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Penicillin G Benzathine
Bicillin L-A (penicillin G benzathine suspension) is prepared by the reaction of dibenzylethylene diamine with two molecules of penicillin G. It is chemically designated as (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid compound with N,N’-dibenzylethylene diamine (2:1), tetrahydrate. It is available for deep intramuscular injection. It contains penicillin G benzathine in aqueous suspension with sodium citrate buffer and, as w/v, approximately 0.5% lecithin, 0.6% carboxymethylcellulose, 0.6% povidone, 0.1% methylparaben, and 0.01% propylparaben. It occurs as a white, crystalline powder and is very slightly soluble in water and sparingly soluble in alcohol. Bicillin L-A suspension in TUBEX® formulation is viscous
and opaque. It is available in 1 mL and 2 mL TUBEX Sterile Cartridge-Needle
Units containing the equivalent of 600,000 units and 1,200,000 units respectively
of penicillin G as the benzathine salt. See CONTRAINDICATIONS,
WARNINGS, PRECAUTIONS,
and DOSAGE AND ADMINISTRATION
sections prior to use.
General Penicillin G benzathine has an extremely low solubility and, thus, the drug is slowly released from intramuscular injection sites. The drug is hydrolyzed to penicillin G. This combination of hydrolysis and absorption results in blood serum levels much lower but much more prolonged than other parenteral penicillins. Intramuscular administration of 300,000 units of penicillin G benzathine in adults results in blood levels of 0.03 to 0.05 units per mL, which are maintained for 4 to 5 days. Similar blood levels may persist for 10 days following administration of 600,000 units and for 14 days following administration of 1,200,000 units. Blood concentrations of 0.003 units per mL may still be detectable 4 weeks following administration of 1,200,000 units. Approximately 60% of penicillin G is bound to serum protein. The drug is distributed throughout the body tissues in widely varying amounts. Highest levels are found in the kidneys with lesser amounts in the liver, skin, and intestines. Penicillin G penetrates into all other tissues and the spinal fluid to a lesser degree. With normal kidney function, the drug is excreted rapidly by tubular excretion. In neonates and young infants and in individuals with impaired kidney function, excretion is considerably delayed. 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 mucopeptide. It is not active against the penicillinase-producing bacteria, which include many strains of staphylococci. The following in vitro data are available, but their clinical significance is unknown. Penicillin G exerts high in vitro activity against staphylococci (except penicillinase-producing strains), streptococci (Groups A, C, G, H, L, and M), and pneumococci. Other organisms susceptible to penicillin G are Neisseria gonorrhoeae, Coiynebacterium diphtheriae, Bacillus anthracis, Clostridia species, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira species. Treponema palildum is extremely susceptible to the bactericidal action of penicillin G. Susceptibility Test: If the Kirby-Bauer method of disc
susceptibility is used, a 20-unit penicillin disc should give a zone greater
than 28 mm when tested against a penicillin-susceptible bacterial strain.
Intramuscular penicillin G benzathine is indicated in the treatment of infections due to penicillin-G-sensitive microorganisms that are susceptible to the low and very prolonged serum levels common to this particular dosage form. Therapy should be guided by bacteriological studies (including sensitivity tests) and by clinical response. The following infections will usually respond to adequate dosage of intramuscular penicillin G benzathine: Mild-to-moderate infections of the upper-respiratory tract due to susceptible streptococci. Venereal infections— Syphilis, yaws, bejel, and pinta. Medical Conditions in which Penicillin G Benzathine Therapy is Indicated as Prophylaxis: Rheumatic fever and/or chorea— Prophylaxis with penicillin G benzathine has proven effective in preventing recurrence of these conditions. It has also been used as follow-up prophylactic therapy for rheumatic heart disease and acute glomerulonephritis.
