PENICILLIN G POTASSIUM

INDICATIONS AND USAGE Therapy Penicillin G Potassium 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 Potassium 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 israelii 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 rhusiopathiae 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) Penicillin G is not the drug of choice in the treatment of gram-negative bacillary infections. Gram-negative bacillary organisms ( i.e. Enterobacteriaceae ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Penicillin G Potassium Injection, USP and other antibacterial drugs, Penicillin G Potassium Injection, USP 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.

DOSAGE AND ADMINISTRATION Penicillin G Potassium Injection, USP should be administered by intravenous infusion. The usual dose recommendations are as follows: Adult patients (*) Because of its short half-life, Penicillin G is administered in divided doses, usually every 4-6 hours with the exception of meningococcal meningitis/septicemia, i.e. , every 2 hours. CLINICAL INDICATION DOSAGE Serious infections due to susceptible strains of streptococci (including S. pneumoniae ) -septicemia, empyema, pneumonia, pericarditis, endocarditis and meningitis 12 to 24 million units/day depending on the infection and its severity administered in equally divided doses every 4-6 hours. Serious infections due to susceptible strains of staphylococci - septicemia, empyema, pneumonia, pericarditis, endocarditis and meningitis 5 to 24 million units/day depending on the infection and its severity administered in equally divided doses every 4-6 hours. Anthrax Minimum of 8 million units/day in divided doses every 6 hours. Higher doses may be required depending on susceptibility of organism. Actinomycosis Cervicofacial disease Thoracic and abdominal disease 1 to 6 million units/day(*) 10 to 20 million units/day(*) Clostridial infections Botulism (adjunctive therapy to antitoxin) Gas gangrene (debridement and/or surgery as indicated) Tetanus (adjunctive therapy to human tetanus immune globulin) 20 million units/day(*) Diphtheria (adjunctive therapy to antitoxin and for the prevention of the carrier state) 2 to 3 million units/day in divided doses for 10-12 days(*) Erysipelothrix endocarditis 12 to 20 million units/day for 4-6 weeks(*) Fusospirochetosis (severe infections of the oropharynx [Vincent’s], lower respiratory tract and genital area) 5 to 10 million units/day(*) Listeria infections Meningitis Endocarditis 15 to 20 million units/day for 2 weeks(*) 15 to 20 million units/day for 4 weeks(*) Pasteurella infections including bacteremia and meningitis 4 to 6 million units/day for 2 weeks(*) Haverhill fever; Rat-bite fever 12 to 20 million units/day for 3-4 weeks(*) Disseminated gonococcal infections, such as meningitis endocarditis, arthritis, etc., caused by penicillin - susceptible organisms 10 million units/day(*); duration depends on the type of infection Syphilis (neurosyphilis) 12 to 24 million units/day, as 2-4 MU every 4 hours for 10-14 days; many experts recommend additional therapy with Benzathine PCN G 2.4 MU IM weekly for 3 doses after completion of IV therapy Meningococcal meningitis and/or septicemia 24 million units/day as 2 million units every 2 hours Pediatric patients This product should not be administered to patients requiring less than one million units per dose (see PRECAUTIONS -Pediatric Use). CLINICAL INDICATION DOSAGE Serious infections, such as pneumonia and endocarditis, due to susceptible strains of streptococci (including S. pneumoniae ) and meningococcus 150,000–300,000 units/kg/day divided in equal doses every 4-6 hours; duration depends on infecting organism and type of infection Meningitis caused by susceptible strains of pneumococcus and meningococcus 250,000 units/kg/day divided in equal doses every 4 hours for 7-14 days depending on the infecting organism (maximum dose of 12-20 million units/day) Disseminated Gonococcal Infections (penicillin-susceptible strains) Weight less than 45 kg: Arthritis 100,000 units/kg/day in 4 equally divided doses for 7-10 days Meningitis 250,000 units/kg/day in equal doses every 4 hours for 10-14 days Endocarditis 250,000 units/kg/day in equal doses every 4 hours for 4 weeks Arthritis, meningitis, endocarditis Weight 45 kg or greater: 10 million units/day in 4 equally divided doses with the duration of therapy depending on the type of infection Syphilis (congenital and neurosyphilis) after the newborn period 200,000-300,000 units/kg/day (administered as 50,000 units/kg every 4-6 hours) for 10-14 days Diphtheria (adjunctive therapy to antitoxin and for prevention of the carrier state) …

CONTRAINDICATIONS A history of a hypersensitivity (anaphylactic) reaction to any penicillin is a contraindication. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

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, hyperventilation, vasodilation with flushing and mild hypotension. The pathogenesis of the Herxheimer reaction may be due to the release from the spirochetes of heat-stable pyrogen. Hypersensitivity reactions: The reported incidence of allergic reactions to all penicillins ranges from 0.7 to 10 percent in different studies (see WARNINGS ). 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 angioneurotic 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 48 hours after administration and may include urticaria, pruritus, fever and, occasionally, laryngeal edema. Delayed reactions to penicillin therapy usually occur within 1-2 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 Potassium, USP (1 million units contains 1.7 mEq of potassium ion) may cause serious and even fatal electrolyte disturbances, i.e. , hyperkalemia, when given intravenously in large doses. 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, and pain at the injection site has been reported with intravenous administration.

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.

DESCRIPTION Penicillin G Potassium, USP is a natural penicillin. It is chemically designated 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, monopotassium salt, [2 S -(2α, 5α, 6β)]. It is crystalline. It is freely soluble in water, in isotonic sodium chloride solution and in dextrose solutions. The structural formula is as shown below. Penicillin G Potassium Injection, USP (equivalent to 2, or 3 million units of penicillin G) is a 50 mL premixed, iso-osmotic, sterile, nonpyrogenic, frozen solution for intravenous administration. Dextrose, USP has been added to the above dosages to adjust osmolality (approximately 1.2 g, and 350 mg as dextrose hydrous, respectively). Sodium Citrate, USP has been added as a buffer (0.20 g and 0.30 g as sodium citrate dihydrate, respectively). The pH has been adjusted with hydrochloric acid and may have been adjusted with sodium hydroxide. The pH is 6.5 (5.5 to 8.0). The solution is contained in a single dose GALAXY container and is intended for intravenous use after thawing to room temperature. This GALAXY container is fabricated from a specially designed multilayer plastic. Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers as well as by tissue culture toxicity studies. Penicillin G Potassium Injection USP Structural Formula

OVERDOSAGE Dose related toxicity may arise with the use of massive doses of intravenous penicillins (40 to 100 million units per day), particularly in patients with severe renal impairment (see PRECAUTIONS ). The manifestations may include agitation, confusion, asterixis, hallucinations, stupor, coma, multifocal myoclonus, seizures and encephalopathy. Hyperkalemia is also possible (see ADVERSE REACTIONS -Metabolic). In case of overdosage, discontinue penicillin, treat symptomatically and institute supportive measures as required. If necessary, hemodialysis may be used to reduce blood levels of Penicillin G, although the degree of effectiveness of this procedure is questionable.

HOW SUPPLIED/STORAGE AND HANDLING Penicillin G Potassium Injection, USP is supplied as a premixed frozen iso-osmotic solution in 50 mL single dose GALAXY containers as follows: 2G3543 NDC 0338-1023-41 2,000,000 units/50 mL (40,000 units/mL) Penicillin G 2G3544 NDC-0338-1025-41 3,000,000 units/50 mL (60,000 units/mL) Penicillin G Store at or below -20°C/-4°F. [See DIRECTIONS FOR USE OF GALAXY CONTAINER ]. Handle frozen product containers with care. Product containers may be fragile in the frozen state.