Version May 2024
Not for IV use. Do not inject IV or admix with other IV solutions. There have been reports of inadvertent IV administration of penicillin G benzathine that has been associated with cardiorespiratory arrest and death. Prior to administration of this drug, carefully read the Warnings, Adverse Reactions, Dosage, and Administration sections of the labeling.
Usual dosage range: IM: 1.2 to 2.4 million units as a single dose.
Skin and soft tissue infection:
Cellulitis, long-term suppression of recurrent infection (off-label use): Note: For patients with recurrent presumptive beta-hemolytic streptococcal cellulitis at the same anatomical site despite addressing predisposing factors (Ref).
IM: 1.2 to 2.4 million units as a single dose every 2 to 4 weeks after completion of treatment (Ref).
Streptococcus, group A:
Pharyngitis: IM: 1.2 million units as a single dose (Ref).
Secondary prophylaxis in patients with rheumatic fever (prevention of recurrent attacks):
Note: In patients at elevated risk of death from cardiovascular compromise with IM penicillin (eg, severe valvular disease, ventricular ejection fraction <50%, NYHA class III/IV symptoms), oral penicillin V potassium may be preferred (Ref).
IM: 1.2 million units once every 21 to 28 days. Duration depends on risk factors, age, and presence of valvular heart disease (Ref).
Chronic carriage (off-label use): Note: Most individuals with chronic carriage do not require antimicrobial treatment (Ref).
IM: 1.2 million units as a single dose in combination with 4 days of oral rifampin (Ref).
Syphilis:
Early syphilis (primary, secondary, and early latent [<1-year duration]): IM: 2.4 million units as a single dose (Ref). Note: Some experts recommend a second dose 1 week after the first dose in patients who are pregnant, given potential pharmacokinetic benefits (Ref).
Late syphilis (late latent [ie, >1-year duration] or tertiary syphilis with normal CSF examination): IM: 2.4 million units once weekly for 3 doses (Ref).
Neurosyphilis (including ocular and otosyphilis): Note: Not indicated for initial treatment; for late neurosyphilis (syphilis exposure >1 year ago), may consider administration of penicillin G benzathine following initial IV penicillin G aqueous or IM penicillin G procaine therapy to provide a comparable total duration of therapy for late syphilis (Ref).
IM: 2.4 million units once weekly for 1 to 3 doses following 10 to 14 days of IV penicillin G aqueous or IM penicillin G procaine therapy (Ref).
Yaws, bejel, and pinta: IM: 1.2 million units as a single dose.
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
There are no dosage adjustments provided in the manufacturer’s labeling.
Refer to adult dosing.
(For additional information see "Penicillin G benzathine (long-acting intramuscular): Pediatric drug information")
Streptococcus, group A:
Pharyngitis/tonsillitis:
Infants, Children, and Adolescents (Ref):
≤27 kg: IM: 600,000 units as a single dose.
>27 kg: IM: 1,200,000 units (1.2 million units) as a single dose.
Rheumatic fever, secondary prevention: Limited data available: Note: In patients at elevated risk of death from cardiovascular compromise with IM penicillin (eg, severe valvular disease, ventricular ejection fraction <50%, NYHA class III/IV symptoms), oral penicillin V potassium may be preferred (Ref). Duration depends on risk factors including number of previous attacks, risk of exposure to group A streptococcal infections, age, and presence of valvular disease (Ref).
Children and Adolescents (Ref):
≤27 kg: IM: 600,000 units every 3 to 4 weeks.
>27 kg: IM: 1,200,000 units (1.2 million units) every 3 to 4 weeks.
Note: Every-4-week administration is recommended in the United States where rheumatic fever incidence is low; every 3 weeks should be used to maintain desirable serum drug concentrations in patients who have had a breakthrough episode despite every-4-week dosing and in areas where incidence of acute rheumatic fever remains high (Ref).
Chronic carriage (Ref): Limited data available: Note: Most individuals with chronic carriage do not require antibiotic treatment.
Children and Adolescents:
≤27 kg: IM: 600,000 units as a single dose in combination with oral rifampin for 4 days.
>27 kg: IM: 1,200,000 units (1.2 million units) as a single dose in combination with oral rifampin for 4 days.
Syphilis: Note: Not recommended for the initial treatment of neurosyphilis (Ref).
Congenital: Limited data available: Note: Not recommended if disease is confirmed or highly probable, or clinical manifestations are present (including abnormal cerebrospinal fluid [CSF] studies); see guidelines for details (Ref).
Infants and Children: IM: 50,000 units/kg/dose once weekly for up to 3 weeks; maximum dose: 2.4 million units/dose (Ref).
