Penicillin G Procaine (Monograph)

Drug class: Natural Penicillins
VA class: AM110
Chemical name: [2S-(2α,5α,6β]-3,3-Dimethyl-7-oxo-6[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compd. with 2-(diethylamino)ethyl 4-aminobenzoate (1:1) monohydrate
Molecular formula: C₁₆H₁₈N₂O₄S•C₁₃H₂O•N₂O₂•H₂O
CAS number: 6130-64-9

Medically reviewed by Drugs.com on Sep 21, 2023. Written by ASHP.

Introduction

Penicillin G procaine, a natural penicillin, is a β-lactam antibiotic. The drug is the procaine monohydrate salt of penicillin G and is a long-acting formulation of penicillin G.

Uses for Penicillin G Procaine

Penicillin G procaine is used only for the treatment of moderately severe infections caused by organisms that are susceptible to the low, prolonged serum concentrations of penicillin G provided by IM penicillin G procaine. When high, sustained concentrations of penicillin G are required for the treatment of severe infections, parenteral penicillin G potassium or sodium should be used.

The fixed combinations of penicillin G benzathine and penicillin G procaine are used for the treatment of moderately severe to severe infections caused by susceptible streptococci (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections). The fixed combinations should not be used for initial treatment of severe pneumococcal infections, including pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, or arthritis. In addition, fixed combinations of penicillin G benzathine and penicillin G procaine should not be used for the treatment of syphilis, yaws, bejel, pinta, or gonorrhea.

Anthrax

IM penicillin G procaine is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following suspected or confirmed exposure to aerosolized Bacillus anthracis spores. Ciprofloxacin or doxycycline are the initial drugs of choice for postexposure prophylaxis following suspected or confirmed exposure to aerosolized anthrax spores, including exposures that occur in the context of biologic warfare or bioterrorism. If penicillin susceptibility is confirmed, consideration can be given to changing prophylaxis to a penicillin in infants and children, pregnant or lactating women, or when the drugs of choice are not tolerated or not available; however, oral amoxicillin or penicillin V usually is recommended.

IM penicillin G procaine is used for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible B. anthracis that occurs as the result of naturally occurring or endemic exposure to anthrax. If cutaneous anthrax occurs in the context of biologic warfare or bioterrorism, the initial drugs of choice are ciprofloxacin and doxycycline. If penicillin susceptibility is confirmed, consideration can be given to changing treatment to a penicillin in infants and children, pregnant or lactating women, or when the drugs of choice are not tolerated or not available; however, oral amoxicillin or penicillin V usually is recommended.

Syphilis

IM penicillin G procaine is used for the treatment of syphilis.

The US Centers for Disease Control and Prevention (CDC) and other clinicians state that IM penicillin G benzathine is the drug of choice for the treatment of primary syphilis (i.e., ulcer or chancre at infection site), secondary syphilis (i.e., manifestations that include, but are not limited to, rash, mucocutaneous lesions, and lymphadenopathy), and tertiary syphilis (i.e., cardiac syphilis, gummatous lesions, tabes dorsalis, and general paresis) in adults, adolescents, and children.

IM penicillin G benzathine also is the drug of choice for the treatment of latent syphilis (i.e., detected by serologic testing but lacking clinical manifestations), including both early latent syphilis (latent syphilis acquired within the preceding year) and late latent syphilis (i.e., all other cases of latent syphilis or syphilis of unknown duration) in all age groups.

For the treatment of neurosyphilis and otic or ocular syphilis, CDC and other clinicians state that IV penicillin G potassium or sodium is the drug of choice and IM penicillin G procaine (with oral probenecid) is an alternative if compliance can be ensured.

For the treatment of congenital syphilis, CDC recommends IV penicillin G potassium or sodium or IM penicillin G procaine in neonates with proven or highly probable congenital syphilis (i.e., abnormal physical examination consistent with congenital syphilis, serum quantitative nontreponemal serologic titer fourfold higher than the mother's titer, or positive darkfield test or polymerase chain reaction [PCR] of lesions or body fluids). CDC recommends IV penicillin G potassium or sodium, IM penicillin G procaine, or IM penicillin G benzathine in neonates with possible congenital syphilis (i.e., normal physical examination and serum quantitative nontreponemal serologic titer no more than fourfold higher than the mother's titer and the mother received a recommended treatment regimen less than 4 weeks before delivery; the mother was not treated or was inadequately treated, including treatment with erythromycin or any regimen not included in CDC recommendations; or there is no documentation that the mother received treatment).

