BICILLIN L-A

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-For IM administration only. NEVER administer intravenously or admix with other IV solutions.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intramuscular Administration
-Administer by deep IM injection into the upper, outer quadrant of the buttock (dorsogluteal) or the ventrogluteal site. In neonates, infants, and small children, the midlateral aspect of the anterolateral thigh (i.e., vastus lateralis) may be preferred. Do not administer in other areas of the anterolateral thigh as quadriceps femoris fibrosis and atrophy have been reported after repeated IM injections of penicillin preparations into the anterolateral thigh.
-When doses are repeated, vary the injection site.
-Because of the high concentration of suspended material in this product, the needle may be blocked if the injection is not made at a slow, steady rate.

Hypersensitivity reactions are among the most frequently reported adverse reactions to the penicillins. Penicillin allergy has been reported in up to 20% of patients; however, around 90% of reported allergies are incorrectly reported and patients lack penicillin-specific IgE antibodies. The actual prevalence of penicillin allergy is likely no greater than 5%. Hypersensitivity or dermatologic reactions include skin eruptions (maculopapular rash to exfoliative dermatitis), urticaria, laryngeal edema, fever, eosinophilia, serum sickness-like reactions (including chills, fever, edema, arthralgia, and prostration), anaphylactoid reactions including anaphylactic shock and death, allergic vasculitis, and pruritus. Urticaria, other skin rash, and serum sickness-like reactions may be controlled with antihistamines or steroids. Whenever such reactions occur, discontinue penicillin G benzathine unless the condition being treated is life-threatening and amenable only to therapy with penicillin G benzathine. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Administer oxygen, intravenous steroids, and airway management, including intubation, as indicated. Rash may develop after the first week and may cover the entire body, including the soles, palms, and oral mucosa. The rash usually disappears in 3 to 7 days. Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected, discontinue penicillin G benzathine immediately and consider alternative treatment.

In general, neurologic symptoms associated with penicillin G, such as penicillin G benzathine, include peripheral neuropathy, nervousness, tremor, dizziness, somnolence (drowsiness), confusion, anxiety, euphoria, transverse myelitis, seizures, and coma. A syndrome manifested by a variety of neurological symptoms such as severe agitation with confusion, hallucinations, and a 'fear of impending death' (Hoigne's syndrome) as been reported with Bicillin C-R (penicillin G benzathine and penicillin G procaine), a combination injectable suspension. Other symptoms associated with this syndrome, such as psychosis, seizures, dizziness, tinnitus, cyanosis, abnormal heartbeat, tachycardia, and abnormal taste perception may occur. Also of note, high-dose penicillin G therapy has been associated with seizures hyperreflexia, myoclonic twitches (myoclonia), and coma. The risk of seizures appears to be higher in neonates, patients with renal impairment, and in patients who receive rapid IV administration.

General adverse events reported in the general population with the use of penicillin G, such penicillin G benzathine, include fatigue, asthenia, pain, headache, and diaphoresis.

Intramuscular injection of penicillin G benzathine can be extremely painful. A local injection site reaction, including pain, inflammation, lump, abscess, necrosis, edema, bleeding, cellulitis, skin atrophy, ecchymosis, and skin ulcer, has been reported. Inadvertent intravascular administration, including inadvertent direct intra-arterial injection or injection immediately adjacent to arteries, of penicillin G benzathine has resulted in severe neurovascular damage, including transverse myelitis with permanent paralysis, gangrene requiring amputation of digits and more proximal portions of the extremities, and tissue necrosis and sloughing at and around the injection site consistent with Nicolau syndrome. Such severe effects have been reported after injections into the buttock, thigh, and deltoid areas. Other serious complications of suspected intravascular administration that have been reported include warmth, vasospasm, immediate pallor, mottling, gangrene, numbness of the extremity, 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. Prompt consultation with an appropriate specialist is indicated if any evidence of compromise of the blood supply occurs at, proximal to, or distal to the site of injection. Quadriceps femoris fibrosis and atrophy have been reported after repeated intramuscular injections into the anterolateral thigh; therefore, administration in the anterolateral thigh is not recommended.

