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.
Syphilis, congenital: Note: Not recommended for treatment of proven or highly probable disease; preferred treatment when congenital syphilis is less likely. See guidelines for criteria to determine probability of disease and treatment recommendations (CDC [Workowski 2015], Red Book [AAP 2018]).
IM: 50,000 units/kg as a single dose.
Group A streptococcal (Streptococcus pyogenes) infection:
Pharyngitis, treatment (primary prevention of rheumatic fever): Note: Empiric treatment is generally not recommended; treatment should be prescribed only when testing confirms presence of Group A Streptococcus (AHA [Gerber 2009]; IDSA [Shulman 2012]; Red Book [AAP 2018]).
Infants, Children, and Adolescents: IM:
≤27 kg: 600,000 units as a single dose.
>27 kg: 1.2 million units as a single dose.
Rheumatic fever, secondary prevention: Note: Duration varies based on risk factors and presence of residual heart disease; see guidelines for details (AHA [Gerber 2009]).
Infants, Children, and Adolescents: IM:
≤27 kg: 600,000 units every 3 to 4 weeks.
>27 kg: 1.2 million units every 3 to 4 weeks.
Note: Every-4-week administration is recommended in the US 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 (AHA [Gerber 2009]; Lue 1994; Red Book [AAP 2018]).
Chronic carriers of Group A Streptococcus, treatment: Limited data available: Note: Antibiotic therapy is generally not recommended for chronic S. pyogenes carriage; however, it may be considered in certain cases (IDSA [Shulman 2012]; Red Book [AAP 2018]).
Infants, Children, and Adolescents: IM:
≤27 kg: 600,000 units as a single dose in combination with oral rifampin for 4 days.
>27 kg: 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 (CDC [Workowski 2015]; Red Book [AAP 2018]).
Congenital; patients with no clinical manifestations and normal cerebrospinal fluid (CSF): Limited data available: Infants and Children: IM: 50,000 units/kg/dose once weekly for up to 3 weeks; maximum dose: 2.4 million units/dose (Bradley 2019; CDC [Workowski 2015]; Red Book [AAP 2018]). Note: See guidelines for treatment of congenital syphilis in patients with clinical manifestations and/or abnormal CSF; aqueous penicillin G is the preferred treatment (Bradley 2019; CDC [Workowski 2015]; Red Book [AAP 2018]).
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 (CDC [Workowski 2015]; Red Book [AAP 2018]).
Re-treatment of primary, secondary, or early latent disease after failure of previous therapy: Infants, Children, and Adolescents: 50,000 units/kg/dose once weekly for 3 weeks; maximum dose: 2.4 million units/dose (CDC [Workowski 2015]; Red Book [AAP 2018]). Note: If CSF examination positive, treat as neurosyphilis (CDC [Workowski 2015]; Red Book [AAP 2018]).
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 (CDC [Workowski 2015]; Red Book [AAP 2018]).
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.
(For additional information see "Penicillin G benzathine (long-acting intramuscular): Drug information")
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 ≥3 episodes/year of known or presumed beta-hemolytic streptococcal cellulitis when predisposing factors cannot be controlled (IDSA [Stevens 2014]).
IM: 1.2 to 2.4 million units as a single dose every 2 to 4 weeks after completion of treatment (Chen 2017; IDSA [Stevens 2014]; Vignes 2006; Wang 1997).
Streptococcus, group A:
Pharyngitis: IM: 1.2 million units as a single dose (AHA [Gerber 2009]; IDSA [Shulman 2012]).
Secondary prophylaxis in patients with rheumatic fever (prevention of recurrent attacks): IM: 1.2 million units once every 21 to 28 days. Duration depends on risk factors, age, and presence of valvular heart disease (AHA [Gerber 2009]).
Chronic carriage (off-label use): Note: Most individuals with chronic carriage do not require antimicrobial treatment (IDSA [Shulman 2012]).
IM: 1.2 million units as a single dose in combination with 4 days of oral rifampin (IDSA [Shulman 2012]).