Neonates with human immunodeficiency virus (HIV) infection who have congenital syphilis and HIV-infected children, adolescents, or adults who have neurosyphilis or primary, secondary, early latent, late latent, or tertiary syphilis should receive the same treatment regimens as those without HIV infection. Because serologic nonresponse and neurologic complications may be more frequent in HIV-infected individuals, close follow-up is essential in those coinfected with syphilis and HIV. In addition, careful neurologic examinations are indicated in all HIV-infected patients coinfected with syphilis.

There are no proven alternatives to penicillin G for the treatment of congenital syphilis in infants and children with known or suspected penicillin hypersensitivity and no proven alternatives to penicillin G for the treatment of any stage of syphilis in pregnant women with penicillin hypersensitivity; therefore, CDC recommends desensitization and treatment with the appropriate penicillin G preparation.

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin C-R, Bicillin C-R 900/300) should not be used for the treatment of any form of syphilis; inadvertent use of one of these fixed-combination preparations may not provide the sustained serum concentrations of penicillin G required for treatment of syphilis and could increase the risk of treatment failure and neurosyphilis, especially in HIV-infected patients.

For additional information regarding treatment of syphilis, the current CDC sexually transmitted diseases treatment guidelines available at [Web] should be consulted.

Penicillin G Procaine Dosage and Administration

Administration

Penicillin G procaine and fixed combinations containing penicillin G benzathine and penicillin G procaine are administered only by deep IM injection.

Special precaution should be taken to avoid inadvertent intravascular or intra-arterial administration of penicillin G procaine or fixed combinations of penicillin G benzathine and penicillin G procaine or injection into or near major peripheral nerves or blood vessels because this may result in severe and/or permanent neurovascular damage. (See Cautions: Adverse Effects.)

Fixed combinations containing penicillin G benzathine and penicillin G procaine must not be given IV or admixed with IV solutions because inadvertent IV administration of penicillin G benzathine has been associated with cardiorespiratory arrest and death.

IM Injection

Penicillin G procaine and fixed combinations containing penicillin G benzathine and penicillin G procaine are provided in prefilled syringes and the appropriate dose should be administered undiluted according to the manufacturer's directions.

In adults, IM injections of penicillin G procaine or fixed combinations of penicillin G benzathine and penicillin G procaine generally should be made deeply into the gluteus maximus (upper outer quadrant of the buttock) or into the midlateral thigh. In neonates, infants, and small children, IM injections of these preparations should be given preferably into the midlateral muscles of the thigh.

IM injections of penicillin G procaine or fixed combinations of penicillin G benzathine and penicillin G procaine should be made at a slow, steady rate to avoid blockage of the needle.

When the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin C-R) is used, the manufacturer states that the dose usually is given at a single session using multiple IM sites; alternatively, if compliance regarding the return visit is ensured, the total dose can be divided and half given on day 1 and half on day 3.

When repeated doses are given, IM injection sites should be varied. Repeated IM injection into the anterolateral thigh, especially in neonates and infants, should be avoided since quadriceps femoris fibrosis and atrophy may occur.

Dosage

Dosage of penicillin G procaine usually is expressed in terms of penicillin G units, but also has been expressed as mg of penicillin G.

Dosage of the fixed combinations containing penicillin G benzathine and penicillin G procaine (Bicillin C-R, Bicillin C-R 900/300) usually is expressed in terms of the total (sum) of penicillin G units of penicillin G benzathine and penicillin G units of penicillin G procaine.

Pediatric Dosage

General Pediatric Dosage

The American Academy of Pediatrics (AAP) states that the usual dosage of IM penicillin G procaine in neonates 28 days of age or younger is 50,000 units/kg once every 24 hours.

For the treatment of mild to moderate infections in pediatric patients beyond the neonatal period, AAP states that the usual dosage of IM penicillin G procaine is 50,000 units/kg daily given in 1 or 2 divided doses. AAP states that IM penicillin G procaine is inappropriate for the treatment of severe infections.

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin C-R) is used in pediatric patients beyond the neonatal period, AAP recommends a single IM dose of 600,000 penicillin G units in those weighing less than 14 kg and a single IM dose of 900,000 to 1.2 million penicillin G units in those weighing 14–27 kg. If this fixed-combination preparation is used in those weighing 27 kg or more, AAP recommends a single dose of 2.4 million penicillin G units.

Staphylococcal Infections

If IM penicillin G procaine is used for the treatment of moderately severe skin and skin structure infections caused by susceptible staphylococci, the manufacturer recommends a dosage of 300,000 units daily in children weighing less than 27 kg and 600,000 to 1 million units daily in others. Because of the high incidence of resistant strains, in vitro culture and susceptibility testing should be performed when treating suspected staphylococcal infections.

