Penicillin G Benzathine and Penicillin G Procaine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Injection, suspension [prefilled syringe]:

Bicillin C-R:

600,000 units: Penicillin G benzathine 300,000 units and penicillin G procaine 300,000 units per 1 mL (1 mL) [DSC]

1,200,000 units: Penicillin G benzathine 600,000 units and penicillin G procaine 600,000 units per 2 mL (2 mL)

2,400,000 units: Penicillin G benzathine 1,200,000 units and penicillin G procaine 1,200,000 units per 4 mL (4 mL) [DSC]

Bicillin C-R 900/300: 1,200,000 units: Penicillin G benzathine 900,000 units and penicillin G procaine 300,000 units per 2 mL (2 mL)

Pharmacology

Mechanism of Action

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs); which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Pharmacokinetics/Pharmacodynamics

Absorption

IM: Released slowly

Distribution

Highest levels in the kidney; lesser amounts in liver, skin, intestines

Time to Peak

Serum: IM: Within 3 hours

Protein Binding

~60%

Use in Specific Populations

Special Populations: Renal Function Impairment

Excretion of the drug is considerably delayed in neonates, children, and individuals with renal function impairment.

Use: Labeled Indications

Pneumococcal infections: Treatment of moderately severe pneumonia and otitis media due to susceptible Pneumococcus spp. (eg, Streptococcus pneumoniae)

Streptococcal infections, group A: Treatment of moderately severe to severe infections, without associated bacteremia, of the upper respiratory tract, scarlet fever, erysipelas, and skin and soft tissue infections due to group A streptococci

Note: Bicillin C-R 900/300 is only indicated in pediatric patients.

Limitations of use: Not considered appropriate for the treatment of sexually transmitted diseases, including syphilis, gonorrhea, yaws, bejel, and pinta. When high, sustained serum levels are required, use alternative penicillin preparations.

Contraindications

Hypersensitivity to penicillin(s), procaine, or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Bicillin C-R 900/300 is only indicated in pediatric patients.

Pneumococcal infections (except meningitis): IM: 1.2 million units on day 1; may be repeated every 2 or 3 days until afebrile for 48 hours.

Streptococcal infections, group A: IM: 2.4 million units in a single dose. Note: Alternatively, 50% of the total dose can be administered on day 1 and 50% on day 3. For treatment of group A streptococcal pharyngitis in adults, penicillin G benzathine (Bicillin L-A) is preferred (IDSA [Shulman 2012]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Pneumococcal infections (except meningitis): Infants and Children: IM:

Bicillin C-R: 600,000 units on day 1; may repeat every 2 to 3 days until afebrile for 48 hours

Bicillin C-R 900/300: 1.2 million units on day 1; may repeat every 2 or 3 days until afebrile for 48 hours

Streptococcal infections, group A:

Infants, Children: IM:

Bicillin C-R:

<14 kg: 600,000 units in a single dose

14 to 27 kg: 900,000 units to 1.2 million units in a single dose

Bicillin C-R 900/300: 1.2 million units in a single dose

Children and Adolescents (>27 kg): IM:

Bicillin C-R: Refer to adult dosing.

Bicillin C-R 900/300: 1.2 million units in a single dose

Note (Bicillin C-R only): Alternatively, 50% of the total dose can be administered on day 1 and 50% on day 3.

Rheumatic fever, primary prevention (Bicillin C-R 900/300) (off-label use): Infants and Children 6 months to 12 years and Adolescents ≤14 years: IM: 1.2 million units as a single dose (Bass 1976; Gerber 2009). Note: The efficacy of this regimen for heavier adolescents is unknown.

Administration

IM: Administer by deep IM injection at a slow, steady rate in the dorsogluteal region (upper outer quadrant of the buttock) or ventrogluteal region (anterolateral thigh). When repeated doses are indicated, vary the injection site. Do not inject near an artery or a nerve; permanent neurological damage or gangrene may result. Do not mix with other IV solutions. Do not administer IV, intravascularly, or intra-arterially.

Storage

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.

