penicillin G for Lyme Disease

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.

Bacteriostatic antibiotics: Bacteriostatic antibiotics, such as tetracycline, erythromycin and chloramphenicol, may antagonize the bactericidal effect of benzylpenicillin by interfering with active bacterial growth necessary to benzylpenicillin’s effect. Oral contraceptives: The efficacy of oral contraceptives may be impaired in case of concomitant therapy with benzylpenicillin, which may result in an unwanted pregnancy. Women taking oral contraceptives should be alerted to this situation and should be informed about the need to adopt alternative methods of contraception. Methotrexate: Penicillins may reduce the renal excretion of methotrexate causing a potential increase in its toxicity. Probenecid: Probenecid decreases the renal tubular secretion of benzylpenicillin. Its concomitant use with benzylpenicillin can prolong blood levels of benzylpenicillin. Probenecid may be used therapeutically for this purpose.

The most common undesirable effects of benzylpenicillin are hypersensitivity reactions, especially skin rashes. Anaphylactic reactions occurred occasionally, which have sometimes been fatal. The overall incidence of allergic reactions to penicillin ranges between 1 and 10%. Anaphylactic reactions occur in approximately 0.05% of patients, usually after parenteral administration. The following undesirable effects were observed with benzylpenicillin: Blood and lymphatic system disorders - Eosinophilia and hemolytic anemia (both with immunological basis), leukopenia and thrombocytopenia. These effects are usually reversible after discontinuation of treatment. Immune system disorders - Hypersensitivity reactions to penicillin cause a wide variety of clinical syndromes. Immediate reactions include anaphylaxis, laryngeal edema, angioedema, urticaria and maculopapular rashes. Late reactions include hemolytic anemia and immune complex self-limited sickness-like reactions, characterized by fever, malaise, urticaria, arthralgia, myalgia, lymphadenopathy and splenomegaly. In order to determine which patients will probably develop severe allergic reactions, hypersensitivity skin tests may be used. Jarisch – Herxheimer reaction. Nervous system disorders - Benzylpenicillin is very irritating to the central and peripheral nervous systems. Neurotoxic reactions include anxiety, asthenia, cerebrovascular accident (CVA), confusion, dizziness, euphoria, nervousness, hallucinations, headache, neuropathy, neurovascular injury, localized or generalized seizures, coma, tremor and vasospasm at the administration site, and occur after parenteral administration of benzylpenicillin potassium. These reactions are most common when the benzylpenicillin is given daily in doses of more than 20,000,000 IU intravenously to renal impaired patients. The accidental injection of preparations of benzylpenicillin into or near by the nerves may produce neuromuscular damage, which rarely may be permanent. Rarely, inadvertent intravascular administration of benzathine benzylpenicillin or procaine benzylpenicillin, including direct administration into an artery - or adjacent to an artery - causes occlusion, thrombosis and severe neurovascular injury, especially in children. Deep injection in the glutes gluteal muscles can cause paralysis, dysfunction and painful irritation of the sciatic nerve. Repeated intramuscular injection of benzylpenicillin preparations in the anterolateral side of the thigh of newborns has rarely caused generalized muscular contractions, as well as atrophy and fibrosis of the quadriceps femoris muscle. After intramuscular administration of benzathine benzylpenicillin may occurs Hoigné syndrome may occur, characterized by agitation accompanied by symptoms such as fear of impending death and visual and auditory hallucinations. Transversal myelitis with permanent paralysis, gangrene requiring amputation of fingers and the more proximal regions of the extremities, and necrosis with formation of scars surrounding the site of injection, have occurred after injections in the buttocks, thighs and deltoid muscle. Eye disorders - Blurred vision, transient blindness. Cardiac disorders - Hypotension, palpitations, syncope, tachycardia, vasodilation and vasovagal syndrome characterized by anxiety, sweating, hypotension, peripheral arterial vasodilation and bradycardia. Cardiopulmonary arrest and death due to inadvertent IV administration. Respiratory, thoracic and mediastinal disorders - Apnea, dyspnea, hypoxia, pulmonary embolism and pulmonary hypertension. Gastro-intestinal disorders - Intestinal necrosis, melena, nausea, vomiting, and pseudomembranous colitis, which can arise during or after treatment. Hepatobiliary disorders - Transient increases in SGOT, hepatitis and cholestatic jaundice. Skin and subcutaneous tissue disorders - Diaphoresis, pruritus and urticaria. Musculo-skeletal, connective tissue and bone disorders - Arthritis, arthropathy, myoglobinuria, periostitis and rhabdomyolysis. Renal and urinary disorders - Hematuria, neurogenic bladder, renal impairment, proteinuria and increased serum BUN and creatinine. Reproductive system and breast disorders - Impotence and priapism General disorders and administration site conditions - Parenteral administration of benzylpenicillin preparations may cause dose-related injection site reactions dose-related and are the result of a direct toxic effect of the drug. IM administration of high doses of benzylpenicillin benzathine (in particular more than 600,000 IU of benzylpenicillin) in a single injection site can result in painful tumefaction and endothelial injury on site. IM administration of benzylpenicillin has been associated with the occurrence of the following side effects at the administration site: inflammation, pain, abscess, edema, hemorrhage, cellulitis, atrophy and cutaneous ulceration. It has also been reported cases of fever and fatigue associated with the use of benzylpenicillin.