Streptococcal Infections

If IM penicillin G procaine is used for the treatment of infections caused by Streptococcus pyogenes (group A β-hemolytic streptococci; GAS), such as moderately severe to severe upper respiratory tract infections, tonsillitis, scarlet fever, erysipelas, and skin and skin structure infections, the manufacturer recommends a dosage of 300,000 units daily for at least 10 days in children weighing less than 27 kg and 600,000 to 1 million units daily for at least 10 days in others.

If IM penicillin G procaine is used for the treatment of moderately severe, uncomplicated respiratory tract infections (pneumonia) caused by susceptible S. pneumoniae, the manufacturer recommends a dosage of 300,000 units daily in children weighing less than 27 kg and 600,000 to 1 million units daily in others.

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin C-R) is used for the treatment of moderately severe to severe infections caused by susceptible S. pyogenes (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections), the manufacturer recommends that children weighing less than 13.6 kg receive a single IM dose of 600,000 penicillin G units, those weighing 13.6–27.2 kg receive a single IM dose of 900,000 to 1.2 million penicillin G units, and those weighing more than 27.2 kg receive a single IM dose of 2.4 million penicillin G units. If this fixed-combination preparation is used for the treatment of moderately severe infections caused by susceptible S. pneumoniae (pneumonia, otitis media), the manufacturer recommends that pediatric patients receive an IM dose of 600,000 penicillin G units once every 2 or 3 days until the patient has been afebrile for 48 hours. Other penicillins are recommended for severe S. pneumoniae infections (e.g., pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, arthritis).

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin C-R 900/300) is used for the treatment of moderately severe to severe infections caused by susceptible S. pyogenes (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections), the manufacturer states that a single IM dose of 1.2 million penicillin G units usually is sufficient in pediatric patients. If this fixed-combination preparation is used for the treatment of moderately severe infections caused by susceptible S. pneumoniae (pneumonia, otitis media), the manufacturer recommends that pediatric patients receive an IM dose of 1.2 million penicillin G units once every 2 or 3 days until the patient has been afebrile for 48 hours. Other penicillins are recommended for severe S. pneumoniae infections (e.g., pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, arthritis).

Anthrax

If IM penicillin G procaine is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis spores, the manufacturer recommends that children receive 25,000 units/kg (up to 1.2 million units) every 12 hours. Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that the total duration of anti-infective prophylaxis should be at least 60 days. The manufacturer states that safety data for penicillin G procaine administered at the dosage recommended for inhalational anthrax (postexposure) supports a duration of 2 weeks or less, and clinicians must consider the risks versus benefits of administering IM penicillin G procaine for longer than 2 weeks or switching to an appropriate alternative anti-infective.

If IM penicillin G procaine is used for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible B. anthracis that occurs as the result of naturally occurring or endemic anthrax exposure, some experts recommend a dosage of 25,000–50,000 units/kg daily (single or 2 divided doses daily) in children weighing less than 20 kg. Although 3–10 days of anti-infective therapy may be adequate for the treatment of mild, uncomplicated cutaneous anthrax that occurs as the result of naturally occurring or endemic exposures to anthrax, some experts recommend a duration of 7–14 days. CDC and other experts state that anti-infectives should be continued for 60 days if cutaneous anthrax occurred as the result of exposure to aerosolized B. anthracis spores in the context of biologic warfare or bioterrorism since the possibility of inhalational anthrax would also exist. Although anti-infective therapy may limit the size of the cutaneous anthrax lesion and it usually becomes sterile within the first 24 hours of treatment, the lesion will still progress through the black eschar stage despite effective treatment.

Diphtheria

When IM penicillin G procaine is used as an adjunct to diphtheria antitoxin (not commercially available in the US, but may be available from CDC) for the treatment of diphtheria caused by Corynebacterium diphtheriae, the manufacturer recommends a dosage of 300,000–600,000 units daily. CDC recommends a 14-day regimen of IM penicillin G procaine given in a dosage of 300,000 units daily in those weighing 10 kg or less and 600,000 units daily in those weighing more than 10 kg for adjunctive treatment of diphtheria. Patients usually are no longer contagious 48 hours after initiation of anti-infective therapy. Eradication of C. diphtheriae should be confirmed 24 hours after completion of treatment by 2 consecutive negative cultures taken 24 hours apart.

If IM penicillin G procaine is used to eliminate the diphtheria carrier state in identified carriers of toxigenic C. diphtheriae, the manufacturer recommends a dosage of 300,000 units daily for 10 days. CDC and AAP recommend IM penicillin G benzathine if a penicillin G preparation is used for elimination of the diphtheria carrier state. Follow-up cultures should be obtained at least 2 weeks after treatment of diphtheria carriers; if cultures are positive, a 10-day course of oral erythromycin should be given and additional follow-up cultures obtained.