Primary, secondary, or early latent (<1 year duration): Infants, Children, and Adolescents: IM: 50,000 units/kg once; maximum dose: 2.4 million units/dose (Ref).
Re-treatment of primary, secondary, or early latent disease after failure of previous therapy: Infants, Children, and Adolescents: IM: 50,000 units/kg/dose once weekly for 3 weeks; maximum dose: 2.4 million units/dose (Ref). Note: If CSF examination positive, treat as neurosyphilis (Ref).
Late latent (>1 year or unknown duration): Infants, Children, and Adolescents: IM: 50,000 units/kg/dose once weekly for 3 weeks; maximum dose: 2.4 million units/dose (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse drug reactions are reported for penicillin G benzathine and/or other parenteral penicillin G formulations.
Postmarketing:
Cardiovascular: Cerebrovascular accident, hypersensitivity angiitis, hypotension, palpitations, pulmonary embolism, syncope, tachycardia, vasodepressor syncope, vasodilation, vasospasm
Dermatologic: Acute generalized exanthematous pustulosis, diaphoresis, exfoliative dermatitis, gangrene of skin and/or other subcutaneous tissues, maculopapular rash, pallor, pruritus, skin mottling, skin or other tissue necrosis (Nicolau syndrome), skin ulceration at injection site, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Gastrointestinal: Blood in stool, Clostridioides difficile associated diarrhea, Clostridioides difficile colitis, intestinal necrosis, nausea, vomiting
Genitourinary: Hematuria, impotence, priapism, proteinuria
Hematologic & oncologic: Eosinophilia, hemolytic anemia, leukopenia, lymphadenopathy, thrombocytopenia
Hepatic: Increased serum aspartate aminotransferase
Hypersensitivity: Anaphylactic shock, anaphylaxis, hypersensitivity reaction
Immunologic: Drug reaction with eosinophilia and systemic symptoms, Jarisch-Herxheimer reaction, serum sickness-like reaction
Local: Abscess at injection site, atrophy at injection site, bleeding at injection site, bruising at injection site, cellulitis at injection site, hypersensitivity reaction at injection site, inflammation at injection site, injection site reaction (neurovascular damage), pain at injection site, residual mass at injection site, swelling at injection site, tissue necrosis at injection site
Nervous system: Anxiety, coma, confusion, dizziness, drowsiness, euphoria, fatigue, headache, localized warm feeling, nervousness, neurologic abnormality (neurogenic bladder), neuropathy, numbness of extremities, pain, seizure, transverse myelitis
Neuromuscular & skeletal: Arthropathy, asthenia, exacerbation of arthritis, myoglobinuria, periosteal disease, rhabdomyolysis, tremor
Ophthalmic: Blindness, blurred vision
Renal: Increased blood urea nitrogen, increased serum creatinine, renal disease, renal failure syndrome
Respiratory: Apnea, cyanosis, cyanotic extremities, dyspnea, hypoxia, laryngeal edema, pulmonary hypertension
Miscellaneous: Fever
Hypersensitivity to penicillin(s) or any component of the formulation
Concerns related to adverse effects:
• Hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity (including cephalosporins), history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids and airway management (including intubation) as indicated.
• Severe cutaneous adverse reactions: Severe cutaneous adverse reactions (SCAR) (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis) have been reported; discontinue immediately if SCAR is suspected.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including Clostridioides difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.
• Syphilis/neurosyphilis use: CDC and AAP do not currently recommend the use of penicillin G benzathine for the initial treatment regimen for congenital syphilis or neurosyphilis due to reported treatment failures and lack of published clinical data on its efficacy (CDC [Workowski 2015]).
Other warnings/precautions:
• Appropriate administration: [US Boxed Warning]: Not for IV use; cardiopulmonary arrest and death have occurred from inadvertent IV administration. Administer by deep IM injection only. Quadriceps femoris fibrosis and atrophy have been reported after repeated IM injections of penicillin preparations into the anterolateral thigh. Injection into or near an artery or nerve could result in severe neurovascular damage or permanent neurological damage.
• Appropriate use: Use only for treatment of infections due to penicillin G sensitive gram positive organisms, few gram-negative organisms such as Neisseria gonorrhoeae, and some anaerobes and spirochetes. Use only for infections susceptible to the low and very prolonged serum concentrations of benzathine penicillin G.
• Prolonged use: Extended duration of therapy or use associated with high serum concentrations (eg, in renal insufficiency) may be associated with an increased risk for some adverse reactions (neutropenia, hemolytic anemia, serum sickness).
