PENICILLIN G BENZATHINE: 1,134 Adverse Event Reports & Safety Profile

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 dibenzylethylene diamine with two molecules of penicillin G. It is chemically designated as (2 S ,5 R ,6 R )-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-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: Molecular Formula (C 16 H 18 N 2 O 4 S) 2 ∙ C 16 H 20 N 2 ∙ 4H 2 O Molecular Wt.

981.19 Penicillin G procaine, (2 S ,5 R ,6 R )-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-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: Molecular Formula C 16 H 18 N 2 O 4 S ∙ C 13 H 20 N 2 O 2 ∙ H 2 O Molecular Wt.

588.72 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.

Chemical Structure Chemical

Structure

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bicillin C-R and other antibacterial drugs, Bicillin C-R should be used only to treat or prevent infections that are proven or strongly suspected to be caused by 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. This drug is indicated in the treatment of moderately severe infections due to penicillin-G-susceptible microorganisms that are susceptible to serum levels common to this particular dosage form. Therapy should be guided by bacteriological studies (including susceptibility testing) and by clinical response. Bicillin C-R is indicated in the treatment of the following in adults and 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 sensitive 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 Streptococcus pneumoniae . 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.

Lentocilin S suspension for injection is to be EXCLUSIVELY administered by DEEP INTRAMUSCULAR (IM) INJECTION. 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.

Posology Adults

Group A streptococcal infections - Upper respiratory tract infections: 1,200,000 IUunits in a single dose. Primary, secondary and early latent syphilis: 2,400,000 unitsIU in a single dose (injection at two different sites). Late latent syphilis or of unknown duration: 2,400,000 unitsIU (injection at two different sites) weekly for 3 consecutive weeks. Tertiary syphilis: 2,400,000 unitsIU (injection at two different sites) weekly for 3 consecutive weeks. Yaws, bejel and pinta: 1,200,000 unitsIU in a single dose. Prophylaxis of rheumatic fever: 1,200,000 unitsIU every 4 weeks. In high-risk patients it is recommended administration of 3 inevery 3 weeks. Prevention of diphtheria, including elimination of the asymptomatic carrier state: 1,200,000 unitsIU in a single dose. Newborns aged ≥ 1 month Asymptomatic congenital syphilis: 50,000 unitsIU/kg in a single dose (maximum dose: 2,400,000 unitsIU/dose). Benzathine benzylpenicillin is not recommended in newborns with proven or highly probable congenital syphilis.

Children

Group A Streptococcal infections - Upper respiratory tract infections: 25,000 - 50,000 unitsIU/kg in a single dose (maximum dose: 1,200,000 IUunits/dose) or weight < 27 kg: 300,000-600,000 IU units in a single dose weight ≥ 27 kg: 1,200,000 unitsIU in a single dose. - Primary, secondary and early latent syphilis: 50,000 unitsIU/kg (maximum dose: 2,400,000 unitsIU/dose) in a single dose. - Late latent syphilis or latent syphilis of unknown duration: 50,000 unitsIU/kg (maximum dose: 2,400,000 unitsIU/dose) weekly for 3 weeks. - Yaws, bejel and pinta: 300,000 unitsIU as a single dose in children aged less than 6 years or 1,200,000 IUunits in a single dose in children aged 6 years and older. -Prophylaxis of rheumatic fever: 25,000 - 50,000 unitsIU/kg in a single dose (maximum dose: 1,200,000 unitsIU/dose) or weight < 27 kg: 300,000 - 600,000 unitsIU in a single dose weight ≥ 27 kg: 1,200,000 unitsIU in a single dose. Prevention of diphtheria (including elimination of the asymptomatic carrier state): - children aged < 6 years (or weight < 30 kg): 600,000 unitsIU in a single dose - children aged ≥ 6 years (or weight ≥ 30 kg): 1,200,000 unitsIU in a single dose. Special populations Elderly - Dose adjustment is not necessary. However, since the elderly have a higher likelihood of decreased renal function, this must be taken into consideration during the selection of the posology and may be useful to monitor renal function. Renal insufficiency - Toxic concentrations of benzylpenicillin following administration of the usually recommended dose are not expected. Liver insufficiency - Dose adjustment is not necessary.

Hypersensitivity to the active substance, to other penicillin or to any of the excipients. Hypersensitivity to lidocaine or local anesthetics of the amide type.

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.

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 BENZATHINE 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 (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 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. Severe cutaneous adverse reactions Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients taking penicillin G (the active moiety in Bicillin C-R 900/300). When SCAR is suspected, Bicillin C-R 900/300 should be discontinued immediately and an alternative treatment should be considered.

Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system (CNS) and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death.

Discontinue

Bicillin C-R 900/300 and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Clostridioides difficile associated diarrhea Clostridioides difficile associated with diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Bicillin C-R 900/300, 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. See administration instructions below. 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 consistent with the diagnosis of Nicolau syndrome. 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.) FOR DEEP INTRAMUSCULAR INJECTION ONLY. There have been reports of inadvertent intravenous administration of penicillin G benzathine which has been associated with cardiorespiratory arrest and death. Therefore, do not inject intravenously or admix with other intravenous solutions. (See DOSAGE AND ADMINISTRATION section.) Administer by DEEP INTRAMUSCULAR INJECTION ONLY in the upper, outer quadrant of the buttock (dorsogluteal) or the ventrogluteal site. Quadriceps femoris fibrosis and atrophy have been reported following repeated intramuscular injections of penicillin preparations into the anterolateral thigh. Because of these adverse effects and the vascularity of this region, administration in the anterolateral thigh is not recommended.

PRECAUTIONS General Prescribing Bicillin C-R 900/300 in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of a development of drug-resistant bacteria. 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 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. Information for Patients Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. 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. Patients should be counseled that antibacterial drugs including Bicillin C-R 900/300 should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

When

Bicillin C-R 900/300 is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bicillin C-R 900/300 or other antibacterial drugs in the future.

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. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Pregnancy Teratogenic effects 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 (the hydrolysate of penicillin G benzathine) 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 sections.)

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 therapy. 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.

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. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine