penicillin G potassium 1000000 UNT/ML Injectable Solution

INDICATIONS AND USAGE Therapy Buffered penicillin G potassium for injection 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 Buffered penicillin G potassium for injection 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 beta-hemolytic streptococcus ), other beta-hemolytic streptococci including groups C, H, G, L and M, Streptococcus pneumoniae and Staphylococcus species (non-penicillinase producing strains) Anthrax Bacillus anthracis Actinomycosis (cervicofacial 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 potassium and other antibacterial drugs, penicillin G potassium 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 for Injection, USP may be given intravenously or intramuscularly. 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 to 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 to 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 to 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 prevention of the carrier state) 2 to 3 million units/day in divided doses for 10 to 12 days (*) Erysipelothrix endocarditis 12 to 20 million units/day for 4 to 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 to 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 to 4 MU every 4 hours for 10 to 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 to 300,000 units/kg/day divided in equal doses every 4 to 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 to 14 days depending on the infecting organism (maximum dose of 12 to 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 to 10 days Meningitis 250,000 units/kg/day in equal doses every 4 hours for 10 to 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 to 300,000 units/kg/day (administered as 50,000 units/kg every 4 to 6 hours) for 10 to 14 days Diphtheria (adjunctive therapy to antitoxin and for prevention of the carrier state) 150,000 to 250,000 units/kg/day in equal doses every 6 hours for 7 to 10 days Rat-bite fever; Haverhill fever (with endocarditis caused by S. moniliformis ) 150,000 to 250,000 units/kg/day in equal doses every 4 hours for 4 weeks Renal Impairment Penicillin G is relatively nontoxic, and dosage adjustments are generally required only in cases of severe renal impairment. The recommended dosage regimens are as follows: Creatinine clearance less than 10 mL/min/1.73 m 2 ; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 8 to 10 hours. Uremic patients with a creatinine clearance greater than 10 mL/min/1.73 m 2 ; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 4 to 5 hours. Additional dosage modifications should be made in patients with hepatic disease and renal impairment. For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. Antibiotic therapy for Group A β-hemolytic streptococcal infections should be maintained for at least 10 days to reduce the risk of rheumatic fever. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Reconstitution The following table shows the amount of solvent required for solution of various concentrations: Approx. Desired Concentration (units/mL) Approx. Volume 1,000,000 units (mL) Solvent for Vial of 5,000,000 units (mL) Infusion Only 20,000,000 units (mL) 50,000 20 - - 100,000 10 - - 250,000 4 18.2 75 500,000 1.8 8.2 33 750,000 - 4.8 - 1,000,000 - 3.2 11.5 When the required volume of solvent is greater than the capacity of the vial, the penicillin can be dissolved by first injecting only a portion of the solvent into the vial, then withdrawing the resultant solution and combining it with the remainder of the solvent in a larger sterile container. Buffered Penicillin G Potassium for Injection, USP is highly water soluble. It may be dissolved in small amounts of Water for Injection, or Sterile Isotonic Sodium Chloride Solution for Parenteral Use. Buffered Penicillin G Potassium for Injection, USP may be given intramuscularly or by continuous intravenous drip for dosages of 500,000, 1,000,000, or 5,000,000 units. It is also suitable for intrapleural, intraarticular, and other local instillations. THE 20,000,000 UNITS DOSAGE MAY BE ADMINISTERED BY INTRAVENOUS INFUSION ONLY. (1) Intramuscular Injection Keep total volume of injection small. The intramuscular route is the preferred route of administration. Solutions containing up to 100,000 units of penicillin per mL of diluent may be used with a minimum of discomfort. Greater concentration of penicillin G per mL is physically possible and may be employed where therapy demands. When large dosages are required, it may be advisable to administer aqueous solutions of penicillin by means of continuous intravenous drip. (2) Continuous Intravenous Drip Determine the volume of fluid and rate of its administration required by the patient in a 24-hour period in the usual manner for fluid therapy, and add the appropriate daily dosage of penicillin to this fluid. For example, if an adult patient requires 2 liters of fluid in 24 hours and a daily dosage of 10 million units of penicillin, add 5 million units to 1 liter and adjust the rate of flow so the liter will be infused in 12 hours. (3) Intrapleural or Other Local Infusion If fluid is aspirated, give infusion in a volume equal to ¼ or ½ the amount of fluid aspirated, otherwise, prepare as for intramuscular injection. (4) Intrathecal Use The intrathecal use of penicillin in meningitis must be highly individualized. It should be employed only with full consideration of the possible irritating effects of penicillin when used by this route. The