Gastrointestinal adverse events may occur in 2% to 5% of patients in the general population receiving penicillins. Nausea, vomiting and diarrhea are commonly reported gastrointestinal side effects of penicillin G therapy. Black hairy tongue (tongue discoloration) have also been reported occasionally. Blood in the stool and intestinal/bowel necrosis has also been reported.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with penicillin G benzathine. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.

In the general population, side effects associated with penicillin G therapy, such as penicillin G benzathine, may include hematologic effects such as hemolytic anemia, leukopenia, and thrombocytopenia.

Lymphadenopathy has been associated with penicillin G in the general population.

Urogenital adverse events associated with penicillin G in the general population include nephropathy, elevated BUN, elevated serum creatinine, neurogenic bladder, hematuria, proteinuria, and renal failure (unspecified).

Cardiovascular adverse events associated with penicillin G in the general population include cardiac arrest, hypotension, sinus tachycardia, palpitations, pulmonary hypertension, pulmonary embolism, vasodilation, vasovagal reaction, cerebrovascular accident, and syncope.

Musculoskeletal adverse events associated with penicillin G in the general population include joint disorder, periostitis, exacerbation of arthritis, myoglobinuria, and rhabdomyolysis.

Hypoxia, apnea, and dyspnea have generally been associated with the use of penicillin G.

Blurred vision and blindness have been associated with the use of penicillin G in the general population.

The Jarisch-Herxheimer reaction is a self-limiting systemic reaction that has been reported in the setting of spirochete infections, such as Lyme disease, syphilis, relapsing fever, and leptospirosis, after the initiation of antimicrobial therapy. It is characterized by fever, chills, myalgias, headache, exacerbation of cutaneous lesions, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. Less commonly, symptoms may include meningitis, pulmonary failure, hepatic and renal dysfunction, myocardial injury, premature uterine contractions in pregnant patients, and worsening cerebral function as well as strokes and seizures. The reaction has been noted in up to 30% of patients with early Lyme disease. The timing of the reaction varies by underlying infection but typically presents within a few hours after the initiation of antibiotics. For Lyme disease, the reaction usually begins within 1 to 2 hours after starting therapy and disappears within 12 to 24 hours. The reaction after treatment in syphilis usually starts at 4 hours, peaks at 8 hours, and subsides by 16 hours whereas it starts at about 1 to 2 hours, peaks at 4 hours, and subsides by 8 hours after treatment in relapsing fever. The pathogenesis of this reaction is unknown but may be due to the release of spirochetal heat-stable pyrogen. Fluids and antipyretics can be used to alleviate symptoms and duration of the reaction if severe.

Penicillin is contraindicated for use in patients with penicillin hypersensitivity. It should be used cautiously in patients with cephalosporin hypersensitivity or carbapenem hypersensitivity. These patients are more susceptible to cross-hypersensitivity reactions. Penicillin can cause a variety of hypersensitivity reactions ranging from mild rash to fatal anaphylaxis. Patients with allergies or allergic conditions including asthma may have a greater risk for hypersensitivity reactions to penicillins..

Penicillin G benzathine is for deep intramuscular injection only. There have been reports of inadvertent intravenous administration of penicillin G benzathine which has been associated with cardiorespiratory arrest and death. Therefore, do not inject intravenously or admix with other intravenous solutions. Inadvertent intravascular administration, including inadvertent direct intraarterial administration or injection immediately adjacent to arteries, of penicillin G benzathine has resulted in severe neurovascular damage.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including penicillin G benzathine, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Penicillin G is eliminated primarily unchanged via renal tubular secretion. With normal renal function the drug is rapidly eliminated. In individuals with renal impairment or renal failure, excretion is considerably delayed. Incomplete development of renal function in neonates and infants may delay elimination of penicillin. Dosages of penicillin G benzathine may need to be reduced in these patients. Large doses of penicillin administered to patients with renal impairment have been associated with seizures.

Administration of penicillin G benzathine may result in laboratory test interference. A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with Tes-tape (glucose Enzymatic Test Strip, USP, Lilly) or Clinistix. Patients with diabetes who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on penicillin treatment.

Serious rash, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported in patients taking beta-lactam antibiotics. When a severe cutaneous adverse reaction (SCAR) is suspected, discontinue penicillin G benzathine immediately and consider alternative treatment.

