Benzylpenicillin benzathine 1.2 Million I.U. powder and solvent for suspension for injection

Summary of Product Characteristics Updated 03-Nov-2020 | Brancaster Pharma Limited

1. Name of the medicinal product

Benzylpenicillin benzathine 1.2 Million I.U. powder and solvent for suspension for injection

2. Qualitative and quantitative composition

1 vial of powder for suspension for injection contains 1.2 Million I.U., equivalent to approximately 918 mg benzylpenicillin benzathine, or approximately 720 mg benzylpenicillin.

1 glass ampoule of 5ml solvent for suspension for injection contains 5ml water for injections.

Excipients with known effect:



Soya lecithin

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for suspension for injection.

Powder: White to off-white coloured powder.

Solvent: Clear, colourless liquid.

4. Clinical particulars
4.1 Therapeutic indications

Benzylpenicillin benzathine is indicated in adults, adolescents, children and neonates for the treatment and prophylaxis of the following infections (see section 5.1):

For the treatment of:

- erysipelas

- syphilis: early syphilis (primary and secondary)

- latent syphilis (except for neurosyphilis and presence of pathological CSF findings)

- yaws

- pinta

For the prophylaxis of:

- rheumatic fever (chorea, rheumatic carditis)

- poststreptococcal glomerulonephritis

- erysipelas

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

4.2 Posology and method of administration


The dosing recommendations depend on the severity and the type of infection, the age and the hepato-renal function of patients.

Dosage and duration of treatment

1. General therapy:

- Adults and adolescents:

1.2 Million I.U.

- Children (> 30 kg body weight):

1.2 Million I.U.

- Children (< 30 kg body weight):

0.6 Million I.U.

Duration of treatment:

Single dose

Note: In streptococcal diseases, a 10-day minimum course of treatment should be observed to avoid secondary diseases. This is generally ensured with a single injection of 0.6 Million I.U., 1.2 Million I.U. or 2.4 Million I.U..

2. Treatment of syphilis:

2.1. Primary and secondary stage

- Adults and adolescents:

2.4 Million I.U.

- Children:

50,000 IU per kg body weight; however not more than 2.4 Million I.U.

Duration of treatment:

Single dose (If clinical symptoms recur or laboratory findings remain strongly positive, treatment should be repeated.)

2.2. Late-stage syphilis (latent seropositive syphilis)

- Adults and adolescents:

2.4 Million I.U.

- Children:

50,000 IU per kg body weight per week; however not more than 2.4 Million I.U.

Duration of treatment:

Once weekly for 3 weeks

2.3. Treatment of congenital syphilis (without neurological involvement)

- Neonates and infants:

50,000 IU per kg body weight

Duration of treatment:

Single dose

3. Treatment of yaws and pinta:

- Adults and adolescents:

1.2 Million I.U.

- Children (> 30 kg body weight):

1.2 Million I.U.

- Children (< 30 kg body weight):

0.6 Million I.U.

Duration of treatment:

Single dose

4. Prophylaxis of rheumatic fever, poststreptococcal glomerulonephritis and erysipelas:

- Adults and adolescents:

1.2 Million I.U.

- Children (> 30 kg body weight):

1.2 Million I.U.

- Children (< 30 kg body weight):

0.6 Million I.U.

Duration of treatment:

a) without cardiac involvement:

at least 5 years (or up to 21 years of age) every 3-4 weeks

b) transient cardiac involvement:

at least 10 years (or up to 21 years of age) every 3-4 weeks

c) persistent cardiac involvement:

at least 10 years (or up to 40 years of age) every 3-4 weeks; life-long prophylaxis is sometimes necessary

Special patient groups

Patients with impaired renal function

Table 1 - Recommended dose adjustments in patients with impaired renal function.

Dosage for adults, adolescents and children based on creatine clearance

Creatinine clearance in ml/min

100 – 60

50 – 10

< 10

Serum creatinine in mg %

0.8 – 1.5

1.5 – 8.0


Proportion of the normal daily dose (%)



20 – 50

(1 – 3 Million I.U. per day maximum.)

