Benzathine benzylpenicillin

Associated long-acting platforms

Aqueous drug particle suspension

Administration route

Intramuscular

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

Not provided

Scale-up prospects

The cost of Bicillin L- A is USD $80–$150 per vial. There is a shortage of benzathine benzylpenicillin which has been extended until 30 November 2026.

Tentative equipment list for manufacturing

1) Round bottom flask - Multi-neck; Ca-Cl₂ drying tube fitted 2) Dropping funnel (500 mL capacity) 3) Hydrogenation apparatus - H2 absorbed at 45 min; 175 mm Hg 4) Vaccum fractionator (Distils 160–175°C / 0.5 mm Hg; n=1.5621) 5) Crystallination vessel ( 95% ethanol; recryst. hot alcohol; M.P. 110–112°C) 6) Suction filter (Vacuum applied; white needle crystals collected) 7) Jacketed mixing vessel 8) Mechanical stirrer 9) Suction filter 10) Spread-layer dryer

Manufacturing

1) ISO Class 5 (Grade A) for aseptic filling, ISO Class 7 (Grade B) as background for aseptic processing, and ISO Class 8 (Grade C/D) for pharmaceutical manufacturing support areas 2) Manufacturing process includes: Step 1 — Prepare the Diamine salt (DBED Diacetate) in 95% EtOH Step 2 — React with sodium penicillin G in cold water (0-4 celsius) Step 3 — Filter, wash, and dry Step 4 — Add excipeints and formulate pre-filled syringe

Specific analytical instrument required for characterization of formulation

1) Refractometer 2) FTIR spectrometer 3) H-NMR spectrometer 4) RP-HPLC system 5) Laser diffraction 6) Light microscope 7) SEM 8) DSC 9) X-ray diffratometer 10) Viscometer 11) Karl Fischer titrator

B8441001

Identifier

NCT03612557

Link

https://clinicaltrials.gov/study/NCT03612557

Phase

Phase I

Status

Completed

Sponsor

Pfizer

More details

This will be an open label study to investigate the pharmacokinetics (PK) and safety of a single intramuscular injection of penicillin G benzathine in Japanese healthy subjects.

Purpose

A Study of Benzathine Benzylpenicillin Intramuscular Injection in Japanese Healthy Subjects

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2018-08-20

Anticipated Date of Last Follow-up
2018-10-08

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2018-10-02

Actual Completion Date
2018-10-02

Studied populations

Age Cohort

• Adults

Genders

• Female

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: * Healthy female subjects (of childbearing or nonchildbearing potential) and/or male subjects * Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg and \<100 kg. Exclusion Criteria: • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (history of penicillin hypersensitivity and/or a history of sensitivity to allergens).

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

8

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

PRESERvE

Identifier

NCT07189208

Link

https://clinicaltrials.gov/study/NCT07189208

Phase

Phase II

Status

Recruiting

Sponsor

University of California, Los Angeles

More details

The goal of this clinical trial is to learn if benzathine penicillin works to prevent maternal syphilis. It will also learn about the safety of benzathine penicillin. The main questions it aims to answer are: * Does benzathine penicillin lower the rate of syphilis in pregnancy? * What medical problems do participants have when taking benzathine penicillin? Researchers will compare benzathine penicillin to routine care to see if benzathine penicillin works to prevent syphilis. Participants will: * Take benzathine penicillin or receive routine care during the third trimester of pregnancy * Visit the clinic once a month for injections and tests * Report any reactions to benzathine penicillin to the study team

Purpose

Evaluation of Antimicrobial Prophylaxis to Prevent Syphilis in Pregnancy in Patients at Risk in Rio de Janeiro, Brazil

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2025-11-01

Anticipated Date of Last Follow-up
2025-11-16

Estimated Primary Completion Date
2030-01-31

Estimated Completion Date
2030-01-31

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults

Genders

• Female

Accepts pregnant individuals
Yes

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: 1. Uncomplicated, viable pregnancy 2. Elevated risk for syphilis acquisition (one or more of the following): 1. Prior history of STIs last 3 years 2. HIV infection 3. Age \< 21 years 4. In a sexual partnership of \< 3 mo., or \> 3 sexual partners in the last 6 mo. 5. Late initiation of prenatal care (\> 14 weeks of pregnancy) 6. Residence in area where syphilis prevalence is 10% or higher. 3. Ability to provide written informed consent 4. No allergy to penicillin 5. Prenatal care at one of the sites participating in the study 6. Ongoing sexual activity during study period. 7. Negative rapid treponemal test at baseline. Exclusion Criteria: 1. Non-viable pregnancy 2. Very high risk pregnancy 3. Inability to provide written informed consent 4. Allergy