Description: Penicillin G benzathine is the salt of the naturally derived antibiotic, Penicillium chrysogenum. Benzathine penicillin is a repository form of penicillin for intramuscular use only; after injection a depot forms in the tissue, from which the drug is hydrolyzed at the intramuscular injection site to penicillin G and slowly released into the blood stream over several days. This provides much lower, but prolonged, serum concentrations compared to aqueous penicillin G. These characteristics increase patient compliance with benzathine penicillin but limit therapeutic indications. Penicillin G benzathine is recommended for prophylaxis and treatment of rheumatic fever, and the management of syphilis. Penicillin G benzathine is FDA approved for use in pediatric patients as young as neonates.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Actinomyces israelii, Bacillus anthracis, Clostridium sp., Corynebacterium diphtheriae, Leptospira sp., Listeria monocytogenes, Neisseria gonorrhoeae, Staphylococcus sp., Streptobacillus moniliformis, Streptococcus agalactiae (group B streptococci), Streptococcus dysgalactiae, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci), Streptococcus sp., Streptococcus sp. (Group C), Streptococcus sp. (Group G), Streptococcus sp. (Group H), Streptococcus sp. (Group L), Streptococcus sp. (Group M), Treponema carateum, Treponema pallidum
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Borrelia burgdorferi, Erysipelothrix rhusiopathiae, Fusobacterium sp., Haemophilus sp., Neisseria meningitidis, Pasteurella multocida, Peptostreptococcus sp., Prevotella melaninogenica, Salmonella sp., Shigella sp., Spirillum minus, Streptococcus bovis, Viridans streptococci
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of upper respiratory tract infections, including group A beta-hemolytic streptococcal (GAS) pharyngitis (primary rheumatic fever prophylaxis) and tonsillitis:
-for the treatment of nonspecific mild to moderate upper respiratory tract infections:
Intramuscular dosage:
Infants and Children weighing less than 27 kg: 300,000 to 600,000 units IM as a single dose.
Children and Adolescents weighing 27 kg or more: 900,000 units IM as a single dose.
-for the treatment of group A beta-hemolytic streptococcal (GAS) pharyngitis (primary rheumatic fever prophylaxis) and tonsillitis:
Intramuscular dosage:
Infants and Children weighing less than 27 kg: 600,000 units IM as a single dose.
Children and Adolescents weighing 27 kg or more: 1.2 million units IM as a single dose.
-for secondary prophylaxis of rheumatic fever and glomerulonephritis:
Intramuscular dosage:
Infants and Children weighing less than 27 kg: 600,000 units IM every 4 weeks, or every 3 weeks in high-risk patients, including those with recurrent rheumatic fever while receiving benzathine penicillin G every 4 weeks. The FDA-approved dose is 1.2 million units IM every 4 weeks or 600,000 units IM every 2 weeks. Guidelines recommend secondary prophylaxis for 10 years or until age 40 years (whichever is longer) for patients who have experienced rheumatic fever with carditis and have residual heart disease (persistent valvular disease). For patients who have experienced rheumatic fever with carditis but have no residual heart disease, prophylaxis is recommended for 10 years or until age 21 years (whichever is longer). For patients who have experienced rheumatic fever without carditis, prophylaxis is recommended for 5 years or until age 21 years (whichever is longer).
Children and Adolescents weighing 27 kg or more: 1.2 million units IM every 4 weeks, or every 3 weeks in high-risk patients, including those with recurrent rheumatic fever while receiving benzathine penicillin G every 4 weeks. The FDA-approved dose is 1.2 million units IM every 4 weeks or 600,000 units IM every 2 weeks. Guidelines recommend secondary prophylaxis for 10 years or until age 40 years (whichever is longer) for patients who have experienced rheumatic fever with carditis and have residual heart disease (persistent valvular disease). For patients who have experienced rheumatic fever with carditis but have no residual heart disease, prophylaxis is recommended for 10 years or until age 21 years (whichever is longer). For patients who have experienced rheumatic fever without carditis, prophylaxis is recommended for 5 years or until age 21 years (whichever is longer).

For the post-exposure diphtheria prophylaxis* of close contacts of persons with diphtheria:
Intramuscular dosage:
Infants and Children weighing less than 30 kg: 600,000 units IM as a single dose.
Children and Adolescents weighing 30 kg or more: 1.2 million units IM as a single dose.