Syphilis

For the treatment of proven or highly probable congenital syphilis in neonates (see Uses: Syphilis), CDC states that IM penicillin G procaine should be given in a dosage of 50,000 units/kg once daily for 10 days. If more than 1 day of treatment is missed in such neonates, the entire course of treatment should be restarted. If IM penicillin G procaine is used in neonates with possible congenital syphilis (see Uses: Syphilis), CDC recommends a dosage of 50,000 units/kg once daily for 10 days.

CDC recommends that treatment of syphilis diagnosed in infants and children 1 month of age or older should be managed by a pediatric infectious disease specialist and that CSF should be examined in those with latent syphilis.

The manufacturer states that children older than 12 years of age with primary, secondary, or latent syphilis with a negative CSF test for syphilis may receive IM penicillin G procaine in a dosage of 600,000 units daily for 8 days (total dosage 4.8 million units) and those with tertiary or latent syphilis with a positive CSF examination or no CSF examination may receive 600,000 units of daily for 10–15 days (total dosage 6–9 million units). CDC and others state that IM penicillin G benzathine is the drug of choice for the treatment of primary, secondary, tertiary, and latent syphilis.

If IM penicillin G procaine is used as an alternative for the treatment of syphilis in adolescents 10–19 years of age, some experts state that those with early syphilis (primary, secondary, or early latent syphilis) can receive a dosage of 1.2 million units once daily for 10–14 days and those with late latent syphilis or syphilis of unknown duration can receive 1.2 million units once daily for 20 days.

Neonates with human immunodeficiency virus (HIV) infection who have congenital syphilis and HIV-infected children and adolescents with any stage of syphilis should receive the same treatment regimens recommended for those without HIV infection.

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin C-R, Bicillin C-R 900/300) should not be used for the treatment of any form of syphilis.

Adult Dosage

Staphylococcal Infections

If IM penicillin G procaine is used for the treatment of moderately severe to severe skin and skin structure infections caused by susceptible staphylococci, the manufacturer recommends that adults receive a dosage of 600,000 to 1 million units daily. Because of high incidence of resistant strains, in vitro culture and susceptibility testing should be performed when treating suspected staphylococcal infections.

Streptococcal Infections

If IM penicillin G procaine is used for the treatment of infections caused by susceptible S. pyogenes (group A β-hemolytic streptococci; GAS), such as moderately severe to severe upper respiratory tract infections, tonsillitis, pharyngitis, scarlet fever, erysipelas, and skin and skin structure infections, the manufacturer recommends that adults receive a dosage of 600,000 to 1 million units daily for at least 10 days.

The manufacturer states that bacterial endocarditis caused by extremely susceptible S. pyogenes may be treated with an IM penicillin G procaine dosage of 600,000 to 1 million units daily. AHA recommends IV penicillin G potassium or sodium if a penicillin G preparation is used for the treatment of endocarditis.

If IM penicillin G procaine is used for the treatment of moderately severe, uncomplicated respiratory tract infections (pneumonia) caused by susceptible S. pneumoniae, the manufacturer recommends that adults receive a dosage of 600,000 to 1 million units daily.

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin C-R) is used for the treatment of moderately severe to severe infections caused by susceptible S. pyogenes (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections), the manufacturer recommends that adults receive a single IM dose of 2.4 million penicillin G units. If this fixed-combination preparation is used for the treatment of moderately severe infections caused by susceptible S. pneumoniae (pneumonia, otitis media) in adults, the manufacturer recommends an IM dosage of 1.2 million penicillin G units given once every 2 or 3 days until the patient has been afebrile for 48 hours. Other penicillins are recommended for severe S. pneumoniae infections (e.g., pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, arthritis).

Anthrax

If IM penicillin G procaine is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following exposure to aerosolized B. anthracis spores, the manufacturer recommends that adults receive 1.2 million units every 12 hours. Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, CDC and other experts recommend that the total duration of anti-infective prophylaxis should be at least 60 days. The manufacturer states that safety data for IM penicillin G procaine administered at the dosage recommended for inhalational anthrax (postexposure) supports a duration of 2 weeks or less, and clinicians must consider the risks versus benefits of administering penicillin G procaine for longer than 2 weeks or switching to an appropriate alternative anti-infective.