Nicolau syndrome or other serious local damage may occur following IM injection; these effects may include intense/severe pain, edema, cutaneous lesion, pallor, mottling, or cyanosis of the extremity, significant necrosis and gangrene requiring fasciotomy or amputation of proximal portions of extremities, paralysis, permanent neurovascular and neurological damage, and in some cases lead to death (De Sousa 2008; Kim 2015; Quincer 2019; Zargarbashi 2023; manufacturer's labeling). Also known as embolia cutis medicamentosa, Nicolau syndrome may occur most often in patients <12 years of age, particularly infants and small children (eg, <3 years of age) (De Sousa 2008; Quincer 2019; manufacturer's labeling). While exact pathogenesis is uncertain, it is likely related to injection into or near the vasculature (Kim 2015; Quincer 2019; manufacturer's labeling). Pain is typically present immediately or within hours of injection and symptom progression follows over the course of hours to days (Alkan Bozkaya 2016; De Sousa 2008; Kim 2015; Ocak 2006; Zargarbashi 2023). Some suggest that the risk of Nicolau syndrome may be reduced through use of proper technique for IM injection of penicillin G benzathine, including appropriate needle length, selection of appropriate injection sites and associated maximum volumes within the muscle, use of the Z-track method for injection, and aspiration for 5 to 10 seconds prior to injection to ensure no blood return; injection should be stopped if the patient complains of severe, intense pain (De Sousa 2008; Goudjo 2022; Ocak 2006; Pullen 2005; Quincer 2019). The manufacturer recommends dorso- or ventrogluteal sites for deep IM injection. Several studies have suggested ventrogluteal injection may be appropriate in term neonates, infants, and young children; risk of severe injury may be lower compared to other locations (deltoid, anterolateral aspect of thigh) as the site is relatively distant to major nerves and blood vessels and thinnest layer of subcutaneous fat (Atay 2017; Cook 2006). Administration in the anterolateral thigh is not recommended because the area is more vascular; repeated IM injections may lead to quadriceps femoris fibrosis and atrophy. With repeat doses or doses that require multiple injections, vary the injection site (Ocak 2006; manufacturer's labeling).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intramuscular:
Bicillin L-A: 2,400,000 units/4 mL (4 mL) [contains methylparaben, propylparaben]
Suspension Prefilled Syringe, Intramuscular:
Bicillin L-A: 600,000 units/mL (1 mL); 1,200,000 units/2 mL (2 mL) [contains methylparaben, propylparaben]
No
Suspension Prefilled Syringe (Bicillin L-A Intramuscular)
600000 units/mL (per mL): $192.10
1200000 units/2 mL (per mL): $166.36
2400000 units/4 mL (per mL): $170.45
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Prefilled Syringe, Intramuscular:
Bicillin L-A: 1,200,000 units/2 mL (2 mL) [contains methylparaben, propylparaben]
IM: Warm to room temperature before administration to lessen the pain associated with injection. Administer by deep IM injection at a slow, steady rate in the dorsogluteal region (upper outer quadrant of the buttock) or the ventrogluteal region. Do not inject near an artery or a nerve; permanent neurological damage or gangrene may result. When doses are repeated, rotate the injection site. Do not administer IV, intra-arterially, or SubQ.
Parenteral: IM: For IM administration only; do not give IV, intra-arterially or SUBQ; inadvertent IV administration has resulted in thrombosis, severe neurovascular damage, cardiac arrest, and death. Do not inject near an artery or a nerve; Nicolau syndrome may occur and/or permanent damage may result.
Warm vial to room temperature before administration to lessen the pain associated with injection (Ref). Application of manual pressure at the injection site immediately prior to administration has also been shown to reduce pain (Ref). Administer undiluted as deep IM injection at a slow, steady rate to avoid discomfort and needle blockage. The manufacturer recommends administration in the dorsogluteal region (upper outer quadrant of the buttock) or ventrogluteal site. Ventrogluteal site injection may be appropriate in term neonates, infants, and young children; risk of severe injury may be lower compared to other locations (deltoid, anterolateral aspect of thigh) (Ref). With repeat doses or when multiple injections must be given for a single dose, rotate the injection site. Administration in the anterolateral thigh is not recommended; repeated IM injections may lead to quadriceps femoris fibrosis and atrophy (Ref). Some suggest that the risk of Nicolau syndrome may be reduced through use of proper technique for IM injection including appropriate needle length, selection of appropriate injection sites and associated maximum volumes within the muscle, use of the Z-track method for injection, and aspiration for 5 to 10 seconds prior to injection to ensure no blood return; injection should be stopped if the patient complains of severe, intense pain (Ref).
Acute glomerulonephritis: Secondary prophylaxis in patients with a history of acute glomerulonephritis.