Dosage interval

1 single administration

1 single administration

in 2 – 3 single administrations

Haemodialysis patients

Benzylpenicillin benzathine can be removed by haemodialysis. There are no data available on the influence of dialysis on the plasma levels of benzylpenicillin. The decision to treat patients on dialysis with Benzylpenicillin benzathine 0.6 Million I.U., 1.2 Million I.U. and 2.4 Million I.U. powder and solvent for suspension for injection needs therefore to be taken on a case by case basis.

Patients with impaired hepatic function

In very severe cases of impaired hepatic and renal function, there may be a delay in the degradation and excretion of penicillin.

Method of administration

The preparation is strictly for intramuscular injection (see section 4.4).

The injection must not be administered into tissue with reduced perfusion (see section 4.4).

Benzylpenicillin benzathine 0.6 Million I.U., 1.2 Million I.U. and 2.4 Million I.U. powder and solvent for suspension for injection should be administered by deep intramuscular injection into the upper, outer quadrant of the gluteus maximus or Hochstetter's ventrogluteal field, with the needle pointing towards the iliac crest or according to von Hochstetter's method. The puncture should be as vertical to the skin surface as possible and the injection as far away from major vessels as possible. In all events, aspiration must be performed prior to the injection. If aspiration of blood or pain occurs during the injection, it must be discontinued.

In children, the mid-lateral thigh muscles (quadriceps femoris) are recommended as an injection site. The deltoid muscle is only suitable if it is well formed; in this case, attention must be paid to the radial nerve.

In infants and young children, the peripheral area of the upper outer quadrant of the gluteal region should be used as the area for injection only in exceptional cases (e.g. widespread burns), in order to avoid sciatic nerve lesions.

For depot preparations, a total volume of 5ml per injection site is stated as the tolerance limit. Thus, no more than 5ml of the ready-to-inject suspension should be administered at any one time into one site.

The injection should be given as slowly as possible and only with the application of low pressure. “Rubbing” after the injection should be avoided.

Severe local reactions may occur during intramuscular administration, especially in young children. If possible, taking into account the therapeutic indications and schedule regimens and weighing the benefit-risk ratio, alternative treatments such as intravenous therapy with a suitable penicillin product should be considered (see also section 4.4).

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 listed in section 6.1.

- History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. cephalosporin, carbapenem or monobactam).

4.4 Special warnings and precautions for use

Benzylpenicillin benzathine should not be used in tissues with reduced perfusion.

Before initiating therapy with benzylpenicillin benzathine, a careful investigation should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity (analphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, benzylpenicillin benzathine must be discontinued and appropriate therapy instituted.

Prior to treatment, a hypersensitivity test should be performed if possible. The patient should be made aware of the possible occurrence of allergic symptoms and of the need to report them.

Caution should be exercised in patients with the following conditions:

- allergic diathesis or bronchial asthma (there is an increased risk of a hypersensitivity reaction):

- renal insufficiency (for dose adjustment, see section 4.2); - impaired hepatic function (see section 4.2).

Based on a general principle, particularly in some exposed patients, medical observation should if possible be ensured for at last half an hour after the administration of this antibiotic, as severe immediate allergic reactions may occur even after the first administration.

Beta-lactams are associated with a risk of encephalopathy (confusion, altered levels of consciousness, epilepsy or movement abnormalities), particularly in cases of overdose or impaired renal function.

When treating syphilis, a Jarisch-Herxheimer reaction may occur as a result of the bactericidal action of penicillin on pathogens. Within 2 to 12 hours after administration headaches, fever, sweating, shivering, myalgia, arthralgia, nausea, tachycardia, increased blood pressure followed by hypotension may occur. These symptoms resolve after 10 to 12 hours. Patients should be informed that this is a usual, transient sequela of antibiotic therapy. Appropriate therapy should be instituted to suppress or attenuate a Jarisch-Herxheimer reaction (see section 4.8).

With long-term treatment (more than a single dose), periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is recommended.

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

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including benzylpenicillin benzathine and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, benzylpenicillin benzathine should be discontinued, a physician be consulted, and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this situation.

If neurological involvement cannot be excluded in patients with congenital syphilis, forms of penicillin that reach a higher level in cerebrospinal fluid should be used.

In diseases such as severe pneumonia, empyema, sepsis, meningitis or peritonitis, which require higher serum penicillin levels, alternative treatment such as the watersoluble alkali salt of benzylpenicillin should be considered.

