Benzathine Benzylpenicillin

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Streptococcal pharyngitis
• Syphilis
• Erysipeloid
• Prevention of recurrence of rheumatic fever

Contraindications

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

Cautions

• Breastfeeding
• Renal impairment
• Hepatic impairment 
• Elderly
• Use in tissues with reduced perfusion
• Atopic individuals 
• Allergic diathesis
• Bronchial asthma
• Long-term treatment (more than a single dose)
• Accidental subcutaneous, intravascular or intra-arterial administration
• Repeated injections into a limited area of muscular tissue
• Peanut or soya allergy
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

Infections caused by: Actinomyces sp. C. diphtheriae, Clostridum sp., E. faecalis (S), Leptospira sp. P. acnes, P. multocida, PeptostreptococciStreptococci of the “Viridans” group, Strep. agalactiae (B), Streptococcus dysgalactiae subsp. equisimilis (Group C & G streptococci), Strep. anginosus gp, Strep. gp C,F,G, Strep. pneumoniae, Strep. pyogenes (A), T. pallidum, Arcanobacter. sp, B. burgdoferi, Kingella sp., L. monocytogenes, N. meningitidis, non-penicillinase-producing Staph. aureus

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See additional prescribing points for administration directions

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Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African Standard Treatment Guidelines indications and dosages

Syphilis
- Early syphilis
Maternal syphilis
- Early syphilis 

• IM: 2 400 000IU (two million four hundred thousand units), as a single dose
  (STG, Adult 2019; PHC 2020)

Syphilis
- Late latent syphilis or syphilis of unknown duration
Maternal syphilis
- Late/latent syphilis or syphilis of unknown duration 

• IM: 2 400 000IU (two million four hundred thousand units), weekly; Treatment duration: 3 weeks
  (STG, Adult 2019; PHC 2020; PHC 2023)

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If the mother has received <3 doses, treat the baby for congenital syphilis

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Prevention of recurrent rheumatic fever 

• IM: 1 200 000IU (one million two hundred thousand units), every 3-4 weeks (preferred treatment); Treatment duration: 10 years or until the age of 21 years for all patients with confirmed rheumatic fever and no persistent rheumatic valvular disease OR lifelong for all patients with confirmed rheumatic fever and persistent rheumatic valvular disease  
  (STG, Adult 2019; PHC 2020)

Acute rheumatic fever
- Eradication of streoptococci in throat

• IM: 1 200 000IU (one million two hundred thousand units), as a single dose
  (STG, Adult 2019; PHC 2020)

Genital ulcer syndrome (GUS)

• IM: 2 400 000IU (two million four hundred thousand units), as a single dose
  (STG, Adult 2019)

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The above treatment is indicated if the syndromic treatment at PHC used doxycycline instead of benzathine penicillin and syphilis is detected on PCR

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Syphilis does not require re-treatment if benzathine penicillin was used to treat GUS

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- Pregnant symptomatic partner
- Pregnant asymptomatic partner

• IM: 2 400 000IU (two million four hundred thousand units), as a single dose
  (STG, PHC 2020)

Tonsillitis and pharyngitis
- Eradication of streptococci

• IM: 1 200 000IU (one million two hundred thousand units), as a single dose
  (STG, PHC 2020)

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South African registered indications and dosages

Streptococcal pharyngitis Erysipeloid

• IM: 1 200 000IU (one million two hundred thousand units) once every 4 weeks

Recurrence of rheumatic fever

• IM: 1 200 000IU (one million two hundred thousand units) once every 3-4 weeks

Syphilis 
Prophylaxis of syphilis contacts

• IM: 2 400 000IU (one million two hundred thousand units) as a single dose

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Administer by deep IM injection only

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In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose must be administered for at least 10 days

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Indications and dosages registered in other jurisdictions

Syphilis - primary and secondary stage

• IM: 2 400 000IU (two million four hundred thousand units) as a single dose; repeat dose if necessary

Dose to be repeated if clinical symptoms recur or laboratory findings remain strongly positive