If IM penicillin G procaine is used for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible B. anthracis in adults, the manufacturer recommends a dosage of 600,000 to 1 million units daily. Some experts recommend that adults receive a dosage of 600,000 to 1.2 million units every 12–24 hours for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible B. anthracis that occurs as the result of naturally occurring or endemic exposure to anthrax. Although 3–10 days of anti-infective therapy may be adequate for the treatment of mild, uncomplicated cutaneous anthrax that occurs as the result of naturally occurring or endemic exposures to anthrax, some experts recommend a duration of 7–14 days. CDC and other experts state that anti-infectives should be continued for 60 days if cutaneous anthrax occurred as the result of exposure to aerosolized B. anthracis spores since the possibility of inhalational anthrax would also exist. Although anti-infective therapy may limit the size of the cutaneous anthrax lesion and it usually becomes sterile within the first 24 hours of treatment, the lesion will still progress through the black eschar stage despite effective treatment.

Diphtheria

When IM penicillin G procaine is used as an adjunct to diphtheria antitoxin (not commercially available in the US, but may be available from CDC) for the treatment of diphtheria caused by C. diphtheriae, the manufacturer recommends a dosage of 300,000–600,000 units daily. CDC recommends a 14-day regimen of IM penicillin G procaine given in a dosage of 600,000 units daily in those weighing more than 10 kg for adjunctive treatment of diphtheria. Patients usually are no longer contagious 48 hours after initiation of anti-infective therapy. Eradication of C. diphtheriae should be confirmed 24 hours after completion of treatment by 2 consecutive negative cultures taken 24 hours apart.

If IM penicillin G procaine is used to eliminate the diphtheria carrier state in identified carriers of toxigenic C. diphtheriae, the manufacturer recommends a dosage of 300,000 units daily for 10 days. CDC and AAP recommend IM penicillin G benzathine if a penicillin G preparation is used for elimination of the diphtheria carrier state. Follow-up cultures should be obtained at least 2 weeks after treatment of diphtheria carriers; if cultures are positive, a 10-day course of oral erythromycin should be given and additional follow-up cultures obtained.

Erysipeloid

If IM penicillin G procaine is used in the treatment of erysipeloid caused by Erysipelothrix rhusiopathiae, the manufacturer recommends a dosage of 600,000 to 1 million units daily.

Necrotizing Ulcerative Gingivitis

If IM penicillin G procaine is used for the treatment of moderately severe infections of the oropharynx caused by Fusobacterium, including Vincent’s gingivitis and pharyngitis, the manufacturer recommends a dosage of 600,000 to 1 million units daily.

Rat-Bite Fever

For the treatment of rat-bite fever caused by Streptobacillus moniliformis (erythema arthriticum epidemicum, Haverhill fever) or Spirillum minus (sodoku), the manufacturer recommends that IM penicillin G procaine be given in a dosage of 600,000 to 1 million units daily. Although IM penicillin G procaine has been given in a dosage of 600,000 units every 12 hours for 10–14 days for the treatment of rat-bite fever, CDC and some clinicians state that IV penicillin G potassium or sodium is preferred.

Syphilis

The manufacturer states that adults with primary, secondary, or latent syphilis with a negative CSF test for syphilis may receive IM penicillin G procaine in a dosage of 600,000 units daily for 8 days (total dosage 4.8 million units) and that those with tertiary syphilis or latent syphilis with a positive CSF examination or no CSF examination may receive 600,000 units daily for 10–15 days (total dosage 6–9 million units). CDC and others state that IM penicillin G benzathine is the drug of choice for the treatment of primary, secondary, tertiary, and latent syphilis in adults.

If IM penicillin G procaine is used as an alternative for the treatment of syphilis in adults, some experts state that those with early syphilis (primary, secondary, or early latent syphilis) can receive a dosage of 1.2 million units once daily for 10–14 days and those with late latent syphilis or syphilis of unknown duration can receive 1.2 million units once daily for 20 days.

For the treatment of neurosyphilis in adults when compliance with the regimen can be ensured (see Uses: Syphilis), CDC recommends that IM penicillin G procaine be given in a dosage of 2.4 million units once daily for 10–14 days in conjunction with oral probenecid (500 mg every 6 hours for 10–14 days). Some clinicians recommend that the penicillin G procaine regimen be followed by a regimen of IM penicillin G benzathine (2.4 million units once weekly for up to 3 weeks).

HIV-infected adults with any stage of syphilis should receive the same treatment regimens recommended for those without HIV infection.

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin C-R, Bicillin C-R 900/300) should not be used for the treatment of any form of syphilis.

Yaws, Pinta, and Bejel

The manufacturer states that the usual dosage of IM penicillin G procaine for the treatment of yaws, pinta, or bejel is the same as that recommended for the corresponding stage of syphilis.

