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Penicillin G Procaine

Medically reviewed by Last updated on Jul 10, 2020.


(pen i SIL in jee PROE kane)

Index Terms

  • APPG
  • Aqueous Procaine Penicillin G
  • Procaine Benzylpenicillin
  • Procaine Penicillin G
  • Wycillin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intramuscular:

Generic: 600,000 units/mL (1 mL, 2 mL)

Pharmacologic Category

  • Antibiotic, Penicillin


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.


IM: Slow


High distribution in kidneys, lesser amounts in liver, skin and intestines. Very small levels found in CSF.


Urine (60% to 90% as unchanged drug); renal clearance is delayed in neonates, young infants, and patients with impaired renal function

Time to Peak

Serum: Within 1 to 4 hours and can persist within the therapeutic range for 15 to 24 hours

Duration of Action

Therapeutic: 15 to 24 hours

Protein Binding


Use: Labeled Indications

Note: When high, sustained serum levels are required, use aqueous penicillin G, either IM or IV.

Diphtheria: As an adjunct to antitoxin for prevention of the carrier stage of diphtheria caused by susceptible Corynebacterium diphtheriae.

Erysipeloid: Treatment of erysipeloid caused by susceptible Erysipelothrix rhusiopathiae.

Fusospirochetosis: Treatment of fusospirochetosis (Vincent gingivitis and pharyngitis) in conjunction with dental care, and moderately severe infections of the oropharynx caused by susceptible fusiform bacilli and spirochetes.

Pneumococcal infection: Treatment of moderately severe infections of the respiratory tract caused by susceptible pneumococci.

Limitations of use: Severe pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, and arthritis of pneumococcal etiology are better treated with aqueous penicillin G during the acute stage.

Rat bite fever: Treatment of rat bite fever caused by susceptible Streptobacillus moniliformis and Spirillum minus organisms.

Streptococcal infections: Treatment of moderately severe to severe infections of the upper respiratory tract, skin and soft tissue infections, scarlet fever, and erysipelas caused by susceptible streptococci (group A, without bacteremia).

Limitations of use: Some streptococcal groups, including group D (enterococcus), are resistant. Aqueous penicillin is recommended for streptococcal infections with bacteremia.

Syphilis: Treatment of syphilis caused by susceptible Treponema pallidum. Note: Centers for Disease Control and Prevention guidelines only recommend penicillin G procaine, in combination with probenecid, as an alternative treatment for neurosyphilis (including ocular syphilis) (CDC [Workowski 2015]).

Yaws, bejel, and pinta: Treatment of yaws, bejel, and pinta caused by susceptible organisms.


Hypersensitivity to any penicillin or any component of the formulation.

Dosing: Adult

Usual dosage range: IM: 600,000 to 1 million units daily; higher doses may be needed for some indications (eg, diphtheria, neurosyphilis).

Indication-specific dosing:

Diphtheria, adjunctive therapy with antitoxin: IM: Patients >10 kg: 600,000 units every 12 hours for 14 days (including oral step-down therapy) (CDC 2015).

Neurosyphilis (including ocular syphilis) (alternative agent): IM: 2.4 million units once daily with concomitant probenecid for 10 to 14 days (CDC [Workowski 2015]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Although FDA approved for some indications, dosing may not be provided if current guidelines do not recommend use (eg, streptococcal or staphylococcal pneumonia or pharyngitis [AHA (Gerber 2009); IDSA (Bradley 2011); IDSA [Shulman 2012]).

General dosing, susceptible infection (mild to moderate) (Red Book [AAP 2015]): Infants, Children, and Adolescents: IM: 50,000 units/kg/day in divided doses every 12 to 24 hours; maximum daily dose: 1.2 million units/day.

Anthrax, inhalational (postexposure prophylaxis): Note: Although FDA approved, penicillin G procaine is not a preferred regimen (AAP [Bradley 2014]).

Infants, Children, and Adolescents: IM: 25,000 units/kg/dose every 12 hours; maximum dose: 1.2 million units/dose. Overall treatment duration should be 60 days. Available safety data suggest continued administration of penicillin G procaine for longer than 2 weeks may incur additional risk for adverse reactions. Clinicians may consider switching to effective alternative treatment for completion of therapy beyond 2 weeks.

Diphtheria infection, adjunctive therapy with antitoxin (CDC 2015):

Infants, Children, and Adolescents:

Patients ≤10 kg: IM: 300,000 units every 12 hours for 14 days (including oral step-down therapy).

Patients >10 kg: IM: 600,000 units every 12 hours for 14 days (including oral step-down therapy).