Drug Interactions

Acemetacin: May increase the serum concentration of Penicillins. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). 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. Avoid combination

Dichlorphenamide: Penicillins may enhance the hypokalemic effect of Dichlorphenamide. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Methotrexate: Penicillins may increase the serum concentration of Methotrexate. 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. Monitor therapy

Nitisinone: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Pretomanid: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Probenecid: May increase the serum concentration of Penicillins. 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. Consider therapy modification

Teriflunomide: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Tetracyclines: May diminish the therapeutic effect of Penicillins. Monitor therapy

Tolvaptan: May increase the serum concentration of OAT1/3 Substrates. Management: Patients being treated with the Jynarque brand of tolvaptan should avoid concomitant use of OAT1/3 substrates. Concentrations and effects of the OAT1/3 substrate would be expected to increase with any combined use. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

May interfere with urinary glucose tests using cupric sulfate (Benedict's solution, Clinitest®); may inactivate aminoglycosides in vitro; positive Coombs' [direct], increased protein

Adverse Reactions

Also see individual agents.

<1%, postmarketing, and/or case reports: Central nervous system disease (Hoigne syndrome), Clostridioides difficile associated diarrhea

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactic/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. Use with caution in asthmatic patients. If a serious reaction occurs, treatment with supportive care measures and airway protection should be instituted immediately.
• Fibrosis and atrophy: Quadriceps femoris fibrosis and atrophy have been reported following repeated IM injections of penicillins into the anterolateral thigh.
• Methemoglobinemia: Has been reported with local anesthetics, including procaine; clinically significant methemoglobinemia requires immediate treatment along with discontinuation of the anesthetic and other oxidizing agents. Onset may be immediate or delayed (hours) after anesthetic exposure. Patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, exposure to oxidizing agents or their metabolites, or infants <6 months of age are more susceptible and should be closely monitored for signs and symptoms of methemoglobinemia (eg, cyanosis, headache, rapid pulse, shortness of breath, lightheadedness, fatigue).
• Procaine sensitivity: If there is a history of hypersensitivity to procaine, test with 0.1 mL of procaine 1% or 2% solution. If erythema, wheal, flare, or eruption occurs, patient may be sensitive to procaine; do not use penicillin G procaine in these patients. Treat sensitivity with supportive measures, including antihistamines.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including Clostridioides (formerly Clostridium) 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. Monitor renal function periodically, especially with high-dose or prolonged therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate administration: [US Boxed Warning]: Not for IV use; cardiopulmonary arrest and death have occurred from inadvertent IV administration. Do not mix with other IV solutions. Administer by deep IM injection only. Injection into or near an artery or nerve could result in severe neurovascular damage or permanent neurological damage or gangrene possibly requiring amputation, necrosis/sloughing at or surrounding the injection site, or other serious complications.
• Limitations of use: Not considered appropriate for the treatment of sexually transmitted diseases, including syphilis, gonorrhea, yaws, bejel, and pinta. When high, sustained serum levels are required, use alternative penicillin preparations.
• Choice of preparation: Penicillin G benzathine-penicillin G procaine (eg, Bicillin C-R) is not the same preparation as penicillin G procaine. Dispensing errors have occurred (CDC 2005).
• 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).

Monitoring Parameters

Hypersensitivity reactions with first dose, injection-site reactions, periodic renal and hematologic function tests with prolonged therapy

Pregnancy

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Maternal use of penicillins has generally not resulted in an increased risk of adverse fetal effects. See individual agents

Patient Education

What is this drug used for?

• It is used to treat bacterial infections.

Frequently reported side effects of this drug

• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bruising
• Bleeding
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Methemoglobinemia like blue or gray color of the lips, nails, or skin; abnormal heartbeat; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath
• Chills
• Sore throat
• Swelling
• Joint pain
• Severe dizziness
• Passing out
• Injection site irritation, lump, dark scab, or hard area
• Severe loss of strength and energy
• Numbness
• Tingling
• Weakness
• Clostridioides (formerly Clostridium) difficile (C. diff)-associated diarrhea like abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.