Syphilis - late-stage (latent seropositive syphilis)

• IM: 2 400 000IU  (two million four hundred thousand units) once a week for 3 weeks

Yaws
Pinta

• IM: 1 200 000IU (one million two hundred thousand units) as a single dose

Prophylaxis of rheumatic fever, post-streptococcal glomerulonephritis and erysipelas

• IM: 1 200 000IU (one million two hundred thousand units) once every 3-4 weeks; Treatment duration: ≥5-10 years

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Treatment duration:
- Without cardiac involvement: ≥5 years (or up to 21 years old)
- Transient cardiac involvement: ≥10 years (or up to 21 years old)
- Persistent cardiac involvement: ≥10 years (or up to 40 years old); life-long prophylaxis is sometimes necessary

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Deep IM injection only

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Benzathine benzylpenicillin should be administered 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

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 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

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For depot preparations, a total volume of 5ml per injection site is stated as the tolerance limit at any one time into one site

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

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The injection must not be administered into tissue with reduced perfusion

Paed. forms avail. and covered in this monograph: inj

Paed. dosages below include:

• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

Infections caused by: Actinomyces sp. C. diphtheriae, Clostridum sp., E. faecalis (S), Leptospira sp. P. acnes, P. multocida, Peptostreptococci, Streptococci of the “Viridans” group, Strep. agalactiae (B), Streptococcus dysgalactiae subsp. equisimilis (Group C & G streptococci), Strep. anginosus gp, Strep. gp C,F,G, Strep. pneumoniae, Strep. pyogenes (A), T. pallidum, Arcanobacter. sp, B. burgdoferi, Kingella sp., L. monocytogenes, N. meningitidis, non-penicillinase-producing Staph. aureus

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See additional prescribing points for administration directions

---

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African Standard Treatment Guidelines indications and dosages

Acute rheumatic fever 
- Eradication of streptococci in throat

• <30kg: IM: 600 000IU (six hundred thousand units), as a single dose
• ≥30kg: IM: 1 200 000IU (one million two hundred thousand units), as a single dose 
  (STG, Paed. 2017; PHC 2020)

-To prevent repeated attacks

• <30kg: IM: 600 000IU (six hundred thousand units), every 3-4 weeks; Continue therapy until the age of 21 years of age if no rheumatic valvular disease, and until 35 years of age in patients with rheumatic valvular disease 
• ≥30kg: IM: 1 200 000IU (one million two hundred thousand units), every 3-4 weeks; Continue therapy until the age of 21 years of age if no rheumatic valvular disease, and until 35 years of age in patients with rheumatic valvular disease  
  (STG, Paed. 2017)

- Prophylaxis for rheumatic fever

• <30kg: IM: 600 000IU (six hundred thousand units), every 3-4 weeks; Treatment duration: 10 years or until the age of 21 years for all patients with confirmed rheumatic fever and no persistent rheumatic valvular disease
• ≥30kg: IM: 1 200 000IU (one million two hundred thousand units), every 3-4 weeks; Treatment duration: 10 years or until the age of 21 years for all patients with confirmed rheumatic fever and no persistent rheumatic valvular disease 
  (STG, PHC 2020)

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Any patient with documented rheumatic fever must receive prophylaxis

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Post streptococcal glomerulonephritis 
-To eradicate streptococci (and unable to take oral medication)

• IM: 30 000IU/kg (thirty thousand units per kilogram), as 2 doses given 5 days apart; Max: 1 200 000IU/dose (one million two hundred thousand units per dose)
  (STG, Paed. 2023)

Sydenham's chorea
- If streptococcal infection, following 10 days of initial antibiotic treatment

• IM: 1 200 000IU (one million two hundred thousand units), every 28 days; Treatment duration: Until 21 years old
  (STG, Paed. 2023)

Early congenital syphilis
- Asymptomatic, well baby
- Mother not fully treated >1 month before delivery

• IM: 50 000IU/kg (fifty thousand units per kilogram), as a single dose into antero-lateral thigh
  (STG, Paed. 2017; PHC 2023)

