BICILLIN L-A Benzathine Benzylpenicillin 900 mg (1,200,000 Units)/2.3mL size Pre-filled syringe and Needle.
BICILLIN L-A (sterile benzathine benzylpenicillin suspension) 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'-dibenzylethylenediamine (2:1), tetrahydrate. Its chemical structure is as follows:
COOH
H
O 3
CH
N
CH2CONH
CH3
S
CH2 CH2 HNCH 2CH2NH
.4H2-0 BICILLIN L-A contains benzathine benzylpenicillin (the benzathine salt of benzylpenicillin) in aqueous suspension with anhydrous sodium citrate buffer; and as w/v, approximately 0.5% lecithin, 0.6% carmellose sodium, 0.6% povidone, 0.1% methyl hydroxybenzoate and 0.01% propyl hydroxybenzoate. BICILLIN L-A suspension in the disposable pre-filled syringe formulation is viscous and opaque.
Benzylpenicillin exerts a bactericidal action against penicillin-sensitive micro-organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell-wall peptidoglycan, rendering the cell wall osmotically unstable. It is not active against the penicillinase-producing bacteria or against organisms resistant to beta-lactams because of alterations in the penicillin-binding proteins. The following in-vitro data are available but the clinical significance is unknown. Benzylpenicillin exerts high in vitro activity against Staphylococci (except penicillinase- producing strains), Streptococci (Groups A, C, G, H, L and M) and Pneumococci. Other organisms sensitive to benzylpenicillin are: Neisseria gonorrhoea, Corynebacterium diphtheria, Bacillus anthracis, Clostridia spp, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes and Leptospira spp. Treponema pallidum is extremely sensitive to the bactericidal action of benzylpenicillin.
Intramuscular benzathine benzylpenicillin is absorbed very slowly into the bloodstream from the intramuscular site and converted by hydrolysis to benzylpenicillin. This combination of hydrolysis and slow absorption results in blood serum levels much lower but much more prolonged than other parenteral penicillins. Intramuscular administration of 225 mg of benzathine benzylpenicillin in adults results in blood levels of 22.5 to 37.5 nanogram per mL, which are maintained for 4 to 5 days. Similar blood levels may persist for 10 days following administration of 450 mg and for 14 days following administration of 900 mg. Blood concentrations of 2.25 nanogram per mL may still be detectable 4 weeks following administration of 900 mg. Approximately 60% of benzylpenicillin 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. Benzylpenicillin 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.
Intramuscular benzathine benzylpenicillin is indicated in the treatment of infections due to penicillin-sensitive micro-organisms 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 benzathine benzylpenicillin: Streptococcal infections (Group A - without bacteraemia). Mild-to-moderate infections of the upper respiratory tract (eg., pharyngitis). Venereal infections - Syphilis, yaws, bejel and pinta. Medical conditions in which benzathine benzylpenicillin therapy is indicated as prophylaxis: Rheumatic fever and/or chorea - Prophylaxis with benzathine benzylpenicillin 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.
Previous hypersensitivity reaction to any of the penicillins.
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more apt to occur in individuals with a history of sensitivity to multiple allergens. There have been well-documented reports of individuals with a history of penicillin hypersensitivity reactions who have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before therapy with a penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins and other allergens. If an allergic reaction occurs, the drug should be discontinued and the patient treated with the usual agents, e.g., pressor amines, antihistamines and corticosteroids. Severe anaphylactoid reactions require emergency treatment with adrenaline. Oxygen and intravenous corticosteroids and airway management, including intubation, should also be administered as indicated. Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma. 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.
There have been reports of inadvertent intravenous administration of benzathine which has been associated with cardiorespiratory arrest and death. (See DOSAGE AND ADMINISTRATION.)
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 oedema requiring anterior and/or posterior compartment fasciotomy in the lower extremity. Severe effects and complications following accidental intravascular administration 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. (See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION sections). Injection into or near a nerve may result in permanent neurological damage. Quadriceps femoris fibrosis and atrophy have been reported following repeated intramuscular injections of penicillin preparations into the anterolateral thigh. Antibiotic-associated pseudomembranous colitis has been reported with many antibiotics including penicillin. 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 Clostridium difficile associated diarrhea (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 antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. The severity of the colitis may range from mild to life-threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases, appropriate therapy with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used. Prolonged use of antibiotics may promote the overgrowth of non-susceptible organisms, including fungi. Should superinfection occur, appropriate measures should be taken.
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. In prolonged therapy with penicillin and particularly with high-dosage schedules, periodic evaluation of the renal and haematopoietic systems is recommended. Fluids, electrolytes and protein replacement therapy should be provided when indicated.