For the treatment of syphilis, including congenital syphilis and neurosyphilis*:
NOTE: The Jarisch-Herxheimer reaction may occur within the first 24 hours of therapy.
-for the treatment of primary, secondary, or early latent (less than 1 year duration) syphilis*:
Intramuscular dosage:
Infants* and Children*: 50,000 units/kg/dose (Max: 2.4 million units/dose) IM as a single dose. Additional doses do not enhance therapy regardless of HIV status. Empirically treat individuals exposed to a sex partner diagnosed with primary, secondary, or early latent syphilis within the past 90 days as they may be infected even if seronegative. Empirically treat individuals exposed more than 90 days before diagnosis in a sex partner if serologic test results are not immediately available and follow-up is uncertain.
Adolescents*: 2.4 million units/dose IM as a single dose. Additional doses do not enhance therapy regardless of HIV status. Empirically treat individuals exposed to a sex partner diagnosed with primary, secondary, or early latent syphilis within the past 90 days as they may be infected even if seronegative. Empirically treat individuals exposed more than 90 days before diagnosis in a sex partner if serologic test results are not immediately available and follow-up is uncertain.
-for the treatment of late latent (greater than 1 year duration) syphilis or latent syphilis of unknown duration*:
Intramuscular dosage:
Infants, Children, and Adolescents: 50,000 units/kg/dose IM (Max: 2.4 million units/dose) once weekly for 3 weeks. It is unclear as to the proper course of action in patients who miss a dose of penicillin. Guidelines suggest that an interval of 10 to 14 days between doses may be acceptable.
-for the treatment of late or tertiary syphilis* (patients with gumma and cardiovascular syphilis*):
Intramuscular dosage:
NOTE: Guidelines recommend ruling out neurosyphilis prior to treatment.
Adolescents: 2.4 million units IM once weekly for 3 weeks.
-for the follow-up treatment of neurosyphilis*:
NOTE: Benzathine penicillin is NOT indicated for treatment of neurosyphilis but only as follow-up after therapy with aqueous penicillin G to provide a comparable duration of therapy as treatment for latent syphilis.
Intramuscular dosage:
Adolescents: 2.4 million units IM once weekly for 1 to 3 weeks may be considered after completion of therapy with aqueous penicillin G or procaine penicillin G plus probenecid.
-for the treatment of congenital syphilis:
NOTE: Current guidelines should be consulted to determine the appropriate course of treatment in neonates born to mothers with syphilis. Therapy is based on physical examination, serum quantitative nontreponemal serologic titer, and whether or not the mother was treated properly before delivery.
Intramuscular dosage:
Neonates: 50,000 units/kg/dose IM as a single dose for neonates with a normal physical exam and a serum quantitative nontreponemal serologic titer the same or less than 4-fold the maternal titer.
Infants and Children: Guidelines recommend aqueous penicillin G for any child older than 1 month suspected of having congenital syphilis or who has neurologic involvement. Penicillin G benzathine may be considered in the following situations: 50,000 units/kg/dose (Max: 2.4 million units/dose) IM once weekly for up to 3 doses in children with no clinical manifestations, a normal CSF examination, and a negative CSF VDRL test; 50,000 units/kg/dose (Max: 2.4 million units/dose) IM as a single dose after completion of a 10-day course of aqueous penicillin G to provide a comparable duration as treatment for late syphilis; or 50,000 units/kg/dose (Max: 2.4 million units/dose) IM as a single dose in patients without any clinical evidence of infection during an aqueous penicillin G shortage.

For the treatment of yaws (Treponema pallidum subsp. pertenue), pinta (Treponema carateum), and bejel (Treponema pallidum subsp. endemicum):
Intramuscular dosage:
Infants and Children 1 month to 9 years: 600,000 units IM as a single injection has been recommended. The FDA-approved labeling does not differentiate doses based on age or weight and recommends 1.2 million units IM as a single injection.
Children and Adolescents 10 to 17 years: 1.2 million units IM as a single injection.