Notes on administering benzylpenicillin benzathine

Painful induration may occur in the event of accidental subcutaneous administration. Ice packs help in such cases.

In the event of inadvertent intravascular injection, Hoigné syndrome may occur (symptoms of shock with mortal fear, confusion, hallucinations, possibly cyanosis, tachycardia and motor disorders, although no circulatory collapse), caused by microemboli of the suspension. The symptoms regress within an hour. If progression is severe, parenteral administration of sedatives is indicated.

In the event of inadvertent intra-arterial injection, particularly in children, serious complications may occur, such as vascular occlusion, thrombosis and gangrene. Initial signs are pale patches in the skin area of the gluteal region. As a result of high injection pressure, retrograde entry of the injected liquid into the common iliac artery, aorta or spinal arteries may occur.

Repeated injections into a limited area of the muscle tissue, which are associated with long term therapy with depot-penicillins (e.g. in the treatment of syphilis) may induce tissue damage and increased local vascularization. Subsequent injections increase the possibility of penetration of injection substance into the blood, either by direct injection into a blood vessel or caused by the injection pressure itself, or by “rubbing” of the depot. During long term therapy it is therefore recommended to administer each injection a large distance from the preceding injection.

Effect on diagnostic laboratory procedures:

- A positive direct Coombs' test often develops (≥ 1% to < 10%) in patients receiving 10 million IU (equivalent to 6 g) benzylpenicillin or more per day. After discontinuation of the penicillin, the direct antiglobulin test may remain positive for 6 to 8 weeks (see section 4.8).

- Determination of urinary protein using precipitation techniques (sulphosalicylic acid, trichloroacetic acid), the Folin-Ciocalteu-Lowry method or the biuret method may lead to false positive results. Urinary protein should therefore be determined by other methods.

- Urinary amino acid determination using the ninhydrin method may likewise lead to false-positive results.

- Penicillins bind to albumin. In electrophoresis methods to determine albumin, pseudobisalbuminaemia may therefore be simulated.

- During therapy with benzylpenicillin benzathine, non-enzymatic urinary glucose detection and urobilinogen detection may exhibit a false positive.

- When determining 17-ketosteroids (using the Zimmermann reaction) in the urine, increased values may occur during therapy with benzylpenicillin benzathine.


Benzylpenicillin benzathine 0.6 Million I.U., 1.2 Million I.U. and 2.4 Million I.U. powder and solvent for suspension for injection contains phospholipids from the soya lecithin. If you are allergic to peanut or soya, do not use this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per vial of 0.6 Million I.U., 1.2 Million I.U. and 2.4 Million I.U., i.e. essentially 'sodium- free'.

Delayed excretion of povidone should be taken into consideration in patients with renal impairment. As this medicinal product contains povidone, it cannot be ruled out that frequent or prolonged use may very rarely lead to the accumulation of povidone in the reticuloendothelial system (RES), or to local deposits and the formation of foreign body granulomas which may be confused with tumours.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of benzylpenicillin benzathine is not recommended with:

- bacteriostatic antibiotics: based on the general principle not to combine bactericidal and bacteriostatic antibiotics.

Caution should be exercised when co-administering the following:

- probenecid: the administration of probenecid leads to inhibition of the tubular secretion of benzylpenicillin, resulting in an increase in the serum concentration and prolongation of the elimination half-life. Furthermore, probenecid inhibits the penicillin transport from the cerebrospinal fluid, so that the concomitant administration of probenecid reduces the penetration of benzylpenicillin into brain tissue even further.

- methotrexate: when taken at the same time as benzylpenicillin benzathine, the excretion of methotrexate is reduced. This can lead to increased methotrexate toxicity. The combination with methotrexate is not recommended.

- anticoagulants: concomitant use with oral anticoagulants may increase the antivitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently and the posology of the antivitamin K drug adjusted accordingly, both during and after treatment with benzylpenicillin benzathine.

4.6 Fertility, pregnancy and lactation


Benzylpenicillin benzathine crosses the placenta. 10-30% of maternal plasma concentrations are found in the foetal circulation. High concentrations are also reached in the amniotic fluid. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Benzylpenicillin benzathine can be used during pregnancy when appropriately indicated and with due consideration of the benefits and risks.


