Benzylpenicillin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BENZYL PENICILLIN (BENZYLPENICILLIN)

Composition:

Active substance: benzylpenicillin;

1 vial contains sterile sodium benzylpenicillin – 500,000 IU or 1,000,000 IU.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white crystalline powder.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Penicillins susceptible to β-lactamase action.

ATC code J01CE01.

Pharmacological Properties.

Pharmacodynamics.

The medicinal product is a water-soluble benzylpenicillin that exerts a bactericidal effect on susceptible microorganisms by inhibiting the biosynthesis of the cell wall. The antimicrobial spectrum of benzylpenicillin includes streptococci of groups A, B, C, G, H, L, and M, Streptococcus pneumoniae, Streptococcus viridans, enterococci, penicillinase-nonproducing strains of staphylococci, as well as Neisseriae, corynebacteria, Bacillus anthracis, actinomycetes, Pasteurella multocida, various spirochetes such as Leptospira, Treponema, Borrelia, and other spirochetes, along with numerous anaerobic microorganisms (peptococci, peptostreptococci, fusobacteria, clostridia). At high concentrations, the drug is also active against other Gram-negative microorganisms, such as Escherichia coli, Proteus mirabilis, salmonellae, shigellae, Enterobacter aerogenes, and Alcaligenes faecalis. In infections caused by staphylococci, enterococci, E. coli, or E. aerogenes, bacteriological investigations, including sensitivity testing, are recommended. Production of penicillinase (e.g., by staphylococci) results in resistance.

Pharmacokinetics.

After administration of high doses of penicillin, therapeutic concentrations are achieved even in poorly accessible tissues such as heart valves, bones, and cerebrospinal fluid. Maximum plasma levels of 150–200 IU/mL are achieved within 15–30 minutes after intramuscular injection of 10 million IU of the drug. Following short-term infusions (30 minutes), levels may reach up to 500 IU/mL. Protein binding to plasma proteins is approximately 55% of the total dose. The majority of the administered dose (50–80%) is excreted unchanged by the kidneys (85–95%). Biliary excretion of the active substance accounts for only a small portion of the dose (approximately 5%).

Because renal and hepatic functions in premature infants and neonates are not fully developed, the elimination half-life from blood serum is approximately 3 hours. Therefore, the dosing interval should be no less than 8–12 hours (depending on the degree of organ maturity). Elimination may also be delayed in elderly patients.

To prolong the dosing interval, the drug may be combined with depot-forming penicillin preparations.

Clinical characteristics.

Indications.

Infectious diseases caused by penicillin-sensitive microorganisms: sepsis, wound infections and skin infections, diphtheria (as an adjunct to antitoxin), pneumonia, empyema, erysipeloid, pericarditis, bacterial endocarditis, mediastinitis, peritonitis, meningitis, brain abscesses, arthritis, osteomyelitis; genital tract infections caused by Fusobacterium; and also in specific infections: anthrax; infections caused by Clostridium, including tetanus, listeriosis, pasteurellosis; rat-bite fever; fusospirochetosis, actinomycosis; treatment of complications caused by gonorrhea and syphilis; Lyme borreliosis after the first stage of the disease.

Contraindications. Hypersensitivity to benzylpenicillin or to other beta-lactam antibiotics (penicillins, cephalosporins, carbapenems). Contraindicated in newborns whose mothers have increased sensitivity to penicillin-group antibiotics. Epilepsy (with intralumbar administration). Severe allergic reactions or history of bronchial asthma, urticaria, or hay fever.

Interaction with other medicinal products and other forms of interaction.

Penicillin preparations, which have a bactericidal effect, should not be used in combination with bacteriostatic antibiotics. Combination with other antibiotics is appropriate only when synergistic action or some additional effect can be expected. Each component of the therapeutic combination should be administered in full dosage (the dose of the more toxic component may be reduced if synergistic action is indicated).