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin C-R, Bicillin C-R 900/300) should not be used for the treatment of yaws, pinta, or bejel.

Cautions for Penicillin G Procaine

Adverse Effects

Adverse effects reported with penicillin G procaine are similar to those reported with other natural penicillins.

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported with penicillins. Rash (maculopapular), exfoliative dermatitis, urticaria, laryngeal edema, fever, eosinophilia, other serum sickness-like reactions (e.g., chills, fever, edema, arthralgia, prostration), and anaphylaxis (including shock and death) have been reported with penicillin G. Fever and eosinophilia may frequently be the only reaction observed.

Jarisch-Herxheimer reactions have been reported in patients receiving IM penicillin G procaine for the treatment of syphilis.

Immediate toxic reactions to procaine have been reported rarely with IM penicillin G procaine, especially when a large single dose (4.8 million penicillin G units) was administered. These reactions may be manifested by mental disturbances (anxiety, confusion, agitation, depression, weakness, seizures, hallucinations, combativeness, fear of impending death) and usually are transient (lasting about 15–30 minutes). A small percentage of the population is hypersensitive to procaine, and sensitivity reactions to IM penicillin G procaine have been reported. (See Cautions: Precautions and Contraindications.)

Inadvertent intravascular administration (including inadvertent direct intra-arterial injection or injection immediately adjacent to arteries) of penicillin G procaine or fixed combinations of penicillin G benzathine and penicillin G procaine has resulted in severe neurovascular damage (e.g., transverse myelitis with permanent paralysis, gangrene requiring amputation of digits and more proximal portions of extremities, necrosis and sloughing at and surrounding the injection site). These severe effects have been reported following injections into the buttock, thigh, and deltoid areas. Other serious complications of suspected intravascular administration include immediate pallor, mottling, or cyanosis of the extremity (both distal and proximal to the injection site), followed by bleb formation or severe edema requiring anterior and/or posterior compartment fasciotomy in the lower extremity. These severe effects and complications have occurred most often in infants and small children.

Precautions and Contraindications

Penicillin G procaine and fixed combinations of penicillin G benzathine and penicillin G procaine are contraindicated in patients hypersensitive to any penicillin or to procaine.

Penicillin G procaine shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed.

Prior to administration of penicillin G procaine or a fixed combination of penicillin G benzathine and penicillin G procaine, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics, including cephalosporins and cephamycins.

Hypersensitivity reactions to penicillins are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Penicillin G procaine and fixed combinations of penicillin G benzathine and penicillin G procaine should be used with caution in individuals with a history of clinically important allergies and/or asthma.

If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate therapy instituted as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).

If use of penicillin G procaine or a fixed combination containing penicillin G procaine is being considered in a patient with a history of procaine sensitivity, a test dose of procaine (0.1 mL of a 1–2% solution of procaine) should be administered intradermally prior to IM administration of full doses of penicillin G procaine or a fixed combination containing penicillin G procaine. Development of erythema or a wheal, flare, or eruption at the intradermal test site indicates procaine sensitivity and the patient should not receive a preparation containing penicillin G procaine. If a hypersensitivity reaction to procaine occurs, it should be treated by usual methods; antihistamines may be beneficial and barbiturates may be indicated if seizures occur.

Special precaution should be taken to avoid IV, intravascular, or intra-arterial administration or injection of penicillin G procaine or fixed combinations containing the drug into or near major peripheral nerves or blood vessels since inadvertent intravascular or intra-arterial injection may produce severe and/or permanent neurovascular damage. In addition, inadvertent IV administration of preparations containing penicillin G benzathine has been associated with cardiorespiratory arrest and death. If evidence of compromise of blood supply occurs at or proximal or distal to the site of injection, an appropriate specialist should be consulted immediately.

Renal and hematologic systems should be evaluated periodically during prolonged therapy with penicillin G procaine or a fixed combination containing penicillin G benzathine and penicillin G procaine, particularly if high dosage is used. In such situations, use of penicillin G procaine for longer than 2 weeks may be associated with an increased risk of neutropenia and an increased incidence of serum sickness-like reactions.

Pediatric Precautions

Renal clearance of penicillin G may be delayed in neonates and young infants because of incompletely developed renal function.

Geriatric Precautions

Clinical studies of penicillin G procaine or penicillin G benzathine did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients. Other clinical experience has not identified differences in responses between geriatric and younger patients.

Penicillin G is substantially eliminated by the kidneys and the risk of adverse effects may be greater in those with impaired renal function. Because geriatric patients are more likely to have reduced renal function, dosage should be selected with caution, usually starting at the low end of the dosage range, and renal function monitoring may be useful.

