Prescription Drugs

CLINICAL PHARMACOLOGY General Penicillin G benzathine and penicillin G procaine have a low solu-bility and, thus, the drugs are slowly released from intramuscular injection sites. The drugs are hydrolyzed to penicillin G. This combination of hydrolysis and slow absorption results in blood serum levels much lower but more prolonged than other parenteral penicillins. Intramuscular administration of 1, 200, 000 units of Bicillin C-R 900/300 (penicillin g benzathine and penicillin g procaine injection) in patients weighing 100 to 140 lbs. usually produces average blood levels of 0. 24 units/mL at 24 hours, 0.039 units/mL at 7 days, and 0. 024 units/mL at 10 days. 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 mucopep-tide. 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, Corynebacterium diphtheriae, Bacillus anthracis, Clostridia species, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira species. Treponema pallidum is extremely susceptible to the bactericidal action of penicillin G. Susceptibility Test: If the Kirby-Bauer method of disc susceptibility is used, a 10-unit penicillin disc should give a zone greater than 28 mm when tested against a penicillin-susceptible bacterial strain.

Bicillin® C-R 900/300 (penicillin G benzathine and penicillin G procaine) Injectable Suspension 2 mL Syringe for deep IM injection only WARNING NOT FOR INTRAVENOUS USE. DO NOT INJECT INTRAVENOUSLY OR ADMIX WITH OTHER INTRAVENOUS SOLUTIONS. THERE HAVE BEEN REPORTS OF INADVERTENT INTRAVENOUS ADMINISTRATION OF PENICILLIN G BENZA-THINE WHICH HAS BEEN ASSOCIATED WITH CARDIORESPIRATORY ARREST AND DEATH. Prior to administration of this drug, carefully read the WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the labeling. DESCRIPTION Bicillin C-R 900/300 (penicillin G benzathine and penicillin G procaine injectable suspension) contains the equivalent of 900, 000 units of penicillin G as the benzathine and 300, 000 units of penicillin G as the procaine salts. It is available for deep intramuscular injection. Penicillin G benzathine is prepared by the reaction of dibenzyleth-ylene diamine with two molecules of penicillin G. It is chemically designated as (2S, 5R, 6R)-3, 3-Dimethyl-7-oxo-6-(2-phenylac-etamido)-4-thia-1-azabicyclo[3. 2. 0]heptane-2-carboxylic acid compound with N, N'-dibenzylethylenediamine (2:1), tetrahydrate. It occurs as a white, crystalline powder and is very slightly soluble in water and sparingly soluble in alcohol. Its chemical structure is as follows: Penicillin G procaine, (2S, 5R, 6R)-3, 3-Dimethyl-7-oxo-6-(2-pheny-lacetamido)-4-thia-1-azabicyclo[3. 2. 0]heptane-2-carboxylic acid compound with 2-(diethylamino)ethyl p-aminobenzoate (1:1) monohydrate, is an equimolar salt of procaine and penicillin G. It occurs as white crystals or a white, microcrystalline powder and is slightly soluble in water. Its chemical structure is as follows: Each 2 mL syringe contains the equivalent of 1, 200, 000 units of penicillin G as follows: penicillin G benzathine equivalent to 900, 000 units of penicillin G and penicillin G procaine equivalent to 300, 000 units of penicillin G in a stabilized aqueous suspension with sodium citrate buffer; and as w/v, approximately 0. 5% lecithin, 0. 55% carboxymethylcellulose, 0. 55% povidone, 0. 1% methylparaben, and 0. 01% propylparaben. Bicillin C-R 900/300 injectable suspension is viscous and opaque. Read CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections prior to use.

INDICATIONS Bicillin C-R 900/300 (penicillin g benzathine and penicillin g procaine injection) is indicated in the treatment of infections as described below that are susceptible to serum levels characteristic of this particular dosage form. Therapy should be guided by bacteriological studies (including susceptibility testing) and by clinical response. Bicillin C-R 900/300 (penicillin g benzathine and penicillin g procaine injection) is indicated in the treatment of the following in pediatric patients: Moderately severe to severe infections of the upper-respiratory tract, scarlet fever, erysipelas, and skin and soft-tissue infections due to susceptible streptococci. NOTE: Streptococci in Groups A, C, G, H, L, and M are very susceptible to penicillin G. Other groups, including Group D (enterococci), are resistant. Penicillin G sodium or potassium is recommended for streptococcal infections with bacteremia. Moderately severe pneumonia and otitis media due to susceptible pneumococci. NOTE: Severe pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, and arthritis of pneumococcal etiology are better treated with penicillin G sodium or potassium during the acute stage. When high, sustained serum levels are required, penicillin G sodium or potassium, either IM or IV, should be used. This drug should not be used in the treatment of venereal diseases, including syphilis, gonorrhea, yaws, bejel, and pinta. DOSAGE AND ADMINISTRATION Streptococcal Infections Group A infections of the upper-respiratory tract, skin and soft-tis-sue infections, scarlet fever, and erysipelas: A single injection of Bicillin C-R 900/300 (penicillin g benzathine and penicillin g procaine injection) is usually sufficient for the treatment of Group A streptococcal infections in pediatric patients. Pneumococcal Infections (except pneumococcal meningitis) One Bicillin C-R 900/300 (penicillin g benzathine and penicillin g procaine injection) repeated at 2- or 3-day intervals until the temperature is normal for 48 hours. Other forms of penicillin may be necessary for severe cases. Method of Administration Bicillin C-R is intended for Intramuscular Injection ONLY. Do not inject into or near an artery or nerve, or intravenously or admix with other intravenous solutions. (See WARNINGS section). 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. 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‚ C-R 900/300 (penicillin G benzathine and penicillin G procaine injectable suspension) is supplied in 2 mL size syringes in packages of 10 syringes as follows: 1, 200, 000 units per syringe (21 gauge, thin-wall 1 inch needle for pediatric use), NDC 60793-602-10. Store in a refrigerator, 2° to 8°C (36° to 46°F). Keep from freezing. Prescribing Information as of December 2006. Manufactured and Distributed by: King Pharmaceuticals, Inc., Bristol, TN 37620