Syphilis:
Primary, Secondary, Early Latent (<1-year duration): IM: 2.4 million units as a single dose (CDC [Workowski 2021]). Note: Some experts recommend a second dose 1 week after the first dose in patients who are pregnant given concern for altered pharmacokinetics and decreased efficacy (CDC [Workowski 2021]; Nathan 1993; Wendel 2002).
Late Latent, Latent with unknown duration, or Tertiary Syphilis (with normal CSF examination): IM: 2.4 million units once weekly for 3 doses (CDC [Workowski 2021]).
Neurosyphilis (including Ocular Syphilis): Not indicated for initial treatment; aqueous penicillin G IV is preferred initial therapy (refer to Penicillin G Parenteral/Aqueous monograph for dosing). Following penicillin G IV initial treatment, may consider administration of penicillin G benzathine 2.4 million units IM once weekly for 1 to 3 weeks to provide a comparable total duration of therapy as for latent syphilis (CDC [Workowski 2021]).
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intramuscular:
Bicillin L-A: 600,000 units/mL (1 mL); 1,200,000 units/2 mL (2 mL); 2,400,000 units/4 mL (4 mL) [contains methylparaben, propylparaben]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intramuscular:
Bicillin L-A: 1,200,000 units/2 mL (2 mL) [contains methylparaben, propylparaben]
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; permanent neurological damage or gangrene may result.
Warm vial to room temperature before administration to lessen the pain associated with injection (AHA [Gerber 2009]; Red Book [AAP 2018]). Application of manual pressure at the injection site immediately prior to administration has also been shown to reduce pain (Derya 2015). 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 (Atay 2017; Cook 2006). When the midlateral aspect of the thigh is used as the injection site for neonates, infants, or small children, rotate the injection site with repeat doses; repeat doses have been associated with quadriceps femoris fibrosis and atrophy.
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.
Store at 2°C to 8°C (36°F to 46°F); do not freeze. Extended storage information at room temperature may be available; contact product manufacturer to obtain current recommendations.
Treatment of endemic treponemal infections including syphilis (FDA approved in all ages); treatment of infections due to microorganisms susceptible to low, sustained concentrations of penicillin G, including mild to moderate upper respiratory tract infections (ie, pharyngitis) caused by susceptible streptococci (FDA approved in infants, children, adolescents, and adults); prophylaxis of post-streptococcal syndromes such as rheumatic fever, rheumatic heart disease, chorea, and acute glomerulonephritis (FDA approved in adults).
Penicillin may be confused with penicillamine
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.
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).
Injection into or near the vasculature may result in permanent neurovascular and neurological damage, gangrene requiring amputation of proximal portions of extremities, necrosis, and sloughing at the injection site consistent with Nicolau syndrome. Other reported complications include immediate pallor, mottling, or cyanosis of the extremity, both distal and proximal to the injection site, followed by bleb formation, and severe edema requiring anterior and/or posterior compartment fasciotomy in the lower extremity. These effects have most often occurred in infants and small children. Administration in the anterolateral thigh is not recommended; repeated IM injections may lead to quadriceps femoris fibrosis and atrophy. 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). If the midlateral aspect of the thigh is chosen as the injection site for neonates, infants, and small children, vary the injection site with repeat doses.
Substrate of OAT1/3
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
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
Fexinidazole: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Management: Avoid use of fexinidazole with OAT1/3 substrates when possible. If combined, monitor for increased OAT1/3 substrate toxicities. Risk D: Consider therapy modification
Immune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors. 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
Nitisinone: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Pretomanid: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Penicillins. 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
Teriflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
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).
CBC and SCr with prolonged therapy. Monitor for allergic reaction and/or anaphylaxis with first dose; observe for changes in bowel frequency.
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
Suspension (Bicillin L-A Intramuscular)
600000 units/mL (per mL): $131.21
1200000 units/2 mL (per mL): $113.62
2400000 units/4 mL (per mL): $116.42
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