Pregnancy and Lactation

Pregnancy

Reproduction studies evaluating penicillin G in mice, rats, and rabbits have not revealed evidence of impaired fertility or harm to the fetus. Although experience with use of penicillins during pregnancy has not shown any evidence of adverse effects on the fetus, there are no adequate or controlled studies using penicillin G procaine in pregnant women.

Some clinicians state that IM penicillin G procaine is considered low risk and safe for use during pregnancy. The drug is included in the US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of syphilis during pregnancy.

The manufacturers state that penicillin G procaine and fixed combinations containing penicillin G benzathine and penicillin G procaine should be used during pregnancy only when clearly needed.

Lactation

Penicillin G is distributed into milk. Some clinicians state that IM penicillin G procaine usually is considered compatible with breast-feeding. The manufacturers and others state that penicillin G procaine and fixed combinations containing penicillin G benzathine and penicillin G procaine should be used with caution in nursing women.

Spectrum

Based on its spectrum of activity, penicillin G procaine is classified as a natural penicillin.

Penicillin G Procaine Pharmacokinetics

Absorption

Because penicillin G procaine is relatively insoluble, IM administration of the drug provides a tissue depot from which the drug is slowly absorbed and hydrolyzed to penicillin G. IM administration of penicillin G procaine results in serum concentrations of penicillin G that are generally more prolonged, but lower, than those attained with an equivalent IM dose of penicillin G potassium or sodium.

Following IM administration of a single dose of penicillin G procaine in adults or neonates, peak serum penicillin G concentrations are attained in 1–4 hours and the drug is usually detectable in serum for 1–2 days; however, penicillin G may be detectable in serum for up to 5 days (depending on the dose). In general, increasing the dose of penicillin G procaine to more than 600,000 units tends to prolong the duration of penicillin G serum concentrations rather than increase peak serum concentrations.

Following a single IM dose of a fixed combination containing 1.2 million penicillin G units (i.e., 600,000 units as penicillin G benzathine and 600,000 units as penicillin G procaine; Bicillin C-R) in adults, peak blood penicillin G concentrations were 2.1–2.6 units/mL within 3 hours and blood concentrations averaged 0.75 units/mL at 12 hours, 0.28 units/mL at 24 hours, and 0.04 units/mL at 7 days.

Following a single IM dose of a fixed combination containing 1.2 million penicillin G units (i.e., 900,000 units as penicillin G benzathine and 300,000 units as penicillin G procaine; Bicillin C-R 900/300) in patients weighing 45–64 kg, average blood penicillin G concentrations were 0.24 units/mL at 24 hours, 0.039 units/mL at 7 days, and 0.024 units/mL at 10 days after the dose.

In children weighing 11.9–22.6 kg, IM administration of a single dose of a fixed combination containing 1.2 million penicillin G units (900,000 units as penicillin G benzathine and 300,000 units as penicillin G procaine) resulted in peak serum penicillin G concentrations that occurred 1 hour after the dose and averaged 3.9 mcg/mL. Serum penicillin G concentrations in these children ranged from 2.5–5.5, 2.5–5.5, 0.7–3.7, and 0.17–0.48 mcg/mL at 1, 2, 4, and 24 hours, respectively, after the dose and from 0.08–0.12, 0.01–0.09, and 0–0.1 mcg/mL at 5, 10, and 18 days, respectively, after the dose.

In a study in neonates younger than 1 week of age with congenital syphilis who received a penicillin G procaine dosage of 50,000 units/kg IM once daily for 7 days, serum penicillin G concentrations averaged 7.4–8.8 mcg/mL 2–12 hours after a dose and 1.5 mcg/mL 24 hours after a dose in neonates younger than 1 week of age. In neonates older than 1 week of age who received the same dosage of penicillin G procaine, serum penicillin G concentrations averaged 5–6 mcg/mL during the first 4 hours after administration of a dose and 0.4 mcg/mL 24 hours after a dose. In another study in neonates who received a single IM penicillin G procaine dose of 50,000 units/kg, peak serum concentrations of penicillin G occurred 4 hours after the dose and ranged from 7.7–41.9 mcg/mL; serum concentrations of the drug ranged from 0.2–5.8 mcg/mL 24 hours after the dose.

Distribution

Following IM administration of penicillin G procaine, penicillin G is widely distributed throughout the body in varying amounts. Highest concentrations generally are attained in the kidneys, with lower amounts in the liver, skin, and intestines.