Benzylpenicillin benzathine is excreted in human milk in small amounts. The concentration in maternal milk may reach 2 to 15% of the mother's serum concentrations.

Although no undesirable effects in infants fed on breast milk have been reported to date, consideration must nevertheless be given to the possibility of sensitisation or interference with the intestinal flora. Breast-feeding should be stopped in the case of occurrence of diarrhoea, candidosis or rash in the child.

In infants also being fed on baby food, mothers should express and discard breast milk during benzylpenicillin benzathine treatment. Breast-feeding can be resumed 24 hours after finishing treatment.


No fertility studies have been conducted in humans. Reproductive studies on mice, rats and rabbits have not revealed any negative effects on fertility. No long-term fertility studies on laboratory animals are available.

4.7 Effects on ability to drive and use machines

Due to the occurrence of possible serious undesirable effects (e.g. anaphylactic shock with collapse and anaphylactoid reactions, see also section 4.8), Benzylpenicillin benzathine can have a major influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most frequent and common adverse reactions related to benzylpenicillin benzathine are: candidiasis, diarrhoea, nausea, laboratory investigation changes.

Table 2 - Tabulated list of adverse drug reactions by MedDRA System Organ Class.


System Organ class

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)

Frequency not known (cannot be estimated from available data)

Infections and infestations


Blood and lymphatic system disorders

Haemolytic anaemia




Immune system disorders

Allergic reactions



Erythema multiform

Exfoliative dermatitis



Anaphylactic shock with collapse and anaphylactoid reactions (asthma, purpura, gastrointestinal symptoms)

Serum sickness

Gastrointestinal disorders



Stomatitis and glossitis


Pseudomembr anous colitis (see section 4.4)

Hepatobiliary disorders



Renal and urinary disorders


Interstitial nephritis

General disorders and administration site conditions

Pain at the injection site

Injection site infiltrates

Hoigné syndrome

Nicolau syndrome


Positive direct

Coombs' test

False-positive urinary protein determination when precipitation techniques are used (Folin- Ciocalteu-Lowry method, biuret method)

False-positive urinary amino acid determination (ninhydrin method)

Simulation of pseudobisalbumin aemia when using electrophoresis methods to determine albumin

False-positive nonenzymatic urinary glucose detection and urobilinogen detection

Increased levels when determining 17ketosteroids in urine (when the Zimmermann reaction is used) (see section 4.4)

Description of selected adverse reactions

When treating syphilis, a Jarisch-Herxheimer reaction may occur as a result of bacteriolysis, characterised by fever, chills, general and focal symptoms. In patients with dermatomycosis, para-allergic reactions may occur, as common antigenicity may exist between penicillins and dermatophyte metabolites.

In infants, local reactions are possible.

It cannot be excluded that, in very rare cases and due to the povidone content, povidone may accumulate in the reticuloendothelial system (RES) or local deposits and foreign body granuloma may occur, which may be confused with tumours.

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 (website: or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9 Overdose

At extremely high doses, penicillins can induce neuromuscular excitability or epileptiform seizures. If overdose is suspected, clinical monitoring and symptomatic measures are indicated. Benzylpenicillin can be haemodialyzed.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group

Antibacterials for systemic use, beta-lactamase sensitive penicillins.

ATC code: J01CE08

Mechanism of action

For benzylpenicillin benzathine, the mechanism of action is based on an inhibition of bacterial cell wall synthesis (during the growth phase) through a blockade of the penicillin-binding proteins (PBPs), such as transpeptidases. This results in a bactericidal action.


Resistance to benzylpenicillin benzathine can be due to the following mechanisms:

- Inactivation by beta-lactamases: benzylpenicillin benzathine is not betalactamase-resistant and therefore has no effect against beta-lactamase- producing bacteria (e.g. staphylococci or gonococci).

- Reduced affinity of PBPs for benzylpenicillin benzathine: the acquired resistance in pneumococci and a few other streptococci to benzylpenicillin benzathine is due to modifications of existing PBPs as a result of mutation. However, the formation of an additional PBP with reduced affinity for benzylpenicillin benzathine is responsible for resistance in methicillin (oxacillin)-resistant staphylococci.

- In Gram-negative bacteria, inadequate penetration of benzylpenicillin benzathine through the outer cell wall can lead to insufficient PBP inhibition.

