PENICILLIN G PROCAINE

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.
-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 procaine unless the condition being treated is life-threatening and amenable only to therapy with penicillin G procaine. 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 procaine immediately and consider alternative treatment.

Procaine can cause adverse reactions independently of penicillin G, especially with high doses. An immediate-onset, toxic reaction lasting 15-30 minutes also known as Hoigne's syndrome can occur in some individuals. Manifestations include anxiety, agitation, confusion, combativeness, depression, hallucinations, weakness, seizures, and 'fear of impending death'. The reaction is transient and supportive care is recommended. 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.

Intramuscular injection of penicillin G procaine 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 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 some reported gastrointestinal side effects of penicillin G therapy. Black or hairy tongue (tongue discoloration) have 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 procaine. 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.

Methemoglobinemia has been reported with local anesthetic use, such as procaine. Signs and symptoms of methemoglobinemia may occur immediately or may be delayed some hours after local anesthetic exposure and are characterized by cyanotic skin discoloration and abnormal coloration of the blood. Other symptoms may include headache, rapid heart rate, shortness of breath, dizziness, and drowsiness. Since methemoglobin concentrations may continue to rise, immediately discontinue penicillin G procaine to avoid serious central nervous system and cardiovascular adverse events including seizures, coma, arrhythmias, and death. Depending on the severity of symptoms, patients may require supportive care, such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

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 procaine is contraindicated in any patient with a history of a procaine hypersensitivity reaction. Patients with a history of sensitivity can be given a test dose of procaine intradermally (0.1 ml of a 1-2% procaine solution); development of erythema, wheal, flare, or eruption indicates procaine sensitivity and penicillin G procaine preparations should not be used.

Penicillin G procaine is for deep intramuscular injection only. Take care to avoid intravenous administration or intraarterial administration or injection into or near major peripheral nerves or blood vessels, since such injections may produce 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, such as penicillin G procaine, 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.

Methemoglobinemia has been reported with local anesthetic use, such as procaine. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), preexisting (congenital or idiopathic) methemoglobinemia, cardiac or pulmonary compromise (cardiac disease or pulmonary disease), neonates and infants younger than 6 months, and those with concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing methemoglobinemia. Monitor such patients closely for signs and symptoms of methemoglobinemia if a local anesthetic must be used. Signs of methemoglobinemia may occur immediately or may be delayed hours after exposure. Immediately discontinue the local anesthetic to avoid serious central nervous system and cardiovascular adverse events, as methemoglobin concentrations may continue to rise. Patients may require supportive care such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

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 procaine 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 procaine 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 procaine immediately and consider alternative treatment.

Description: Penicillin G procaine is an equimolar compound of procaine and penicillin G antibiotic for intramuscular use. It provides a tissue depot from which a plateau type of blood level is achieved that lasts over several hours. Procaine penicillin is indicated for the treatment of moderately severe infections such as group A streptococcal infections, syphilis, pneumonia, and for post-exposure to anthrax; however, this agent is generally not considered the drug of choice for most of these infections. Penicillin G procaine is FDA approved in pediatric patients as young as neonates.

NOTE: Penicillin G Procaine provides low, prolonged serum concentrations of penicillin G. If high sustained serum concentrations of penicillin G are required, aqueous penicillin G should be used.

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 sp., Bacillus anthracis, Clostridium sp., Corynebacterium diphtheriae, Erysipelothrix rhusiopathiae, Leptospira sp., Listeria monocytogenes, Neisseria meningitidis, Spirillum minus, Staphylococcus sp., Streptobacillus moniliformis, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci), 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.

For the treatment of moderately severe pneumococcal pneumonia, moderately severe to severe staphylococcal infections, and moderately severe to severe group A streptococcal (GAS) infections (tonsillitis, erysipelas, scarlet fever, upper respiratory tract infections, skin and skin structure infections):
Intramuscular dosage:
Infants and Children weighing less than 27 kg: 300,000 units IM once daily. For group A streptococcal (GAS) infections, treat for at least 10 days.
Children and Adolescents weighing 27 kg or more: 600,000 to 1.2 million units IM once daily. For group A streptococcal (GAS) infections, treat for at least 10 days.

For the adjunctive treatment of diphtheria and to prevent establishment of carrier state:
Intramuscular dosage:
Infants, Children, and Adolescents: 50,000 units/kg/dose IM once daily (Max: 1.2 million units/day) for 14 days as an adjunct to diphtheria antitoxin. The FDA-approved dose is 300,000 to 600,000 units IM once daily.

For postexposure anthrax prophylaxis:
Intramuscular dosage:
Infants, Children, and Adolescents: 25,000 units/kg/dose (Max: 1.2 million units/dose) IM twice daily for 60 days.