Category A - Drugs which have been taken by a large number of pregnant women and women of child-bearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed. Although generally considered to be safe, BICILLIN L-A should be used during pregnancy only if clearly needed.
Soluble penicillin is excreted in breast milk. The effect on the infant, if any, is not known. Caution should be used when BICILLIN L-A is administered to a nursing woman.
(See INDICATIONS and DOSAGE AND ADMINISTRATION sections.)
Clinical studies of benzylpenicillin 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 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.
No long-term animal studies have been conducted with this drug.
Tetracycline may antagonise the bactericidal effect of penicillin and concurrent use of these drugs should be avoided. The rate of excretion of the penicillins is decreased by concomitant administration of probenecid which prolongs, as well as increases, blood levels of the penicillins.
Penicillins can interfere with the copper sulphate reagent method of testing for glycosuria, resulting in falsely elevated or falsely decreased readings. Such interference does not occur with the glucose oxidase method.
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 adverse reactions have been reported:
General:
Hypersensitivity reactions including the following: skin eruptions (maculopapular to exfoliative dermatitis), urticaria, laryngeal oedema, fever, eosinophilia; other serum sickness-like reactions (including chills, fever, oedema, arthralgia and prostration), and anaphylactic/anaphylactoid reaction (including shock and death).
Fever and eosinophilia may frequently be the only reaction observed.
Gastrointestinal:
Pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. (See PRECAUTIONS section.)
Haematologic: Haemolytic anaemia, leucopenia, thrombocytopenia Neurologic: Neuropathy
Urogenital:
Nephropathy, acute interstitial nephritis
As with other treatments for syphilis, the Jarisch-Herxheimer reaction has been reported. The following adverse events have been temporally associated with parenteral administration of benzylpenicillin:
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; vasodilation; vasovagal reaction; cerebrovascular accident; syncope.
Gastrointestinal: Nausea, vomiting; blood in stool; intestinal necrosis. Haematological: Lymphadenopathy.
Injection Site:
Injection site reactions including pain, inflammation, lump, abscess, necrosis, edema, haemorrhage, 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 benzylpenicillin procaine and, less commonly, after injection of the combination of benzylpenicillin benzathine and benzylpenicillin 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; apnoea; dyspnoea. Skin: Diaphoresis.
Special Senses:
Blurred vision; blindness.
Urogenital: Neurogenic bladder; haematuria; proteinuria; renal failure; impotence; priapism.
The stated volume of 2.3mL is a theoretical volume based on potency at the time of manufacture. Use a concentration of 442mg/mL when measuring part doses.
A single injection of 900 mg (1,200,000 Units) for adults. A single injection of 675 mg (900,000 Units) for older children. A single injection of 225 mg to 450 mg (300,000 to 600,000 Units) for infants and for children under 27 kg.
Syphilis - Primary, secondary and latent - 1.8 g ((2,400,000 Units) (1-dose). Late (tertiary including neurosyphilis) - 1.8 g at 7-day intervals for three doses. Congenital (with normal CSF) - under 2 years of age: 37.5 mg (50,000 Units)/kg body weight; ages 2-12 years; adjust dosage based on adult dosage schedule. Yaws, bejel and pinta - 900 mg (1,200,000 Units) (single injection).
Following an acute attack, benzathine benzylpenicillin (parenteral) may be given in doses of 900 mg (1,200,000 Units) once a month or 450 mg (600,000 Units) every 2 weeks.
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. Administer by DEEP, INTRAMUSCULAR INJECTION in the upper, outer quadrant of the buttock. In infants and small children, the midlateral aspect of the thigh may be preferable. When doses are repeated, vary the injection site. 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. Discard any unused portion.
There have been no reported overdoses with BICILLIN L-A. Penicillin in overdosage has the potential to cause neuromuscular hyperirritability and convulsive seizures. This is particularly so if the penicillin is given intravenously or to patients with renal failure.
BICILLIN L-A benzathine benzylpenicillin injection is supplied as follows: 2.3 mL size, containing 900 mg (1,200,000 Units) benzathine benzylpenicillin per pre-filled syringe. (The stated volume of 2.3mL is a theoretical volume based on potency at the time of manufacture. Use a concentration of 442mg/mL when measuring part doses.)
Store at 2 to 8oC. Refrigerate, do not freeze.
Prescription Only Medicine.
Pfizer New Zealand Ltd P O Box 3998 Auckland, New Zealand Toll Free Number: 0800 736 363
08 June 2012
Registered Trade Mark