Minimal concentrations of penicillin G are generally attained in CSF following IM administration of penicillin G procaine in patients with uninflamed meninges. Higher penicillin G concentrations are attained in CSF when the meninges are inflamed or when oral probenecid is administered concomitantly. The minimum treponemicidal concentration of penicillin G is generally defined as 0.03 units/mL or 0.02 mcg/mL. In one study, CSF concentrations of penicillin G were undetectable to 0.6% of concurrent serum concentrations in patients receiving IM penicillin G procaine in a dosage of 600,000 units once daily without probenecid; however, CSF concentrations of the drug were 2.1–6.6% of concurrent serum concentrations in patients receiving 600,000 units IM once daily with concomitant oral probenecid (500 mg every 6 hours). In a study in adults following IM administration of penicillin G procaine in a dosage of 2.4 million units once daily with oral probenecid (500 mg every 6 hours), CSF concentrations of penicillin G ranged from 0.12–0.6 mcg/mL in specimens obtained 3–3.5 hours after a dose on the third or fourth day of therapy. In another study in adults with syphilis who received IM penicillin G procaine in a dosage of 2.4 million units once daily with oral probenecid (500 mg every 6 hours), CSF penicillin G concentrations ranged from 0.07–1.5 mcg/mL in specimens obtained 2–10 hours after a dose on the second through ninth day of therapy; concurrent serum penicillin G concentrations ranged from 6.3–7.9 mcg/mL.

In a study in neonates younger than 3 days of age who received a single IM penicillin G procaine dose of 10,000 units/kg, penicillin G concentrations in CSF 4 hours after the dose averaged 0.06 mcg/mL and concurrent serum concentrations averaged 6.1 mcg/mL. IM administration of a single penicillin G procaine dose of 50,000 units/kg in these neonates resulted in CSF concentrations averaging 0.14 mcg/mL 4 hours after the dose and concurrent serum concentrations averaging 13.2 mcg/mL. In another study in neonates who received a single penicillin G procaine dose of 50,000 units/kg, peak CSF concentrations of penicillin G occurred 12 hours after the dose and ranged from 0.09–1.98 mcg/mL; CSF concentrations of the drug 24 hours after the dose ranged from 0.03–0.27 mcg/mL.

Penicillin G is about 60% bound to serum proteins.

Penicillin G crosses the placenta and is distributed into milk.

Elimination

Following IM administration of penicillin G procaine, the drug is slowly absorbed and hydrolyzed to penicillin G and elimination of penicillin G in urine continues over a prolonged period of time. Penicillin G and its metabolites are excreted in urine mainly by tubular secretion.

Concurrent administration of oral probenecid increases and prolongs serum penicillin G concentrations by decreasing the apparent volume of distribution and slowing the rate of excretion by competitively inhibiting renal tubular secretion of penicillin.

The serum half-life of penicillin G may be prolonged in patients with impaired renal function.

Renal clearance of penicillin G is delayed in neonates and young infants.

Renal clearance of penicillin G may be increased in pregnant women during the second and third trimesters.

Chemistry and Stability

Chemistry

Penicillin G procaine is a natural penicillin. The drug is the procaine monohydrate salt of penicillin G which is prepared by reacting equimolar amounts of penicillin G sodium or potassium and procaine hydrochloride. Penicillin G procaine is hydrolyzed in vivo to penicillin G and is frequently referred to as a long-acting, depot, or repository form of penicillin G.

Penicillin G procaine occurs as white crystals or a white, microcrystalline powder. The drug is slightly soluble in water. Potency of penicillin G procaine generally is expressed in terms of penicillin G units, but also has been expressed as mg of penicillin G.

Commercially available penicillin G procaine sterile suspension for injection is a viscous, opaque suspension of the drug in sterile water for injection. The IM suspension is buffered with sodium citrate and contains methylparaben and propylparaben as preservatives, povidone, lecithin, and carboxymethylcellulose.

Penicillin G procaine also is commercially available in fixed combination with penicillin G benzathine as a viscous, opaque, aqueous suspension for IM injection. Each 2 mL of fixed-combination suspension contains the equivalent of 1.2 million units of penicillin G in a formulation containing the equivalent of 600,000 units of penicillin G as the benzathine salt and 600,000 units of penicillin G as the procaine salt (Bicillin C-R) or a formulation containing the equivalent of 900,000 units of penicillin G as the benzathine salt and 300,000 units of penicillin G as the procaine salt (Bicillin C-R 900/300).

Stability

Commercially available penicillin G procaine suspension for IM injection should be stored at 2–8°C; freezing should be avoided.

The fixed combinations of penicillin G benzathine and penicillin G procaine for IM injection should be stored at 2–8°C; freezing should be avoided.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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