Bactericidal antibiotics used in combination with the drug include isoxazolylpenicillins, e.g., flucloxacillin, and other narrow-spectrum beta-lactam antibiotics, aminopenicillins, aminoglycosides. These should be administered by slow intravenous injection prior to benzylpenicillin administration. If possible, aminoglycosides should be administered intramuscularly separately. Possible competitive inhibition of elimination from the body should be considered when benzylpenicillin is used concomitantly with anti-inflammatory, antirheumatic, and antipyretic agents (indomethacin, phenylbutazone, high-dose salicylates). Aspirin, probenecid, thiazide diuretics, furosemide, and ethacrynic acid increase the half-life of benzylpenicillin, thereby increasing its plasma concentration and increasing the risk of toxic effects by influencing renal tubular secretion. Allopurinol increases the risk of allergic reactions (skin rashes). The use of benzylpenicillin may in some cases reduce the effectiveness of oral contraceptives.

Concomitant use with chloramphenicol, erythromycin, tetracycline, and sulfonamides should be avoided.

When used concomitantly with methotrexate, excretion of the latter is reduced and the risk of its toxicity increases.

Concomitant use of methotrexate and benzylpenicillin should be avoided if possible. If concomitant use is necessary, the dose of methotrexate should be reduced and serum methotrexate levels should be monitored. Close monitoring for possible additional adverse reactions, including leukopenia, thrombocytopenia, and skin suppuration, is required.

When benzylpenicillin is administered concomitantly with anti-inflammatory, antirheumatic, or antipyretic medicinal products (especially indomethacin, phenylbutazone, high-dose salicylates), excretion is competitively inhibited, resulting in increased serum concentration and prolonged elimination half-life.

When penicillin is used concomitantly with acenocoumarol or warfarin, prothrombin time or other appropriate coagulation parameters should be carefully monitored. Dose adjustment of the oral anticoagulant may also be required.

Effect on laboratory test parameters

• A positive result in the direct Coombs test is frequently observed (from 1% to 10%) in patients receiving 10,000,000 IU (equivalent to 6 g) or more of benzylpenicillin per day. After discontinuation of penicillin, the test result may remain positive for 6–8 weeks.
• False-positive results may be obtained when determining urinary protein using precipitation methods (sulfosalicylic acid, trichloroacetic acid), the Folin–Ciocalteu–Lowry method, or the Biuret method. Therefore, results of such tests should be interpreted cautiously in patients receiving penicillin. Penicillin does not affect protein determination using test strips.
• False-positive results may be obtained when determining uric acid using the ninhydrin method.
• Penicillins bind to albumin. When electrophoresis is used to determine albumin, pseudobisalbuminemia may occur.
• During penicillin therapy, non-enzymatic determination of glucose in urine may yield false-positive results. Patients taking penicillin should use enzymatic tests for glucose determination in urine.
• An increase in urinary 17-ketosteroids (using the Zimmerman reaction) may be observed.

Special precautions for use

If there is a possibility of hypersensitivity reactions to penicillins and cephalosporins, it is recommended to perform a preliminary test within a specialized medical facility. The test should be conducted by experienced personnel according to a standardized procedure, capable of interpreting test results.

Cross-allergy may occur in patients with hypersensitivity to cephalosporins.

Severe and sometimes fatal hypersensitivity reactions (anaphylactic reactions, hay fever, urticaria) have been observed in patients undergoing penicillin therapy. Such reactions occur more frequently in patients with a history of severe allergic reactions. If symptoms of hypersensitivity occur, benzylpenicillin therapy must be discontinued and appropriate alternative treatment initiated. Treatment of anaphylactic reaction symptoms may be required, for example, immediate administration of adrenaline, corticosteroids (intravenously), and emergency management of respiratory failure.

The drug should be used with particular caution in patients with other allergic disorders, patients with severe cardiac diseases or severe electrolyte imbalances of any origin (attention should be paid to electrolyte intake, especially potassium); renal impairment; hepatic dysfunction; cerebral edema or meningitis (increased risk of seizures, especially when high doses (> 20 million IU) of penicillin are administered); patients with dermatomycoses (parallergic reactions are possible due to potential cross-antigenicity between penicillins and metabolites of dermatophytes).