- Benzylpenicillin benzathine can be actively transported from the cell by efflux pumps.

- Benzylpenicillin benzathine is partially or completely cross-resistant to other penicillins and cephalosporins.

PK/PD relationship

Efficacy largely depends on the length of time that the active substance level remains above the minimum inhibitory concentration (MIC) of the pathogen.


Table 3 - EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints.




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 breakpoints *

≤ 0.25 mg/l

> 2 mg/l

* Based mainly on serum pharmacokinetics

# Infections other than meningitis

The prevalence of acquired resistance in individual species may vary geographically and with time for selected species and local information on the resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Table 4 - Commonly susceptible species.

Aerobic Gram-positive micro-organisms

Streptococcus pyogenes

Streptococcus dysgalactiae subsp. equisimilis °

(Group C & G streptococci)

Streptococci of the “Viridans” group° ^

Other micro-organisms

Treponema pallidum °

° Information derived from published literature, clinical experience and therapeutic guidelines.

^ Collective name for a heterogeneous group of streptococci species. The resistance rate can vary depending on the streptococci species present.

5.2 Pharmacokinetic properties

Pharmacokinetic data are based on an old dossier and information derived from them are limited. However published literature, clinical experience and therapeutic guidelines can be taken into account.


Following intramuscular administration, benzylpenicillin benzathine is absorbed slowly and converted by hydrolysis to benzylpenicillin. Peak plasma levels are reached 24 hours (children) or 48 hours (adults) post-injection.


After intramuscular injection serum levels of benzylpenicillin are sustained:

• 14 days after intramuscular injection of 2.4 Million I.U. a serum level of 0.12 µ g/ml was measured.

• 21 days after intramuscular injection of 1.2 Million I.U. a serum level of 0.06 µ g/ml was measured.

The volume of distribution is around 0.3-0.4 l/kg in adults and about 0.75 l/kg in children. Plasma protein binding is approximately 55%.

Biotransformation and elimination

Elimination largely takes place (50 - 80%) as unchanged substance via the kidneys (85 - 95%) and, to a lesser extent, in active form within the bile (about 5%).

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

Kinetics in special patient groups

- Preterm and newborn infants: due to the immaturity of kidneys and liver at this age, the serum half-life is up to three hours (and more). The dosing interval must therefore be no shorter than 8 - 12 hours (depending on the degree of maturity).

- Elderly patients: elimination processes may also be delayed with advanced age.

The dosage should therefore be adjusted to individual renal function.

5.3 Preclinical safety data

Reproductive studies in mice, rats and rabbits revealed no negative effects on fertility or on the foetus. No long-term studies on laboratory animals are available with regard to carcinogenicity, mutagenicity and fertility.

6. Pharmaceutical particulars
6.1 List of excipients


Soya lecithin

Polysorbate 80

Carmellose sodium

Sodium citrate, anhydrous



Water for injections

6.2 Incompatibilities

Data on compatibility are available with water for injections.

6.3 Shelf life

48 months

Following reconstitution, benzylpenicillin benzathine should be used immediately.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Powder vials and glass ampoules of solvent for suspension of injection in a carton.

Pack of

1 vial and

1 glass ampoule of solvent

6.6 Special precautions for disposal and other handling

No special requirements.

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

Reconstitution of the suspension for intramuscular injection:

The suspension must be prepared aseptically.

The contents of the vial should be reconstituted in at least 2 ml (0.6 Million I.U.), 4 ml (1.2 Million I.U.), or 5 ml (2.4 Million I.U.) water for injections which is included in the pack.

To reconstitute the suspension for injection, agitate this suspension carefully for at least 20 seconds until a homogeneous suspension is obtained.

The suspension for injection is intended for single use only.

The product should be used immediately after opening the ampoule and reconstituting the suspension.

Prior to injection, intravascular administration should be excluded by aspiration. The injection site should be changed with repeated injections.

7. Marketing authorisation holder

Brancaster Pharma Limited

Church House, 48 Church Street

Reigate, Surrey


United Kingdom

8. Marketing authorisation number(s)

PL 41542/0006

9. Date of first authorisation/renewal of the authorisation


10. Date of revision of the text


Company Contact Details
Brancaster Pharma Limited

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+44 (0)1737 243 407

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