Streptococcal (Group A) Upper-respiratory Infections (for example, pharyngitis) Adults—a single injection of 1,200,000 units; older pediatric patients—a single injection of 900,000 units; infants and pediatric patients under 60 lbs.—300,000 to 600,000 units. Syphillis Primary, secondary, and latent—2,400,000 units (1 dose). Late (tertiary and neurosyphilis)—2,400,000 units at 7-day intervals for three doses. Congenital—under 2 years of age: 50,000 units/kg/body weight; ages 2 to 12 years: adjust dosage based on adult dosage schedule. Yaws, Bejel, and Pinta—1,200,000 units (1 injection). Prophylaxis—for rheumatic fever and glomerulonephritis. Following an acute attack, penicillin G benzathine (parenteral) may be given in doses of 1,200,000 units once a month or 600,000 units every 2 weeks. Administer by DEEP INTRAMUSCULAR INJECTION in the upper, outer quadrant of the buttock. In neonates, infants and small children, the midlateral aspect of the thigh may be preferable. When doses are repeated, vary the injection site. The Wyeth-Ayerst TUBEX® cartridge for this product incorporates several features that are designed to facilitate the visualization of blood aspiration if a blood vessel is inadvertently entered. The design of this cartridge is such that blood which enters its needle will be quickly visualized as a red or dark-colored “spot.” This “spot” will appear on the barrel of the glass cartridge immediately proximal to the blue hub. The TUBEX is designed with two orientation marks, in order to determine where this “spot” can be seen. First insert and secure the cartridge in the TUBEX injector in the usual fashion. Locate the yellow rectangle at the base of the blue hub. This yellow rectangle is aligned with the blood visualization “spot.” An imaginary straight line, drawn from this yellow rectangle to the shoulder of the glass cartridge, will point to the area on the cartridge where the “spot” can be visualized. When the needle cover is removed, a second yellow rectangle will be visible. The second yellow rectangle is also aligned with the blood visualization “spot” to assist the operator in locating this “spot.” If the 2 mL metal or plastic syringe is used, the glass cartridge should be rotated by turning the plunger of the syringe clockwise until the yellow rectangle is visualized. If the 1 mL metal syringe is used, it will not be possible to continue to rotate the glass cartridge clockwise once it is properly engaged and fully threaded; it can, however, then be rotated counterclockwise as far as necessary to properly orient the yellow rectangles and locate the observation area. (In this same area in some cartridges, a dark spot may sometimes be visualized prior to injection. This is the proximal end of the needle and does not represent a foreign body in, or other abnormality of, the suspension.) Thus, before the needle is inserted into the selected muscle, it is important for the operator to orient the yellow rectangles so that any blood which may enter after needle insertion and during aspiration can be visualized in the area on the cartridge where it will appear and not be obscured by any obstructions. After selection of the proper site and insertion of the needle into the selected muscle, aspirate by pulling back on the plunger. While maintaining negative pressure for 2 to 3 seconds, carefully observe the barrel of the cartridge in the area previously identified (see above) for the appearance of a red or dark-colored “spot.” Blood or “typical blood color” may not be seen if a blood vessel has been entered—only a mixture of blood and Bicillin L-A. The appearance of any discoloration is reason to withdraw the needle and discard the glass TUBEX cartridge. If it is elected to inject at another site, a new cartridge should be used. If no blood or discoloration appears, inject the contents of the cartridge slowly. Discontinue delivery of the dose if the subject complains of severe immediate pain at the injection site or if, especially in infants and young children, symptoms or signs occur suggesting onset of severe pain. Some TUBEX cartridges may contain a small air bubble which should be disregarded, since it does not affect administration of the product. DO NOT clear any air bubbles from the cartridge or needle as this may interfere with the visualization of any blood or discoloration during aspiration. 