Rare cases of prolonged prothrombin time have been reported in patients receiving penicillins. Appropriate monitoring should be performed in patients taking anticoagulants. Dose adjustment of the anticoagulant may be necessary.

Penicillin is not recommended for treatment of patients with acute lymphocytic leukemia or infectious mononucleosis due to an increased risk of erythematous skin rashes. It should be noted that in patients with diabetes mellitus, absorption of the active substance from intramuscular depots may be reduced.

In patients receiving high doses of the drug for more than 5 days, electrolyte balance, blood count, and renal function should be monitored.

In patients with severe renal dysfunction, high doses of penicillin may cause neurological disturbances, seizures, or coma.

Caution should be exercised when administering the drug to infants, patients with severe cardiopathy, hypovolemia, epilepsy, or impaired renal or hepatic function.

When administering the drug intravenously in high doses (more than 10 million IU/day), the injection site should be changed every 2 days to prevent superinfection and thrombophlebitis.

Intramuscular administration of the drug to infants may lead to serious local reactions; therefore, intravenous administration is preferred.

Prolonged use of the drug may lead to colonization by resistant microorganisms or fungi. Superinfection may occur, requiring careful monitoring of such patients.

If severe diarrhea characteristic of pseudomembranous colitis (in most cases caused by Clostridium difficile) develops, discontinuation of the drug is recommended and appropriate measures should be taken. Use of agents that inhibit peristalsis is contraindicated. In the treatment of sexually transmitted diseases with suspected syphilis, serological tests should be performed before starting therapy and repeated for 4 months after its completion.

In the treatment of Lyme borreliosis or syphilis, the Jarisch–Herxheimer reaction may result from the bactericidal effect of penicillin on pathogens, characterized by fever, chills, and general and focal symptoms (usually occurring from 2 to 12 hours after the first dose). Patients should be informed that this is usually a transient complication of antibacterial therapy.

To suppress or alleviate the Jarisch–Herxheimer reaction, administer 50 mg of prednisolone or its equivalent at the first dose of the drug. In patients with syphilis in stages involving the cardiovascular system, blood vessels, or meninges, the Jarisch–Herxheimer reaction can be prevented by administering prednisolone 50 mg daily or an equivalent steroid for 1–2 weeks.

For patients with severe pneumonia, empyema, sepsis, meningitis, or peritonitis who require higher serum levels of penicillin, treatment with water-soluble alkaline salts of benzylpenicillin is necessary.

If neurological involvement cannot be excluded in patients with congenital syphilis, penicillin formulations achieving the highest concentrations in cerebrospinal fluid should be used.

Due to possible electrolyte imbalances, benzylpenicillin should be administered slowly and not more than 10 million IU at a time, because epileptic seizures may occur after administration of more than 20 million IU.

Freshly prepared injectable or infusion solutions must be used immediately. Even when stored in a refrigerator, aqueous solutions of sodium benzylpenicillin decompose, forming degradation products and metabolites.

Use during pregnancy or breastfeeding

Benzylpenicillin crosses the placental barrier, and its concentration in fetal plasma 1–2 hours after administration corresponds to the concentration in maternal serum. Available data on the use of the drug during pregnancy indicate no adverse effects on the fetus/newborn. The use of the drug during pregnancy is possible only after careful assessment of the benefit-risk ratio.

Benzylpenicillin passes into breast milk in small amounts; therefore, the risk of hypersensitivity in the infant cannot be excluded. The use of the medicinal product during breastfeeding is possible only when the expected benefit to the mother outweighs the potential risk to the infant.

In infants receiving partial artificial feeding, breastfeeding should be discontinued if the mother is taking benzylpenicillin. Resumption of breastfeeding is possible 24 hours after discontinuation of treatment.