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Penicillin in overdosage has the potential to cause neuromuscular hyperirritability or convulsive seizures. CONTRAINDICATIONS A previous hypersensitivity reaction to any penicillin or to procaine is a contraindication.

SIDE EFFECTS 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. 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, intra-venous 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 section.) Hematologic: Hemolytic anemia, leukopenia, thrombocytopenia. Neurologic: Neuropathy. Urogenital: Nephropathy. The following adverse events have been temporally associated with parenteral administrations of penicillin G benzathine, although a causal relationship has not necessarily been established: Body as a Whole: Hypersensitivity reactions including allergic vas-culitis, pruritis, fatigue, asthenia, and pain; aggravation of existing disorder; headache. Cardiovascular: Cardiac arrest; hypotension; tachycardia; palpitations; pulmonary hypertension; pulmonary embolism; vasodilation; 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, hypersen-sitivity, 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, tinni-tus, 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. 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.

WARNINGS WARNING: NOT FOR INTRAVENOUS USE. DO NOT INJECT INTRAVENOUSLY OR ADMIX WITH OTHER INTRAVENOUS SOLUTIONS. THERE HAVE BEEN REPORTS OF INADVERTENT INTRAVENOUS ADMINISTRATION OF PENICILLIN G BENZA-THINE WHICH HAS BEEN ASSOCIATED WITH CARDIORESPIRATORY ARREST AND DEATH. Prior to administration of this drug, carefully read the WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the labeling. The combination of penicillin G benzathine and penicillin G procaine should only be prescribed for the indications listed in this insert. Anaphylaxis SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANA-PHYLACTIC) 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 C-R CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, BICILLIN C-R 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 with diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Bicillin C-R 900/300 (penicillin g benzathine and penicillin g procaine injection) , 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. Method of Administration Do not inject into or near an artery or nerve. Injection into or near a nerve may result in permanent neurological damage. Inadvertent intravascular administration, including inadvertent direct intra-arterial injection or injection immediately adjacent to arteries, of Bicillin C-R 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 PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections.) Do not inject intravenously or admix with other intravenous solutions. There have been reports of inadvertent intravenous administration of penicillin G benzathine which has been associated with cardiorespiratory arrest and death. (See DOSAGE AND ADMINISTRATION section.) Quadriceps femoris fibrosis and atrophy have been reported following repeated intramuscular injections of penicillin preparations into the anterolateral thigh. PRECAUTIONS 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 admin-istration, or injection into or near major peripheral nerves or blood vessels, since such injections may produce neurovascular damage. (See WARNINGS, and DOSAGE AND ADMINISTRATION sections. ) A small percentage of patients are sensitive to procaine. If there is a history of sensitivity, make the usual test:Inject intradermally 0. 1 mL of a 1 to 2 percent procaine solution. Development of an erythema, wheal, flare, or eruption indicates procaine sensitivity. Sensitivity should be treated by the usual methods, including barbiturates, and procaine penicillin preparations should not be used. Antihistaminics appear beneficial in treatment of procaine reactions. The use of antibiotics may result in overgrowth of nonsusceptible organisms. Constant observation of the patient is essential. If new infections due to bacteria or fungi appear during therapy, the drug should be discontinued and appropriate measures taken. 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. In prolonged therapy with penicillin, and particularly with high-dosage schedules, periodic evaluation of the renal and hematopoietic systems is recommended. 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. 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. 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 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 Soluble penicillin G is excreted in breast milk. Caution should be exercised when penicillin G benzathine and penicillin G procaine are administered to a nursing woman. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been conducted with these drugs. Pediatric Use (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION section.) Geriatric Use Clinical studies of penicillin G benzathine and penicillin G procaine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug thera-py. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function (see CLINICAL PHARMACOLOGY). Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 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, 242:1289, 1979.