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. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration; whenever solution and container permit. HOW SUPPLIED Bicillin® L-A( penicillin G benzathine suspension) is supplied in packages of 10 TUBEX® Sterile Cartridge-Needle Units as follows: 1 mL size, containing 600,000 units per TUBEX® (21 gauge, thin-wall 1 inch needle for pediatric use), NDC 0008-0021-37. 2 mL size, containing 1,200,000 units per TUBEX® (21 gauge, thin-wall 1-1/4 inch needle), NDC 0008-0021-35. Store in a refrigerator. Keep from freezing. Also Available Bicillin L-A (penicillin G benzathine suspension) is also available in packages of 10 disposable syringes as follows: 4 mL size, containing 2,400,000 units per syringe (18 gauge x 2 inch needle), NDC 0008-0021-12. Bicillin L-A (penicillin G benzathine suspension) is also available in packages of single multiple-dose vials as follows: 10 mL size, containing 300,000 units per mL, NDC 0008-0163-01. PLEASE NOTE: THE WYETH-AYERST METAL TUBEX HYPODERMIC SYRINGE AND TUBEX FAST-TRAK SYRINGE HAVE BEEN DISCONTINUED AND REPLACED BY THE TUBEX INJECTOR. EXCHANGE OF THESE DISCONTINUED SYRINGES IS AVAILABLE, FREE OF CHARGE, FROM YOUR WYETH-AYERST SALES REPRESENTATIVE, OR FROM WYETH-AYERST DIRECTLY. FOR LOADING AND UNLOADING INFORMATION ON THESE DISCONTINUED SYRINGES, CONTACT THE MEDICAL AFFAIRS DEPARTMENT AT WYETH-AYERST LABORATORIES, P.O. Box 8299, PHILADELPHIA, PA 19101. TUBEX ® Injector NOTE: The TUBEX Injector is REUSABLE: do not discard. DIRECTIONS: FOR USE: BEFORE PROCEEDING, SEE IMPORTANT INFORMATION UNDER Dosage and Administration SECTION. NOTE: USE ASEPTIC TECHNIQUE FOR ALL MANIPULATIONS OF STERILE PARTS. To load a TUBEX Sterile Cartridge-Needle Unit into the TUBEX Injector 1. Turn the ribbed collar to the “OPEN” position until it stops. 2. Hold the Injector with the open end up and fully insert the TUBEX Sterile Cartridge Needle Unit. Firmly tighten the ribbed collar in the direction of the “CLOSE” arrow. 3. Thread the plunger rod into the plunger of the TUBEX Sterile Cartridge-Needle Unit until slight resistance is felt. The Injector is now ready for use in the usual manner. To load an E.S.I. DOSETTE ® Sterile Cartridge-Needle Unit into the TUBEX Injector 1. Turn the ribbed collar to the “OPEN” position until it stops. 2. Hold the Injector with the open end up and fully insert the E.S.I. DOSETTE Sterile Cartridge-Needle Unit. Firmly tighten the ribbed collar in the direction of the “CLOSE” arrow. 3. Thread the plunger rod into the plunger of the E.S.I. DOSETTE Sterile Cartridge-Needle Unit until slight resistance is felt. 4. Engage the needle-cap assembly by pulling the cap down over the silver cartridge hub. The needle is fully engaged when the silver hub is completely covered. The Injector is now ready for use in the usual manner. To administer TUBEX/DOSETTE Sterile Cartridge-Needle Units Method of administration is the same as with conventional syringe. Remove needle cover by grasping it securely; twist and pull. Introduce needle into patient, aspirate by pulling back slightly on the plunger, and inject. To remove the empty TUBEX/DOSETTE Cartridge-Needle Unit and dispose into a vertical needle disposal container 1. Do not recap the needle. Disengage the plunger rod. 2. Hold the Injector, needle down, over a vertical needle disposal container and loosen the ribbed collar. TUBEX/DOSETTE Cartridge-Needle Unit will drop into the container. 3. Discard the needle cover. To remove the empty TUBEX/DOSETTE Cartridge-Needle Unit and dispose into a horizontal (mailbox) needle disposal container 1. Do not recap the needle. Disengage the plunger rod. 2. Open the horizontal (mailbox) needle disposal container. Insert TUBEX/DOSETTE Cartridge-Needle Unit, needle pointing down, halfway into container. Close the container lid on cartridge. Loosen ribbed collar; TUBEX/DOSETTE Cartridge-Needle Unit will drop into the container. 