ In at least one region, the resistance rate is over 50%. ^ Collective name for a heterogeneous group of streptococci species. The resistance rate can vary depending on the streptococci species present.

5.2 Pharmacokinetic properties

Absorption

Benzylpenicillin sodium rapidly appears in the blood following intramuscular injection of water-soluble salts and maximum concentrations are usually reached in 15-30 minutes. Peak plasma concentrations of about 12 mcg/ml have been reported after doses of 600 mg with therapeutic plasma concentrations for most susceptible organisms detectable for about 5 hours.

Distribution

Approximately 60% of the dose injected is reversibly bound to plasma protein.

In adults with normal renal function the plasma half-life is about 30 minutes.

Elimination

Most of the dose (60-90%) undergoes renal elimination, 10% by glomerular filtration and 90% by tubular secretion. Tubular secretion is inhibited by probenecid, which is sometimes given to increase plasma penicillin concentrations. Biliary elimination of benzylpenicillin sodium accounts for only a minor fraction of the dose.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

Benzylpenicillin sodium and solutions that contain metal ions should be administered separately.

Benzylpenicillin sodium should not be administered in the same syringe / giving set as amphotericin B, cimetidine, cytarabine, flucloxacillin, hydroxyzine, methylprednisolone, or promethazine since it is incompatible with these drugs.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products,

6.3 Shelf life

Unopened 36 months.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store below 25°C.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I glass vial (10 ml) with a chlorobutyl rubber stopper and an aluminium seal incorporating a plastic 'flip-top' cap.

Pack size: 10 vials.

6.6 Special precautions for disposal

Only freshly prepared solutions should be used.

Reconstituted solutions of benzylpenicillin sodium are intended for immediate administration.

Intravenous injection:

Dissolve in 4 ml of Sodium Chloride Injection BP or Water for Injections BP (displacement value: approximately 0.4 ml).

Intravenous infusion:

Dissolve in at least 10 ml of Sodium Chloride Injection BP or Water for Injections BP.

Intramuscular injection

Dissolve in 1.6 to 2.0 ml of Water for Injections BP.

After contact with skin, wash immediately with water. In case of contact with eyes, rinse immediately with plenty of water and seek medical advice if discomfort persists.

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

7 MARKETING AUTHORISATION HOLDER

Istituto Biochimico Italiano G. Lorenzini S.p.A.

Via Fossignano 2

04011 Aprilia (LT)

Italy

8 MARKETING AUTHORISATION NUMBER(S)

PL 05448/0021

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

24/03/2026

10 DATE OF REVISION OF THE TEXT

24/03/2026