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

500

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Not provided

Use case

Treatment

Key resources

GOAL

Identifier

NCT03346525

Link

https://clinicaltrials.gov/study/NCT03346525

Phase

Phase II

Status

Unknown status

Sponsor

Children's National Research Institute

More details

Rheumatic heart disease (RHD) affects at least 32.9 million people, mostly children living in low-resource settings. Long-term intramuscular benzathine penicillin G (BPG) prophylaxis is proven to prevent progression of chronic valve changes in patients with established rheumatic heart disease (RHD) and to allow regression of valve changes in patients with a history of acute rheumatic fever (ARF) with mild RHD. However, in low-resource settings ARF is an elusive diagnosis, and most patients (85%) are diagnosed only when RHD is severe and irreversible, medications ineffective, and surgical intervention is expensive and/or unavailable. Identification of latent RHD might be an opportunity to substantially reduce RHD morbidity and mortality. However, detection of latent RHD is only important i

Purpose

Determining the Impact of Penicillin in Latent RHD: The GOAL Trial

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2018-06-26

Anticipated Date of Last Follow-up
2019-09-27

Estimated Primary Completion Date
2020-11-30

Estimated Completion Date
2020-11-30

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Children will be eligible for study participation if they are (1) between the ages of 5-17 years and (2) have a new diagnosis of latent RHD detected through primary school echo screening and confirmed by blinded consensus review. All children will be recruited from schools in Gulu District in Uganda. Exclusion Criteria: * Patients will be excluded from the study for the following reasons: * Known history of ARF or RHD * Newly diagnosed RHD by echo screening consider to be "missed clinical RHD" as compared to true latent RHD including: \> mild pathological valvular regurgitation at the mitral valve or aortic valve, mitral stenosis (mean MV gradient ≥ 5mmHg) (WHF, definite B), aortic stenosis (mean AV gradient ≥ 20mmHg) * Structural or functional cardiac defec

Health status

Study type

Interventional (clinical trial)

Enrollment

807

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Single blind masking

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

Cares-1

Identifier

NCT06921213

Link

https://clinicaltrials.gov/study/NCT06921213

Phase

Phase II

Status

Not yet recruiting

Sponsor

London School of Hygiene and Tropical Medicine

More details

CARES-1 is a randomised, open-label, phase II pharmacokinetic (PK) and safety study of ambulatory antibiotics for the treatment of neonates with "all-risk" asymptomatic congenital syphilis.

Purpose

Comprehensive Ambulatory Antibiotics for the Treatment of Congenital Syphilis

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
2025-10-01

Actual Start Date
Not provided

Anticipated Date of Last Follow-up
2025-04-30

Estimated Primary Completion Date
2026-12-31

Estimated Completion Date
2027-06-30

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: 1. Infants at risk of congenital syphilis at birth defined as: 1. an infant born to a mother who tests positive for syphilis in pregnancy using registered and licensed locally-available diagnostic tests for example but not limited to a Treponemal rapid POCT, an RPR or both. AND 2. the mother is untreated in the current pregnancy defined as: i. she tested positive at antenatal care and received no treatment OR ii. she was never tested during antenatal care OR iii. she tested negative at antenatal care and positive on re-testing at delivery OR c. the mother is inadequately treated in the current pregnancy defined as: i. Having received a non-penicillin based treatment regimen; and/or ii. Does not have documentation of 3 doses of IM Benzathine Pe

Health status

Study type

Interventional (clinical trial)

Enrollment

90

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Single blind masking

Masking description

Not provided

Frequency of administration

Not provided

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

AMOXSYP

Identifier

NCT06877351

Link

https://clinicaltrials.gov/study/NCT06877351

Phase

Phase III

Status

Not provided

Sponsor

Hospital de Niños R. Gutierrez de Buenos Aires

More details

The goal of this clinical trial is to learn if oral amoxicillin has comparable therapeutic response than penicillin G benzathine for the treatment of acquired pediatric syphilis. It will also learn about the adverse events and biomarkers of therapeutic response associated with oral amoxicillin. The main questions it aims to answer are: * Does comparable therapeutic response oral amoxicillin to penicillin G benzathine in the treatment of acquired pediatric syphilis? * Does adequate serologic response to treatment participants with syphilis when taking oral amoxicillin? Researchers will compare oral amoxicillin to intramuscular procaine benzathine penicillin to see if oral amoxicillin works similar to treat acquired pediatric syphilis. Participants will: * Take 40-50mg/kg oral amoxicillin

Purpose

Oral Amoxicillin Compared to Penicillin G Benzathine for the Treatment of Acquired Syphilis.

