INDICATIONS AND USAGE

Therapy

Penicillin G Sodium for Injection, USP is indicated in the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below. Appropriate culture and susceptibility tests should be done before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to penicillin G. Therapy with Penicillin G Sodium for Injection, USP may be initiated before results of such tests are known when there is reason to believe the infection may involve any of the organisms listed below, however, once these results become available, appropriate therapy should be continued.

Clinical Indication	Infecting Organism
Septicemia, empyema, pneumonia, pericarditis, endocarditis, meningitis	Streptococcus pyogenes (group A β-hemolytic streptococcus), other β-hemolytic streptococci including groups C, H, G, L and M, Streptococcus pneumoniae and Staphylococcus species (non- penicillinase producing strains)
Anthrax	Bacillus anthracis
Actinomycosis (cervico- facial disease and thoracic and abdominal disease)	Actinomyces Israelil
Botulism (adjunctive therapy to antitoxin), gas gangrene, and tetanus (adjunctive therapy to human tetanus immune globulin)	Clostridium species
Diphtheria (adjunctive therapy to antitoxin and prevention of the carrier state)	Corynebacterium diphtheriae
Erysipelothrix endocarditis	Erysipelothrix rhusiopthiae
Fusospirochetosis (severe infections of the oropharynx [Vincent’s], lower respiratory tract and genital area)	Fusobacterium species and spirochetes
Listeria infections including meningitis and endocarditis	Listeria monocytogenes
Pasteurella infections including bacteremia and meningitis	Pasteurella multocida
Haverhill fever	Streptobacillus moniliformis
Rat-bite fever	Spirillum minus or Streptobacillus moniliformis
Disseminated gonococcal infections	Neisseria gonorrhoeae (penicillin-susceptible)
Syphilis (congenital and neurosyphilis)	Treponema pallidum
Meningococcal meningitis and/or septicemia	Neisseria meningitidis
Gram-negative bacillary infections (bacteremias)	Escherichia coli, Enterobacter aerogenes, Alcaligenes faecalis, salmonella, shigella and Proteus mirabilis, Penicillin G is not the drug of choice in the treatment of gram-negative bacillary infections.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of penicillin G sodium and other antibacterial drugs, penicillin G sodium should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

A history of hypersensitivity (anaphylactic) reaction to any penicillin is a contraindication.

ADVERSE REACTIONS

Body as a Whole

The Jarisch-Herxheimer reaction is a systemic reaction, that may occur after the initiation of penicillin therapy in patients with syphilis or other spirochetal infections (i.e., Lyme disease and Relapsing fever). The reaction begins one to two hours after initiation of therapy and disappears within 12 to 24 hours. It is characterized by fever, chills, myalgias, headache, exacerbation of cutaneous lesions, tachycardia, hyperventiliation, vasodilation with flushing and mild hypotension. The pathogenesis of the Herxheimer reaction may be due to the release from the spirochaete of host stable pyrogen.

Hypersensitivity Reactions

The reported incidence of allergic reactions to all penicillins ranges from 0.7 to 10 percent in different studies (seeWARNINGS). Sensitization is usually the result of previous treatment with a penicillin, but some individuals have had immediate reactions when first treated. In such cases, it is postulated that prior exposure to penicillin may have occurred via trace amounts present in milk or vaccines.

Two types of allergic reactions to penicillin are noted clinically – Immediate and delayed.

Immediate reactions usually occur within 20 minutes of administration and range in severity from urticaria and pruritus to angloneurotic edema, laryngospasm, bronchospasm, hypotension, vascular collapse and death (see WARNINGS). Such immediate anaphylactic reactions are very rare and usually occur after parenteral therapy, but a few cases of anaphylaxis have been reported following oral therapy. Another type of immediate reaction, an accelerated reaction, may occur between 20 minutes and 45 hours after administration and may include urticaria, pruritus, fever and, occasionally, laryngeal edema.

Delayed reactions to penicillin therapy usually occur within 1 to 2 weeks after initiation of therapy. Manifestations include serum sickness-like symptoms, i.e., fever, malaise, urticaria, myalgia, arthralgia, abdominal pain and various skin rashes, ranging from maculopapular eruptions to exfoliative dermatitis.

Contact dermatitis has been observed in individuals who prepare penicillin solutions.

Gastrointestinal System

Pseudomembranous colitis has been reported with the onset occurring during or after penicillin G treatment. Nausea, vomiting, stomatitis, black or hairy tongue, and other symptoms of gastrointestinal irritation may occur, especially during oral therapy.