3. Discard the needle cover. The TUBEX Injector is reusable and should not be discarded. Used TUBEX/DOSETTE Cartridge-Needle Units should not be employed for successive injections or as multiple-dose containers. They are intended to be used only once and discarded. NOTE: Any graduated markings on TUBEX/DOSETTE Sterile Cartridge-Needle Units are to be used only as a guide in administering doses. Wyeth-Ayerst does not recommend and will not accept responsibility for the use of any cartridge-needle units other than TUBEX/E.S.I. DOSETTE Cartridge-Needle Units in the TUBEX Injector. TUBEX is a registered trademark of Wyeth-Ayerst Laboratories. REFERENCES 1. SHAW, E.: Transverse myelitis from injection of penicillin. Am. J. Dis. Child., 111:548, 1966. 2. KNOWLES, J.: Accidental intra-arterial injection of penicillin. Am. J. Dis. Child., 111:552, 1966. . 3. DARBY, C. et al: Ischemia following an intragluteal injection of benzathine-procaine penicillin G mixture in a one-year-old boy. Clin. Pediatrics, 12:485, 1973. 4. BROWN, L. & NELSON, A.: Postinfectious intravascular thrombosis with gangrene. Arch. Surg., 94:652, 1967. 5. BORENSTINE, J.: Transverse myelitis and penicillin (Correspondence). Am. J. Dis. Child., 112:166, 1966. 6. ATKINSON, J.: Transverse myelopathy secondary to penicillin injection. J. Pediatrics, 75:867, 1969. 7. TALBERT, J.: et al: Gangrene of the foot following intramuscular injection in the lateral thigh: A case report with recommendations for prevention. J. Pediatrics, 70:110, 1967. 8. FISHER, T.: Medicolegal affairs. Canad. Med. Assoc J,. 112:395, 1975. 9. SCHANZER, H. et al: Accidental intra-arterial injection
of penicillin G. JAMA, 242:1 289, 1979.
As with other penicillins, untoward reactions of the sensitivity phenomena are likely to occur, particularly in individuals who have previously demonstrated hypersensitivity to penicillins or in those with a history of allergy, asthma, hay fever, or urticaria. As with other treatments for syphilis, the Jarisch-Herxheimer reaction has been reported. The following have been reported with parenteral penicillin G: General: Hypersensitivity reactions including the following: skin eruptions (maculopapular to exfoliative dermatitis), urticaria, laryngeal edema, fever, eosinophilia; other serum sickness-like reactions (including chills, fever, edema, arthralgia, and prostration); and anaphylaxis including shock and death. Note: Urticaria, other skin rashes, and serum sickness-like reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, penicillin G should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to therapy with penicillin G. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated. Gastrointestinal: Pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. See WARNINGS. Hematologic: Hemolytic anemia, leukopenia, thrombocytopenia. Neurologic: Neuropathy. Urogenital: Nephropathy. The following adverse events have been temporally associated with parenteral administration of penicillin G benzathine, although a causal relationship has not necessarily been established.: Body as a Whole: Hypersensitivity reactions including allergic vasculitis, pruritus, fatigue, asthenia, and pain; aggravation of existing disorder; headache. Cardiovascular: Cardiac arrest; hypotension; tachycardia; palpitations; pulmonary hypertension; pulmonary embolism; vasodilatation; vasovagal reaction; cerebrovascular accident; syncope. Gastrointestinal: Nausea, vomiting; blood in stool; intestinal necrosis. Hemic and Lymphatic: Lymphadenopathy. Injection Site: Injection site reactions including pain, inflammation, lump, abscess, necrosis, edema, hemorrhage, cellulitis, hypersensitivity, atrophy, ecchymosis, and skin ulcer. Neurovascular reactions including warmth, vasospasm, pallor, mottling, gangrene, numbness of the extremities, cyanosis of the extremities, and neurovascular damage. Metabolic: Elevated BUN, creatinine, and SGOT. Musculoskeletal: Joint disorder; periostitis; exacerbation of arthritis; myoglobinuria; rhabdomyolysis. Nervous System: Nervousness; tremors; dizziness; somnolence; confusion; anxiety; euphoria; transverse myelitis; seizures; coma. A syndrome manifested by a variety of CNS symptoms such as severe agitation with confusion, visual and auditory hallucinations, and a fear of impending death (Hoigne’s syndrome), has been reported after administration of penicillin G procaine and, less commonly, after injection of the combination of penicillin G benzathine and penicillin G procaine. Other symptoms associated with this syndrome, such as psychosis, seizures, dizziness, tinnitus, cyanosis, palpitations, tachycardia, and/or abnormal perception in taste, also may occur. Respiratory: Hypoxia; apnea; dyspnea. Skin: Diaphoresis. Special Senses: Blurred vision; blindness. Urogenital: Neurogenic bladder; hematuria; proteinuria;