Congenital: Infants and Children: IM: 50,000 units/kg/day once daily for 10 days; maximum daily dose: 2.4 million units/day; if more than 1 day of therapy is missed, the entire course should be restarted (CDC [Workowski 2015]); in HIV-exposed/-positive patients, penicillin G procaine is not the preferred therapy due to poor CNS penetration (HHS [OI pediatric 2016]).

Neurosyphilis (including ocular or otic syphilis): HIV-exposed/-positive: Adolescents: IM: 2.4 million units once daily for 10 to 14 days; give in combination with probenecid (HHS [OI adult 2016]).


IM: Procaine suspension for deep IM injection only; rotate the injection site; do not administer IV, intravascularly, or intra-arterially since severe and/or permanent neurovascular damage may occur


Store at 2°C to 8°C (36°F to 46°F). Keep from freezing.

Drug Interactions

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

Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. 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: Avoid concomitant use of OAT1/3 substrates in patients receiving the Jynarque brand of tolvaptan. Concentrations and effects of the OAT1/3 substrate would be expected to increase with 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

Positive Coombs' [direct], false-positive urinary and/or serum proteins

Adverse Reactions

Frequency not defined.

<1%, postmarketing, and/or case reports: Anaphylaxis, central nervous system toxicity, Clostridioides difficile colitis, exfoliative dermatitis, hypersensitivity reaction, Jarisch-Herxheimer reaction, maculopapular rash, serum sickness-like reaction, skin rash, urticaria


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, and/or history of sensitivity to multiple allergens. Use with caution in asthmatic patients. If an allergic reaction occurs, discontinue therapy and institute appropriate supportive measures.

• 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 G6PD 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).

• Neurovascular damage: Avoid IV, intravascular, or intra-arterial administration since severe and/or permanent neurovascular damage (eg, transverse myelitis with permanent paralysis, gangrene requiring digit or proximal extremity amputation, necrosis and sloughing at and surrounding the injection site) may occur. These reactions have occurred following injection into the deltoid, thigh, or buttock areas. Other serious complications of suspected intravascular administration (eg, immediate distal and proximal pallor, mottling or cyanosis of the extremity around the injection site followed by bleb formation or severe edema requiring anterior and/or posterior compartment fasciotomy in the lower extremity) occur most often in infants and small children. If any evidence of blood supply compromise is noted, consult appropriate specialists promptly.

• Procaine neuropsychiatric reactions: Immediate toxic reactions (eg anxiety, confusion, agitation, depression, weakness, seizures, hallucinations, combativeness and expressed “fear of impending death”) have been reported. Mental disturbance reactions are more common in patients receiving a large single dose (eg 4.8 million units). Reactions are transient and last 15 to 30 minutes.

• Procaine sensitivity: If there is a history of hypersensitivity to procaine, test with 0.1 mL of 1% or 2% procaine 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 C. 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 severe renal impairment; dosage adjustment may be necessary.

• 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.

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 use: Do not use for the treatment of gonorrhea.

• Choice of preparation: Penicillin G procaine is not the same preparation as penicillin G benzathine-penicillin G procaine (eg, Bicillin C-R). 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, mental status post injection, periodic renal and hematologic function tests with prolonged therapy.

Pregnancy Considerations

Penicillin G crosses the placenta.

Maternal use of penicillins has generally not resulted in an increased risk of adverse fetal effects.

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; Heinonen 1977; Lamont 2014; Muanda 2017a; Muanda 2017b).

Penicillin G procaine may be used in the treatment of syphilis during pregnancy (CDC [Workowski 2015]). Untreated maternal syphilis can cause congenital syphilis, which is associated with bone deformities, neurologic impairment, stillbirth, or neonatal death (USPSTF 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 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, procaine penicillin is not a recommended agent in any of the penicillin regimens based on syphilis staging. 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 women 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 women. This reaction may induce early labor or fetal distress; however, it is not a reason to prevent or delay maternal therapy (CDC [Workowski 2015]).

Penicillin G procaine is also approved for the management of Bacillus anthracis; however, other agents are preferred for use in pregnant women (Meaney-Delman 2014).

Patient Education

What is this drug used for?

• It is used to treat bacterial infections.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Diarrhea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Bruising

• Bleeding

• Chills

• Swelling

• Joint pain

• Severe dizziness

• Passing out

• Anxiety

• Confusion

• Agitation

• Depression

• Severe loss of strength and energy

• Seizures

• Sensing things that seem real but are not

• Behavioral changes

• Numbness

• Tingling

• Weakness

Clostridioides (formerly Clostridium) difficile-associated diarrhea like stomach pain or cramps, very loose or watery stools, or bloody stools

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.