Lentocilin S suspension for injection should ONLY be administered by INTRAMUSCULAR ROUTE. To avoid injury, Lentocilin S suspension should not be administered by intravenous, intraarterial or subcutaneous route, in the adipose layer, into or near a peripheral nerve or blood vessel. Before injecting the suspension, the position of the needle should be controlled by aspiration. If blood shows up in the syringe, pull back the needle and inject on another site. Administer Lentocilin S suspension EXCLUSIVELY by DEEP INTRAMUSCULAR INJECTION in the external upper quadrant of the buttock. In children and infants, the IM injections should be done, preferably, in the middle of the external lateral side of the thigh. In infants younger than 2 years, and if considered necessary, the dosage may be divided and administered in two separate sites. The IM injection site should be changed in case of repeated doses. Deep IM administration of this medicine requires a rigorous technique and should be performed only by experienced health technicians and in places prepared for the emergency treatment of a possible anaphylactic reaction. A needle to use in the administration of the injectable suspensions should have a minimum internal diameter of 0.8 mm (caliber: 18 gauge). The deep IM injection should be made slowly and with a constant flow rate to prevent needle blockage. If the needle is clogged, replace it with a new needle. The deep IM injection should be discontinued if there are signs or symptoms of immediate acute pain, especially in children and infants. Serious hypersensitivity reactions (anaphylactic reactions), sometimes fatal, have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, therapy with Lentocillin S should be discontinued immediately and the appropriate therapy instituted. In case of severe anaphylactic reaction, immediate emergency treatment (including adrenaline, corticosteroids, airway management, oxygen) is required. Usually, subcutaneous, or intravenous adrenaline is the treatment of choice for an immediate or accelerated hypersensitivity reaction to a penicillin. Before initiating therapy with benzylpenicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporins, and other beta-lactam antibiotics. Contact with the penicillin during handling the product should be avoided due to the possibility of skin sensitization. To minimize the overgrowth of resistant bacteria and maintain the effectiveness of benzylpenicillin, this medicine should only be used in the treatment of infections proven to be caused by susceptible bacteria. Therapy should be based on bacteriological studies (including sensitivity tests) and the patient's clinical response. Prolonged administration of Lentocilin S can occasionally result in overgrowth of non-susceptible organisms particularly Candida, Pseudomonas or Enterobacter. Antibiotic treatment modifies the commensal flora of the colon, allowing the growth of Clostridium difficile. This microorganism produces toxins, which are responsible for diarrhea associated to antibiotherapy, which can range from mild diarrhea to fatal colitis. Patients with diarrhea during or even up to two months after treatment with antibiotics should be subject to investigation and differential diagnosis. Confirming pseudomembranous colitis, treatment should be discontinued and, if necessary, use supportive hydro-electrolyte measures, recommended antibiotherapy and protein supplement. Because of the risk of neurotoxicity, caution is recommended especially in the case of administration of high doses of benzylpenicillin to renal impaired patients. During prolonged treatment with high doses of benzylpenicillin is recommended to monitor the renal and haematological functions. The use of benzylpenicillin for more than 2 weeks may be associated with an increased risk of neutropenia and incidence of immune complex self-limited sickness-like reactions. Special precautions should be taken in order to avoid intravenous and intraarterial administration or injection into or near major peripheral nerve or blood vessel, since such injections may produce severe and/or permanent neuromuscular damage. In case of evidence of impaired blood flow at the injection site - proximal or distal – an appropriate specialized physician should be immediately consulted. Special caution is recommended when treating patients with spirochetal infections, particularly syphilis, due to the possibility of a Jarisch - Herxheimer reaction. This is a very common reaction when benzylpenicillin is used to treat syphilis, occurring in 50% of patients with primary syphilis, 75% of those treated for secondary syphilis and 30% of those treated for neurosyphilis. This reaction usually occurs 2-12 hours after initiation of penicillin therapy and is characterized by the occurrence of headache, fever, chills, sweating, sore throat, myalgia, arthralgia, malaise, increased heart rate and an increase in blood pressure followed by its decrease. This reaction is probably caused by the release of endotoxins from the treponemes and should not be confused with a hypersensitivity reaction. The reaction may be dangerous in cardiovascular syphilis or when there is a serious risk of increased local lesions such as optic atrophy. It is recommended the use of oxidative enzymatic methods when testing glucose in urine during therapy with benzylpenicillin. False positive results can occur with the use of non-enzymatic methods. Benzylpenicillin may interfere with other diagnostic tests such as the Coombs test, tests for the determination of proteins in plasma and urine and the test for the determination of plasmatic uric acid (copper-chelate method). Due to the lidocaine content (present in the ampoule), Lentocilin S should be used with caution in the following situations: - presence of cardiovascular, hepatic or renal dysfunction, inflammation and/or infection at the injection site or sensitivity to local anesthetics of the amide type, - children, the elderly and patients with acute illnesses or debilitated, - patients on concomitant CNS depressant drugs.

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.

CLINICAL PHARMACOLOGY Aqueous penicillin G is rapidly absorbed following both intramuscular and subcutaneous injection. Initial blood levels following parenteral administration are high but transient. Penicillins bind to serum proteins, mainly albumin. Therapeutic levels of the penicillins are easily achieved under normal circumstances in extracellular fluid and most other body tissues. Penicillins are distributed in varying degrees into pleural, pericardial, peritoneal, ascitic, synovial, and interstitial fluids. Penicillins are excreted in breast milk. Penetration into the cerebrospinal fluid, eyes, and prostate is poor. Penicillins are rapidly excreted in the urine by glomerular filtration and active tubular secretion, primarily as unchanged drug. Approximately 60 percent of the total dose of 300,000 units is excreted in the urine within this 5-hour period. For this reason, high and frequent doses are required to maintain the elevated serum levels desirable in treating certain severe infections in individuals with normal kidney function. In neonates and young infants, and in individuals with impaired kidney function, excretion is considerably delayed. 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 3.0 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 most 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 in 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 exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall peptidoglycan rendering the cell wall osmotically unstable. It is not active against the penicillinase-producing bacteria, which include many strains of staphylococci or against organisms resistant to beta-lactams because of alterations in the penicillin-binding proteins, such as methicillin-resistant staphylococci. Penicillin G is highly active in vitro against streptococci (groups A, B, C, G, H, L and M), and Neisseria meningitidis . Other organisms susceptible to penicillin G are N. gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, Clostridium spp., Actinomyces species, “Spirillum minus”, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira spp.; Treponema pallidum is extremely sensitive to the bactericidal action of penicillin G. 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 spp. and Shigella spp.; 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 .