Ability to influence reaction speed when driving or operating machinery
No negative effect on reaction speed when driving or operating machinery has been observed.

Administration and Dosage.

The medicinal product is administered intramuscularly, subcutaneously, intravenously (by bolus or infusion), intrathecally, or into body cavities. The most common route of administration is intramuscular.

Intravenous administration:
For moderate infections, the usual single dose for adults is 250,000–500,000 IU, daily dose 1,000,000–2,000,000 IU; for severe infections, up to 10,000,000–20,000,000 IU per day; for gas gangrene, up to 40,000,000–60,000,000 IU per day. The usual daily dose for children under 1 year of age is generally 50,000–100,000 IU/kg; for children aged 1 year and older, 50,000 IU/kg. If necessary, the daily dose may be increased to 200,000–300,000 IU/kg, and in life-threatening situations, up to 500,000 IU/kg. The drug should be administered 4–6 times daily. Benzylpenicillin solution should be prepared immediately before use. For intravenous bolus injection, dissolve a single dose (1,000,000–2,000,000 IU) in 5–10 mL of sterile water for injections or 0.9% sodium chloride solution and administer slowly over 3–5 minutes. For intravenous infusion, dissolve 2,000,000–5,000,000 IU of antibiotic in 100–200 mL of 0.9% sodium chloride solution or 5% glucose solution and administer at a rate of 60–80 drops per minute.

The drug should be administered intravenously 1–2 times daily, in combination with intramuscular injections.

Intramuscular administration:
For moderate infections, the usual single dose for adults is 250,000–500,000 IU, daily dose 1,000,000–2,000,000 IU; for severe infections, up to 10,000,000–20,000,000 IU per day; for gas gangrene, up to 40,000,000–60,000,000 IU per day. The usual daily dose for children under 1 year of age is 50,000–100,000 IU/kg; for children aged 1 year and older, 50,000 IU/kg. If necessary, the daily dose may be increased to 200,000–300,000 IU/kg, and in life-threatening situations, up to 500,000 IU/kg. The drug should be administered 4–6 times daily. For intramuscular injection, add 1–3 mL of sterile water for injections, 0.9% sodium chloride solution, or 0.5% procaine solution to the vial contents. The resulting solution should be injected deeply into the muscle of the upper outer quadrant of the buttock.

Subcutaneous administration:
Benzylpenicillin may be used for infiltration injections at a concentration of 100,000–200,000 IU in 1 mL of 0.25–0.5% procaine solution. Into body cavities (peritoneal, pleural), administer Benzylpenicillin solution at a concentration of 10,000–20,000 IU/mL for adults and 2,000–5,000 IU/mL for children. Dissolve in sterile water for injections or 0.9% sodium chloride solution. Treatment duration is 5–7 days, followed by transition to intramuscular administration.

Intrathecal administration:
The drug is administered in purulent diseases of the brain, spinal cord, and meninges. For adults, the dose is 5,000–10,000 IU; for children aged 1 year and older, 2,000–5,000 IU, administered slowly at a rate of 1 mL per minute, once daily. Dilute the drug in sterile water for injections or 0.9% sodium chloride solution at a concentration of 1,000 IU/mL. Before injection, remove 5–10 mL of cerebrospinal fluid from the spinal canal and mix it with the antibiotic solution in equal proportion. Repeat injections for 2–3 days, then switch to intramuscular administration.

Treatment of patients with syphilis and gonorrhea should follow specially developed regimens. Depending on the form and severity of the disease, Benzylpenicillin should be administered for 7–10 days up to 2 months or longer (e.g., in sepsis, septic endocarditis).

Children.

May be used in children from birth. The medicinal product should be used with particular caution in children under 2 years of age.

Overdose.

Symptoms of overdose largely correspond to the nature of adverse effects. Gastrointestinal disturbances and electrolyte imbalance may occur. Increased neuromuscular excitability or predisposition to cerebral seizures is possible.