Tonsillitis and pharyngitis
- Eradication of streptococci

• <30kg: IM: 600 000IU (six hundred thousand units), as a single dose;
• ≥30kg: IM: 1 200 000IU (one million two hundred thousand units), as a single dose
  (STG, PHC 2020)

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South African registered indications and dosages

Rheumatic fever

• >30kg: IM: 1 200 000IU (one million two hundred thousand units) once every 3-4 weeks;
• <30kg: IM: 600 000IU (six hundred thousand units) once every 3-4 weeks; Treatment duration: ≥5-10 years

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Treatment duration:
- Without cardiac involvement: ≥5 years (or up to 21 years old)
- Transient cardiac involvement: ≥10 years (or up to 21 years old)
- Persistent cardiac involvement: ≥10 years (or up to 40 years old); life-long prophylaxis is sometimes necessary

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Deep IM injection only

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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

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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.

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For depot preparations, a total volume of 5ml per injection site is stated as the tolerance limit at any one time into one site

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

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The injection must not be administered into tissue with reduced perfusion

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Indications and dosages registered in other jurisdictions

Syphilis - primary and secondary stage

Children

• IM: 50 000IU/kg (fifty thousand units per kilogram) as a single dose; repeat dose if necessary; Max: 2 400 000IU (two million four hundred thousand units)/dose

Adolescents

• See adult dosage

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Dose to be repeated if clinical symptoms recur or laboratory findings remain strongly positive

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Syphilis - late-stage (latent seropositive syphilis)

Children

• IM: 50 000IU/kg (fifty thousand units per kilogram) once a week for 3 weeks; Max: 2 400 000IU (two million four hundred thousand units)/dose

Adolescents

• See adult dosage

Congenital syphilis (without neurological involvement)

Children

• IM: 50 000IU/kg (fifty thousand units per kilogram) as a single dose

Adolescents

• See adult dosage

Yaws
Pinta

Children

• >30kg: IM: 1 200 000IU/kg (one million two hundred thousand units per kilogram) as a single dose;
• <30kg: IM: 600 000IU/kg (six hundred thousand units per kilogram) as a single dose;

Adolescents

• See adult dosage

Prophylaxis of rheumatic fever, post-streptococcal glomerulonephritis and erysipelas

Children

• >30kg: IM: 1 200 000IU (one million two hundred thousand units) once every 3-4 weeks;
• <30kg: IM: 600 000IU (six hundred thousand units) once every 3-4 weeks; Treatment duration: ≥5-10 years

Adolescents

• See adult dosage

 Pregnancy

• Safe; no evidence of risk in studies
• 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

 Breastfeeding

• Caution
• Benzylpenicillin benzathine is excreted in human milk in small amounts. The concentration in maternal milk may reach 2-15% 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. Breastfeeding 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. Breastfeeding can be resumed 24 hours after finishing treatment

Fertility

• 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

Renal Impairment

• CrCl 60-100ml/min: Caution; no dose adjustment recommended
• CrCl >50-<60ml/min: Caution; no information available
• CrCl ≤50ml/min: Caution; dose adjustment recommended
• Haemodialysis: Caution, no information available 
  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 benzathine benzylpenicillin need to be taken on a case by case basis

CrCl (ml/min)	Proportion of normal daily dose (%)	Dosage interval
10-50	75	in 1 single administration
<10	20 – 50 (Max: 1 000 000–3 000 000IU (one to three million units)/24hrs)	in 2–3 single administrations

Hepatic Impairment

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

Elderly

• Caution; dose adjustment recommended
  Elimination processes may be delayed with advanced age. Therefore, the dose should be adjusted to individual renal function

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Hoignés syndrome

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Stomatitis and glossitis
• Pseudomembranous colitis

Hepatobiliary Disorders

• Hepatitis
• Cholestasis
• Simulation of pseudoalbuminaemia (when using electrophoresis methods to determine albumin)
• False-positive urinary amino acid determination (ninhydrin method)