Hematologic System

Reactions include neutropenia, which resolves after penicillin therapy is discontinued; Coombs-positive hemolytic anemia, an uncommon reaction, occurs in patients treated with intravenous penicillin G in doses greater than 10 million units/day and who have previously received large doses of the drug; and with large doses of penicillin, a bleeding diathesis, can occur secondary to platelet dysfunction.

Metabolic

Penicillin G Sodium for injection, USP (1 million units contains 1.68 mEq of sodium ion) may cause serious and even fatal electrolyte disturbances when given intravenously in large doses.

Cardiovascular System

High dosage of penicillin G sodium may result in congestive heart failure due to high sodium intake.

Nervous System

Neurotoxic reactions including hyperreflexia, myoclonic twitches, seizures and coma have been reported following the administration of massive intravenous doses, and are more likely in patients with impaired renal function.

Urogenital System

Renal tubular damage and interstitial nephritis have been associated with large intravenous doses of penicillin G. Manifestations of this reaction may include fever, rash, eosinophilia, proteinuria, eosinophiluria, hematuria and a rise in serum urea nitrogen. Discontinuation of penicillin G results in resolution in the majority of patients.

Local Reactions

Phlebitis and thrombophlebitis may occur with intravenous administration.

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (anaphylactic) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH PENICILLIN G, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PENICILLIN G SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including penicillin G sodium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General

Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma (seeWARNINGS). Whenever allergic reactions occur, penicillin should be withdrawn unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to penicillin therapy.

Penicillin G Sodium for injection, USP by the intravenous route in high doses (above 10 million units) should be administered slowly because of the potential adverse effects of electrolyte imbalance from the sodium content of the penicillin. Penicillin G Sodium for injection, USP contains 1.68 mEq of sodium per million units of penicillin G.

The use of antibiotics may promote overgrowth of nonsusceptible organisms, including fungi. Indwelling intravenous catheters encourage superinfections. Should superinfection occur, appropriate measures should be taken.

When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy.

Prescribing penicillin G sodium in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Laboratory Tests

Periodic assessment of organ system function, including frequent evaluation of electrolyte balance, hepatic, renal and hematopoietic systems, and cardiac and vascular status should be performed during prolonged therapy with high doses of intravenous penicillin G (seeADVERSE REACTIONS). If any impairment of function is suspected or known to exist, a reduction in the total dosage should be considered (seeDOSAGE AND ADMINISTRATION).

In suspected staphylococcal infections, proper laboratory studies, including susceptibility tests should be performed.

All infections due to Group A beta-hemolytic streptococci should be treated for at least 10 days.

Patients being treated for gonococcal infection should have a serologic test for syphilis before receiving penicillin. All cases of penicillin treated syphilis should receive adequate follow-up including clinical and serological examinations. The recommended follow-up varies with the stage of syphilis being treated. See CDC recommendations.

Drug Interactions

Bacteriostatic antibacterials (i.e., chloramphenicol, erythromycins, sulfonamides or tetracyclines) may antagonize the bactericidal effect of penicillin, and concurrent use of these drugs should be avoided. This has been documented in vitro, however, the clinical significance of this interaction is not well-documented.

Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins.

Other drugs may compete with Penicillin G for renal tubular secretion and thus prolong the serum half-life of penicillin. These drugs include: aspirin, phenylbutazone, sulfonamides, indomethacin, thiazide diuretics, furosemide and ethacrynic acid.

Drug/Laboratory Test Interactions

After treatment with penicillin G, a false-positive reaction for glucose in the urine may occur with Benedict’s solution, Fehling’s solution or Clinitest® tablet, but not with the enzyme-based tests, such as Clinistix® and Tes-Tape®.

Penicillin G has been associated with pseudoproteinuria by certain test methods.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been conducted with this drug.

Pregnancy

Teratogenic Effects

Reproduction studies performed in the mouse, rat, and rabbit have revealed no evidence of impaired fertility or harm to the fetus due to penicillin G. Human experience with the penicillins during pregnancy has not shown any positive evidence of adverse effects on the fetus. There are, however, no adequate and well controlled studies in pregnant women showing conclusively that harmful effects of these drugs on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Penicillins are excreted in human milk. Caution should be exercised when penicillins are administered to a nursing woman.

Pediatric Use

lncompletely developed renal function in newborns may delay elimination of penicillin; therefore, appropriate reductions in the dosage and frequency of administration should be made in these patients. All newborns treated with penicillins should be monitored closely for clinical and laboratory evidence of toxic or adverse effects (seePRECAUTIONS).

Pediatric doses are generally determined on a weight basis and should be calculated for each patient individually. Recommended guidelines for pediatric dosages are presented inDOSAGE AND ADMINISTRATION.

The potential for toxic effects in children from chemicals that may leach from the single dose premixed intravenous preparation in plastic containers has not been evaluated.