renal failure; impotence; priapism.
Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of penicillin, and concurrent use of these drugs should be avoided. Concurrent administration of penicillin and probenecid increases and
prolongs serum penicillin levels by decreasing the apparent volume of
distribution and slowing the rate of excretion by competitively inhibiting
renal tubular secretion of penicillin.
Penicillin G benzathine should only be prescribed for the indications listed in this insert. 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 BICILLIN L-A, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, BICILLIN L-A 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. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including penicillin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis”. After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Inadvertent intravascular administration , including inadvertent direct
intra-arterial injection or injection immediately adjacent to arteries,
of Bicillin L-A and other penicillin preparations has resulted in severe
neurovascular damage, including transverse myelitis with permanent paralysis,
gangrene requiring amputation of digits and more proximal portions of
extremities, and necrosis and sloughing at and surrounding the injection
site. Such severe effects have been reported following injections into
the buttock, thigh and deltoid areas. Other serious complications of suspected
intravascular administration which have been reported include immediate
pallor, mottling, or cyanosis of the extremity both distal and proximal
to the injection site, followed by bleb formation; severe edema requiring
anterior and/or posterior compartment fasciotomy in the lower extremity.
The above-described severe effects and complications 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.1-9
See CONTRAINDICATIONS, Quadriceps femoris fibrosis and atrophy have been reported following repeated intramuscular injections of penicillin preparations into the anterolateral thigh. Injection into or near a nerve may result in permanent neurological damage.
General Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma. Care should be taken to avoid intravenous or intra-arterial administration,
or injection into or near major peripheral nerves or blood vessels, since
such injection may produce neurovascular damage. See CONTRAINDICATIONS,
Prolonged use of antibiotics may promote the overgrowth of nonsusceptible organisms, including fungi. Should superinfection occur, appropriate measures should be taken. Laboratory Tests In streptococcal infections, therapy must be sufficient to eliminate the organism; otherwise, the sequelae of streptococcal disease may occur. Cultures should be taken following completion of treatment to determine whether streptococci have been eradicated. . Drug Interactions Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of penicillin, and concurrent use of these drugs should be avoided. Concurrent administration of penicillin and probenecid increases and prolongs serum penicillin levels by decreasing the apparent volume of distribution and slowing the rate of excretion by competitively inhibiting renal tubular secretion of penicillin. Pregnancy Category B Reproduction studies performed in the mouse, rat, and rabbit have revealed no evidence of impaired fertility or harm to the fetus due to pencillin 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 Soluble penicillin G is excreted in breast milk. Caution should be exercised when penicillin G benzathine is administered to a nursing woman. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been conducted with this drug. Pediatric Use See INDICATIONS AND USAGE and
DOSAGE AND ADMINISTRATION.
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