Genitourinary Disorders

• Interstitial nephritis
• Nephropathy
• Increased levels of 17-ketosteroids in urine (when the Zimmermann is used)
• False-positive nonenzymatic urinary glucose detection and urobilinogen detection
• False-positive urinary protein determination when precipitation techniques are used (Folin-Clocalteu-Lowry method, biuret method)

Musculoskeletal Disorders

• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Angioedema
• Erythema multiform
• Exfoliative dermatitis
• Injection site pain
• Injection site infiltrates
• Nicolau syndrome

Immune, Blood and Lymphatic System Disorders

• Jarisch-Herxheimer reaction
  - Fever
  - Chills
  - General and focal symptoms
• Allergic reactions
• Fever
• Anaphylactic shock with collapse and anaphylactoid reactions
  - Asthma
  - Purpura
  - Gastrointestinal symptoms
• Serum sickness
• Overgrowth of non-susceptible organisms or yeasts
• Candidiasis
• Haemolytic anaemia
• Leukopenia
• Thrombocytopenia
• Agranulocytosis
• Positive direct Coomb's test

Others

• Povidone accumulation in the reticuloendothelial system (RES) or local deposits and foreign body granuloma (certain formulations)

• Bacteriostatic antibiotics
• Probenecid
• Methotrexate
• Anticoagulants

None routine. Specific cases may require

• Renal function
• Hepatic function
• Haematopoietic function
• INR

Additional observations

• Signs and symptoms of anaphylaxis (after first dose)
• Signs and symptoms of superinfections

Considerations for use

• 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 water-soluble alkali salt of benzylpenicillin should be considered

Reconstitution directions
- South African

• For the 1 200 000IU (one million two hundred thousand unit) vial:
  - Manufacturer: Reconstitute with 3-3.5ml water for injection.  Confirm amount of water for injection required on product-specific instructions
  - STG guidelines: Reconstitute with 3.2ml lidocaine 1% without adrenaline (epinephrine) or 3ml water for injection
• For the 2 400 000IU (two million four hundred thousand units) vial:
  - Manufacturer: Reconstitute with 5-7ml water for injection. Confirm amount of water for injection required on product-specific instructions
  - STG guidelines: Reconstitute with 6ml of lidocaine 1% without adrenaline (epinephrine)

- International

• For the 1 200 000IU (one million two hundred thousand unit) vial:
  - Manufacturer: Reconstitute with at least 4ml water for injection. Confirm amount of water for injection required on product-specific instructions
• For the 2 400 000IU (two million four hundred thousand units) vial:
  - Manufacturer: Reconstitute with at least 5ml water for injection. Confirm amount of water for injection required on product-specific instructions

Caution for administration

• Administer by deep IM injection only
• 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 6g) benzylpenicillin or more per day. After discontinuation of the penicillin, the direct antiglobulin test may remain positive for 6 to 8 weeks
• 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

Benzathine Benzylpenicillin, a beta-lactamase sensitive penicillin, inhibits bacterial cell wall synthesis during the growth phase. It acts through the blockade of penicillin-binding proteins (PBPs), such as transpeptidase, resulting in bactericidal action.

Spectrum of activity: Actinomyces sp. C. diphtheriae, Clostridum sp., E. faecalis (S), Leptospira sp. P. acnes, P. multocida, Peptostreptococci Streptococci of the “Viridans” group Strep. agalactiae (B), Streptococcus dysgalactiae subsp. equisimilis (Group C & G streptococci), Strep. anginosus gp, Strep. gp C,F,G, Strep. pneumoniae, Strep. pyogenes (A), T. pallidum, Arcanobacter. sp, B. burgdoferi, Kingella sp., L. monocytogenes, N. meningitidisnon-penicillinase-producing Staph. aureus

Injection (per vial) 1.2 MU

• Benzathine Penicillin Fresenius (Fresenius Kabi) originator
• Penilente LA (Biotech Lab)
• Ultracillin (Cape Pharma)

Injection (per vial) 2.4 MU

• Benzathine Penicillin Fresenius (Fresenius Kabi) originator
• Penilente LA (Biotech Lab)