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-08-14

Anticipated Date of Last Follow-up
2025-03-11

Estimated Primary Completion Date
2027-01-01

Estimated Completion Date
2027-06-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children
• Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: 1. Age up to 18 years. 2. Diagnosis of primary, secondary, or early latent syphilis, based on national and international standards (16, 17, 18). 3. Signed informed consent and assent. 4. Ability to comply with the study protocol requirements. 5. For women of childbearing potential, use of a highly effective contraceptive method (e.g., abstinence, hormonal contraception, or intrauterine device (IUD) is required. Contraception must be maintained for 1 week after the completion of treatment. 6. Male participants are advised to use condoms during sexual intercourse to prevent the transmission of syphilis to their partners. Exclusion Criteria: * 1\. Known allergy or hypersensitivity to any of the investigational drugs or their excipients, particularly to penicillin, cepha

Health status

Study type

Interventional (clinical trial)

Enrollment

120

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Not provided

Studied LA-formulation(s)

Not provided

Studied route(s) of administration

Not provided

Use case

Not provided

Key resources

Trep-AB

Identifier

NCT05069974

Link

https://clinicaltrials.gov/study/NCT05069974

Phase

Phase III

Status

Not provided

Sponsor

Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

More details

The Trep-AB clinical trial will test the efficacy of an investigational neuropenetrative drug, Linezolid (LZD), compared to standard treatment, Benzathine penicillin G (BPG), for early syphilis in humans. The overarching idea of the work proposed herein is to investigate the use of LZD to treat syphilis, conducting a randomized controlled clinical trial to evaluate this new indication of a known antibacterial agent.

Purpose

Alternative Antibiotics for Syphilis

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-10-14

Anticipated Date of Last Follow-up
2025-07-17

Estimated Primary Completion Date
2026-04-01

Estimated Completion Date
2026-04-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: 1. Age 18 years or older at baseline visit. 2. Primary, secondary or early latent syphilis diagnosis based on SEIMC/IUSTI Guidelines\* 1. Primary syphilis is defined as typical ulcer (chancre) and positive test using darkfield examination (DFE) or Polymerase chain reaction (PCR) detection of T.p. with/without positive serological test for syphilis. 2. Secondary syphilis is defined based on typical clinical symptoms with positive treponemal and non-treponemal tests. 3. Early latent syphilis is defined as positive serological treponemal and non-treponemal tests with no clinical evidence of infection, with a previous negative syphilis serology,or a four-fold increase in RPR titer of a non-treponemal test within the past 12 months.Serological tests for syphilis p

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

224

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Single blind masking

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

1) Methyl hydroxybenzoate 2) Propyl hydroxybenzoate. 3) Lecithin 4) Polysorbate 80 5) Carmellose sodium 6) Sodium citrate, anhydrous 7) Povidone

Residual solvents used

Not provided

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

Gartlan WA, Rahman S, Pellegrini MV, et al. Benzathine Penicillin. [Updated 2024 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507723/

This activity delves into the multifaceted clinical applications of benzathine penicillin, a potent antibiotic derived from the reaction between penicillin G molecules and diphenylethylene diamine. With broad-spectrum activity against gram-positive bacteria, benzathine penicillin emerges as a formidable agent, effectively combating diverse strains such as β-hemolytic streptococci (groups A, B, C, G, H, L, and M). Its exceptional efficacy against Treponema pallidum and T. carateum positions benzathine penicillin as a cornerstone in treating syphilis and yaws. Importantly, its unparalleled record is underscored by the absence of reported resistance in Streptococcus pyogenes, solidifying its status as a reliable therapeutic tool for specific infections.

This educational initiative offers an in-depth exploration of benzathine penicillin, providing healthcare professionals with comprehensive insights into its indications, dosing regimens, administration modalities, potential adverse effects, and specific contraindications. By unraveling the robust mechanism of action against various bacterial species, this CME activity aims to empower healthcare professionals with an enhanced understanding of the clinical utility of benzathine penicillin. The goal is to foster informed decision-making and optimize therapeutic strategies, ensuring the effective management of bacterial infections susceptible to this antibiotic. Participants will gain valuable knowledge to navigate the nuances of benzathine penicillin therapy, ultimately contributing to improved patient outcomes.

Pharmacokinetics and Safety of Intramuscular Injectable Benzathine Penicillin G in Japanese Healthy Participants, Yinhua Li PhD, Akifumi Okayama MS, Toshiaki Hagi MS, Chieko Muto PhD, Susan Raber PharmD, MPH, Masahito Nagashima BS. 12 May 2024. https://doi.org/10.1002/jcph.2454

An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first-line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post-dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to Cmax (tmax) of 48 h post-dose. After the achievement of Cmax, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half-life of 189 h. Geometric mean AUCinf and Cmax were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well-accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439-608 h [18-25 days]), which reached and exceeded the necessary duration of 7-10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment.

Additional documents

• MSDS Sheet

Useful links

• WHO publication

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(1) Efficacy - benzathine benzylpenicillin arm achieved a 93% cure rate in the per-protocol analysis at 6 months for syphilis (2) Safety - Common side effects include: hypersensitivity, Jarisch-Herxheimer reaction, and injection-site pain. No TEAE; Mild AE in the phase 1 study, which was nasopharyngitis reported in 12% of participants