For group A streptococci chronic pharyngeal carriage eradication* in combination with oral rifampin:
Intramuscular dosage:
Infants and Children weighing less than 27 kg: 600,000 units IM as a single dose. Most chronic streptococcal carriers do not need antimicrobial therapy. Treatment may be considered during a community outbreak of acute rheumatic fever, acute poststreptococcal glomerulonephritis or invasive group A streptococcal (GAS) infection; during an outbreak of GAS pharyngitis in a closed or partially closed community; in the presence of a family or personal history of acute rheumatic fever; in a family with excessive anxiety about GAS infections; or when tonsillectomy is being considered only because of carriage.
Children and Adolescents weighing 27 kg or more: 1.2 million units IM as a single dose. Most chronic streptococcal carriers do not need antimicrobial therapy. Treatment may be considered during a community outbreak of acute rheumatic fever, acute poststreptococcal glomerulonephritis or invasive group A streptococcal (GAS) infection; during an outbreak of GAS pharyngitis in a closed or partially closed community; in the presence of a family or personal history of acute rheumatic fever; in a family with excessive anxiety about GAS infections; or when tonsillectomy is being considered only because of carriage.

For diphtheria carriage eradication*:
Intramuscular dosage:
Infants and Children weighing less than 30 kg: 600,000 units IM as a single dose.
Children and Adolescents weighing 30 kg or more: 1.2 million units IM as a single dose.

Maximum Dosage Limits:
-Neonates
50,000 units/kg/day IM.
-Infants
50,000 units/kg/day IM (Max: 600,000 units/day).
-Children
50,000 units/kg/day IM (Max: 2.4 million units/day).
-Adolescents
50,000 units/kg/day IM (Max: 2.4 million units/day).

Patients with Hepatic Impairment Dosing
No dosage adjustment required. If hepatic impairment is in conjunction with renal impairment, dosage adjustments may be necessary.

Patients with Renal Impairment Dosing
Penicillin G is rapidly eliminated via renal tubular excretion and clearance is significantly delayed in patients with decreased renal function. Specific dosage adjustment recommendations are not available for penicillin G benzathine.

Intermittent hemodialysis
Penicillin G is removed during hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Penicillin G benzathine is a beta-lactam antibiotic. It is mainly bactericidal in action. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several different steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of penicillin G, as well as the other penicillins, against a particular organism depends on its ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, penicillin G's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.

Beta-lactams exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism. This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval.

For penicillin, the MICs are defined for beta-hemolytic Streptococcus sp. as susceptible at 0.12 mcg/mL or less.

Pharmacokinetics: Benzathine penicillin G is administered by intramuscular injection and is approximately 60% bound to serum protein. After administration of penicillin G benzathine, elimination occurs over an extended period of time due to the slow release from the intramuscular injection site. Penicillin G is rapidly eliminated via renal tubular excretion and is significantly delayed in patients with decreased renal function. Serum concentrations may still be detectable 4 weeks after administration.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intramuscular Route
After intramuscular administration, a tissue depot is created at the site of IM injection. Benzathine penicillin G is hydrolyzed and active drug is slowly released into the systemic circulation. Higher doses generally result in more sustained serum concentrations rather than higher serum concentrations.


-Special Populations
Pediatrics
Neonates
Renal clearance of penicillin is delayed in neonates due to, comparatively, decreased renal function. In a single dose study of penicillin G benzathine (50,000 units IM) in 125 full-term neonates weighing > 2500 g, the peak penicillin concentration occurred between 13 and 24 hours (mean 1.23 mcg/ml) and concentrations of 0.65-0.92 mcg/ml persisted for 4 days.

Infants, Children, and Adolescents
In a study of 12 pediatric patients (ages 1.8-10.7 years) receiving penicillin G benzathine 600,000 units IM for those weighing < 27 kg or 1.2 million units IM for those weighing > 27 kg, mean peak serum concentrations were 0.16 mcg/mL and 0.15 mcg/ml, respectively, at approximately 24 hours after the dose. Additionally, serum concentrations remained similar throughout 18 days with both resulting in mean serum concentrations of 0.01 mcg/ml at day 18. In 8 of the 9 patients had no penicillin activity in the serum on day 30 had measurable urine concentrations (0.6-12.5 mcg/ml).

Hepatic Impairment
In patients with altered renal function, the presence of hepatic insufficiency further reduces the elimination of penicillin G.

Renal Impairment
Penicillin G is eliminated via renal tubular excretion and is significantly delayed in patients with decreased renal function.