Treatment: There is no specific antidote. Management includes hemodialysis, gastric lavage, and symptomatic therapy; particular attention should be paid to maintaining water and electrolyte balance.

Adverse Reactions

Blood and lymphatic system disorders: eosinophilia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, agranulocytosis, pancytopenia. Hemolytic anemia, coagulation disorders, and positive Coombs test. Prolongation of bleeding time and prothrombin time.

Immune system disorders: allergic reactions, including urticaria, erythema multiforme, exfoliative dermatitis, contact dermatitis, angioneurotic edema, fever, arthralgia, anaphylactic or anaphylactoid reactions (bronchial asthma, thrombocytopenic purpura, gastrointestinal symptoms).

Parallergic reactions may occur in patients with dermatomycoses, possibly due to antigenic cross-reactivity between penicillin and metabolites of dermatophytes. Serum sickness and Jarisch–Herxheimer reaction in association with spirochetal infections (syphilis and Lyme disease) have been reported.

Nervous system disorders: with high-dose infusion (over 20 million IU in adults), there is an increased risk of seizures, particularly in patients with severe renal impairment, epilepsy, meningitis, cerebral edema, or when using extracorporeal circulation devices. Neurotoxic reactions including hyperreflexia, myoclonic jerks; coma, meningism symptoms, paresthesia, neuropathy.

Metabolism and nutrition disorders: electrolyte imbalance may occur with rapid administration of doses exceeding 10 million IU, increased serum nitrogen levels.

Gastrointestinal disorders: stomatitis, glossitis, black hairy tongue, nausea, vomiting, diarrhea. If diarrhea occurs during treatment, pseudomembranous colitis should be considered.

Skin disorders: pemphigoid.

Hepatobiliary disorders: hepatitis, cholestasis.

Renal and urinary disorders: interstitial nephritis, nephropathy (with intravenous doses exceeding 10 million IU), albuminuria, cylindruria, hematuria. Oliguria or anuria, usually reversible within 48 hours after discontinuation of therapy. Diuresis may be restored after administration of 10% mannitol solution.

Other: local reactions at the site of administration; phlebitis or thrombophlebitis may occur with intravenous administration; severe local reactions after intramuscular injection in infants; prolonged antibiotic use may lead to secondary superinfections caused by resistant microorganisms; candidiasis. In the treatment of syphilis or other spirochetal infections, bacterial lysis may trigger the Jarisch–Herxheimer reaction, characterized by fever, chills, myalgia, headache, exacerbation of skin symptoms, tachycardia, vasodilation, and changes in blood pressure; hypersensitivity reactions (pruritus, laryngospasm, bronchospasm, arterial hypotension, vascular collapse); serum sickness, including symptoms such as fever, weakness, arthralgia, abdominal pain, rash (all types); high doses of the drug may lead to congestive heart failure.

Shelf life. 4 years.

Storage conditions.

In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility. To prevent undesirable chemical reactions, do not mix two injectable or infusion drugs in the same container. Avoid using solutions containing glucose.

The drug is incompatible with metal ions, especially copper, mercury, zinc, and zinc compounds, which may be present in rubber stoppers of infusion vials. Substances with oxidizing and reducing properties, alcohol, glycerin, macrogols, and other hydroxyl-containing compounds may also inactivate the drug. The drug is rapidly inactivated in slightly alkaline solutions by cysteine and other aminothiol compounds. Sympathomimetic amines are also incompatible with benzylpenicillin.

The drug should not be administered in glucose solution.

Do not mix with injectable solutions containing cimetidine, cytarabine, chlorpromazine, dopamine, heparin, hydroxyzine, lactate, lincomycin, metaraminol, sodium bicarbonate, oxytetracycline, pentobarbital, tetracycline, sodium thiopental, vancomycin. Benzylpenicillin is incompatible in solution with vitamin B complex and ascorbic acid.

Packaging.

500,000 IU or 1,000,000 IU in vials; 10 vials per pack.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.

139 Saksaganskoho Street, Kyiv, 01032, Ukraine.