Streptococcus, group A: Secondary prophylaxis for rheumatic fever (prevention of secondary attacks).
Streptococcal pharyngitis, group A: Treatment of pharyngitis caused by group A Streptococcus.
Syphilis and other venereal diseases: Treatment of syphilis, yaws, bejel, and pinta.
Cellulitis, long-term suppression of recurrent infection; Streptococcal (group A) chronic carriage
Penicillin may be confused with penicillAMINE
Penicillin G benzathine may be confused with penicillin G (parenteral/aqueous), penicillin G procaine, penicillin V potassium
Bicillin may be confused with Wycillin
Penicillin G benzathine may only be administered by deep intramuscular injection; intravenous administration of penicillin G benzathine has been associated with cardiopulmonary arrest and death.
Bicillin C-R (penicillin G benzathine and penicillin G procaine) may be confused with Bicillin L-A (penicillin G benzathine). Penicillin G benzathine is the only product currently approved for the treatment of syphilis. Administration of penicillin G benzathine and penicillin G procaine combination instead of Bicillin L-A may result in inadequate treatment response.
Substrate of OAT1/3
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acemetacin: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Risk C: Monitor therapy
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Dichlorphenamide: Penicillins may enhance the hypokalemic effect of Dichlorphenamide. Risk C: Monitor therapy
Fecal Microbiota (Live) (Oral): May diminish the therapeutic effect of Antibiotics. Risk X: Avoid combination
Fecal Microbiota (Live) (Rectal): Antibiotics may diminish the therapeutic effect of Fecal Microbiota (Live) (Rectal). Risk X: Avoid combination
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Sodium Benzoate: Penicillins may diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Tetracyclines: May diminish the therapeutic effect of Penicillins. Risk C: Monitor therapy
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Penicillin G benzathine crosses the placenta (Nathan 1993; Weeks 1997).
Penicillin is widely used in pregnant women. Based on available data, penicillin is generally considered compatible for use during pregnancy (Ailes 2016; Bookstaver 2015; Crider 2009; Damkier 2019; Galvao 2013; Heinonen 1977; Lamont 2014; Muanda 2017a; Muanda 2017b).
Penicillin G is the drug of choice for treatment of syphilis during pregnancy (CDC [Workowski 2021]). Untreated maternal syphilis can cause congenital syphilis which is associated with bone deformities, neurologic impairment, stillbirth, or neonatal death (USPSTF [Curry 2018]). Symptoms of congenital syphilis may include hepatosplenomegaly, jaundice, nonimmune hydrops, pseudoparalysis of an extremity, rhinitis, or skin rash. The Centers for Disease Control and Prevention (CDC) Sexually Transmitted Diseases Treatment Guidelines provide recommendations for the treatment of syphilis in pregnant patients. The penicillin regimen (dose, duration, and preparation) for the treatment of pregnant patients is the same as for a nonpregnant patient and depends on the stage of syphilis. However, parenteral penicillin G is the only agent with documented efficacy in pregnancy. Patients who are allergic to penicillin should be desensitized and treated with penicillin. Pregnant patients being treated for latent syphilis must repeat the full course of therapy if any doses are missed. A Jarisch-Herxheimer reaction may occur in any patient within the first 24 hours of therapy, including pregnant patients. This reaction may induce early labor, fetal distress, or stillbirth (rare); however, it is not a reason to prevent or delay maternal therapy (CDC [Workowski 2021]).
Use of penicillin G benzathine should be continued for the secondary prophylaxis of rheumatic fever/heart disease during pregnancy when indicated (Russell 2018).
Soluble penicillin G is present in breast milk.
Concentrations of penicillin class antibiotics in breast milk are limited (Nau 1987). In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea (WHO 2002).
Although the manufacturer recommends that caution be exercised when administering penicillin G benzathine to breastfeeding patients, penicillin G benzathine is considered compatible with breastfeeding when used in usual recommended doses (WHO 2002).
Observe for signs and symptoms of anaphylaxis during first dose
Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria
Duration: 1 to 4 weeks (dose dependent); larger doses result in more sustained levels
Absorption: IM: Slow
Distribution: Minimal concentrations attained in CSF with inflamed or uninflamed meninges; highest levels in the kidney; lesser amounts in liver, skin, intestines
Protein Binding: ~60%
Time to peak, serum: Within 12 to 24 hours; serum levels are usually detectable for 1 to 4 weeks depending on the dose; larger doses result in more sustained levels rather than higher levels
Excretion: Excreted by renal tubular excretion; penicillin G is detected in urine for up to 12 weeks after a single IM injection; renal clearance is delayed in neonates, young infants, and patients with impaired renal function
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