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:
Adolescents: Not recommended by guidelines. The FDA-approved dosage is 600,000 units IM once daily for 8 days.
-for the treatment of late latent (greater than 1 year duration) or tertiary syphilis:
Intramuscular dosage:
Adolescents: Not recommended by guidelines. The FDA-approved dosage is 600,000 units IM once daily for 10 to 15 days.
-for the treatment of neurosyphilis:
Intramuscular dosage:
Adolescents: 2.4 million units IM once daily plus probenecid for 10 to 14 days as an alternative when compliance can be ensured. Follow-up dosing with penicillin G benzathine for 1 to 3 weeks may be considered after completion to provide a comparable duration as treatment for late syphilis. The FDA-approved dosage is 600,000 units IM once daily for 10 to 15 days.
-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 the mother was treated properly before delivery.
Intramuscular dosage:
Neonates: 50,000 units/kg/dose IM once daily for 10 days as an alternative. If more than 1 day of therapy is missed, the entire course should be restarted.
Infants and Children: 50,000 units/kg/dose (Max: 2.4 million units/dose) IM once daily for 10 days may be considered during an aqueous penicillin G shortage. If more than 1 day of therapy is missed, the entire course should be restarted.

For diphtheria carriage eradication:
Intramuscular dosage:
Infants, Children, and Adolescents: 300,000 units IM once daily for 10 days.

For the treatment of yaws, pinta, and bejel:
-for the treatment of primary, secondary, or early latent (less than 1 year duration) yaws, pinta, and bejel:
Intramuscular dosage:
Adolescents: 600,000 units IM once daily for 8 days.
-for the treatment of late latent (greater than 1 year duration) or tertiary yaws, pinta, and bejel:
Intramuscular dosage:
Adolescents: 600,000 units IM once daily for 10 to 15 days.

For the treatment of inhalational anthrax:
Intramuscular dosage:
Infants, Children, and Adolescents: 25,000 units/kg/dose (Max: 1.2 million units/dose) IM twice daily for 60 days.

Maximum Dosage Limits:
-Neonates
50,000 units/kg/day IM.
-Infants
50,000 units/kg/day IM.
-Children
50,000 units/kg/day IM up to 2.4 million units/day IM.
-Adolescents
50,000 units/kg/day IM up to 2.4 million units/day IM.

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 procaine.

Intermittent hemodialysis
Penicillin G is removed during hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Penicillin G procaine 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.

The susceptibility interpretive criteria for penicillin are delineated by pathogen. The MICs are defined for Streptococcus pneumoniae in cases without meningitis as susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more. The MICs are defined for beta-hemolytic Streptococcus sp. as susceptible at 0.12 mcg/mL or less. The MICs are defined for Staphylococcus sp. as susceptible at 0.12 mcg/mL or less and resistant at 0.25 mcg/mL or more. The MICs are defined for Streptococcus sp. viridans group as susceptible at 0.12 mcg/mL or less, intermediate at 0.25 to 2 mcg/mL, and resistant at 4 mcg/mL or more.

Pharmacokinetics: Penicillin G procaine is administered by intramuscular injection. Approximately 60% of penicillin G is bound to serum protein. The highest drug concentrations are found in the kidneys with lesser amounts in the liver, skin, and intestines. Penicillin G penetrates into other tissues to a lesser degree with a very small amount found in the cerebral spinal fluid. Penicillin G is rapidly eliminated via renal tubular excretion. Approximately 60-90% of the dose is excreted in the urine within 24-36 hours..

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intramuscular Route
After intramuscular administration, a tissue depot is created at the site of IM injection and active drug is slowly released into the systemic circulation. Penicillin G serum concentrations are lower but more prolonged with penicillin G procaine compared to aqueous penicillin G administration. Compared with penicillin G benzathine, however, penicillin G procaine reaches higher serum concentrations but has less prolonged drug concentrations. Intramuscular administration of penicillin G procaine, results in penicillin serum concentrations which peak within 4 hours and slowly decrease over the next 15-20 hours.


-Special Populations
Pediatrics
Neonates
Renal clearance of penicillin is delayed in neonates due to, comparatively, decreased renal function. In a study of 25 neonates receiving penicillin G procaine at doses of 50,000 units/kg IM, the mean peak penicillin serum concentration at 4 hours after the dose was 17.1 +/- 6.3 mcg/ml. Serum penicillin concentrations of 2.1 +/- 0.98 mcg/mL were present at 24 hours after the administered dose. In a study of 7 neonates receiving penicillin G procaine at doses of 50,000 units/kg IM, the mean penicillin serum concentration at 2-12 hours after the dose was 7.4-8.8 mcg/ml in patients < 7 days with a mean serum concentration of 1.5 mcg/ml at 24 hours. Mean penicillin concentrations in the first 4 hours after the dose was 5-6 mcg/ml in patients > 7 days with a concentration of 0.4 mcg/ml at 25 hours.

Infants, Children, and Adolescents
At penicillin G procaine doses of 30 mg/kg IM (approximately 1000 units/mg), peak penicillin serum concentrations are approximately 9 mcg/ml in infants and children with a half-life of approximately 8 hours.

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 which is significantly delayed in patients with decreased renal function.