Information for Patients

Patients should be counseled that antibacterial drugs including penicillin G sodium should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When penicillin G sodium is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by penicillin G sodium or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

CLINICAL PHARMACOLOGY

After an intravenous infusion of penicillin G, peak serum concentrations are attained immediately after completion of the infusion. In a study of ten patients administered a single 5 million unit dose of penicillin G intravenously over 3 to 5 minutes, the mean serum concentrations were 400 mcg/mL, 273 mcg/mL and 3 mcg/mL at 5 to 6 minutes, 10 minutes and 4 hours after completion of the injection, respectively. In a separate study, five healthy adults were administered one million units of penicillin G intravenously, either as a bolus over 4 minutes or as an infusion over 60 minutes. The mean serum concentration eight minutes after completion of the bolus was 45 mcg/mL and eight minutes after completion of the infusion was 14.4 mcg/mL.

The mean β-phase serum half-life of penicillin G administered by the intravenous route in ten patients with normal renal function was 42 minutes, with a range of 31 to 50 minutes.

The clearance of penicillin G in normal individuals is predominantly via the kidney. The renal clearance, which is extremely rapid, is the result of glomerular filtration and active tubular transport, with the latter route predominating. Urinary recovery is reported to be 58 to 85% of the administered dose. Renal clearance of penicillin is delayed in premature infants, neonates and in the elderly due to decreased renal function. The serum half-life of penicillin G correlates inversely with age and clearance of creatinine and ranges from 3.2 hours in infants 0 to 6 days of age to 1.4 hours in infants 14 days of age or older.

Nonrenal clearance includes hepatic metabolism and, to a lesser extent, biliary excretion. The latter routes become more important with renal impairment.

Probenecid blocks the renal tubular secretion of penicillin. Therefore, the concurrent administration of probenecid prolongs the elimination of penicillin G and, consequently, increases the serum concentrations.

Penicillin G is distributed to more areas of the body including lung, liver, kidney, muscle, bone and placenta. In the presence of inflammation, levels of penicillin in abscesses, middle ear, pleural, peritoneal and synovial fluids are sufficient to inhibit most susceptible bacteria. Penetration into the eye, brain, cerebrospinal fluid (CSF) or prostate is poor in the absence of inflammation. With inflamed meninges, the penetration of penicillin G into the CSF improves, such that the CSF/serum ratio is 2 to 6%. Inflammation also enhances its penetration into the pericardial fluid. Penicillin G is actively secreted into the bile resulting in levels at least 10 times those achieved simultaneously in serum. Penicillin G penetrates poorly into human polymorphonuclear leukocytes.

In the presence of impaired renal function, the β-phase serum half-life of penicillin G is prolonged. β-phase serum half-lives of one to two hours were observed in azotemic patients with serum creatinine concentrations <3 mg/100 mL and ranged as high as 20 hours in anuric patients. A linear relationship, including the lowest range of renal function, is found between the serum elimination rate constant and renal function as measured by creatinine clearance.

In patients with altered renal function, the presence of hepatic insufficiency further alters the elimination of penicillin G. In one study, the serum half- lives in two anuric patients (excreting <400 mL urine/day) were 7.2 and 10.1 hours. A totally anuric patient with terminal hepatic cirrhosis had a penicillin half-life of 30.5 hours, while another patient with anuria and liver disease had a serum half-life of 16.4 hours.The dosage of penicillin G should be reduced in patients with severe renal impairment, with additional modifications when hepatic disease accompanies the renal impairment.

Hemodialysis has been shown to reduce penicillin G serum levels.

Microbiology

Penicillin G is bactericidal against penicillin-susceptible microorganisms during the stage of active multiplication. It acts by inhibiting biosynthesis of cell-wall mucopeptide. It is not active against the penicillinase-producing bacteria, which include many strains of staphylococci. Penicillin G is highly active in vitro against staphylococci (except penicillinase-producing strains), streptococci (groups A, B, C, G, H, L and M), pneumococci and Neisseria meningitidis. Other organisms susceptible in vitro to penicillin G are Neisseria gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, clostridia, Actinomyces species, Spirillum minus, Streptobacillus monillformis, Listeria monocytogenes, and leptospira; Treponema pallidum is extremely susceptible.

Some species of gram-negative bacilli were previously considered susceptible to very high intravenous doses of penicillin G (up to 80 million units/day) including some strains of Escherichia coli, Proteus mirabilis, salmonella, shigella, Enterobacter aerogenes (formerly Aerobacter aerogenes) and Alcaligenes faecalis. Penicillin G is no longer considered a drug of choice for infections caused by these organisms.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.