Benethamine Penicillin/Benzylpenicillin 213

Preparations
USP 31: Penicillin V Benzathine Oral Suspension.

Proprietary Preparations (details are given in Part 3)

Austral.: Abbocillin-V; Cilicaine V; Austria: Ospen; Canad.: Pen-Vee;
Cz.: Ospen; Fr.: Oracilline; Ger.: InfectoBicillin; Gr.: Ospen; Hung.: Ospen;
Oxybion; Pol.: Ospen; Rus.: Ospen (); Spain: Benoral; Switz.:
Ospen; Phenocillin; Turk.: Pen-Os; Venez.: Ospen.

Benzylpenicillin (BAN, rINN)

Bencilpenicilina; Bensylpenicillin; Bentsyylipenisilliini; Benzil Penisiliin; Benzylpnicilline; Benzylpenicillinum; Crystalline Penicillin G;
Penicillin; Penicillin G; Penisilin G. (2S,5R,6R)-3,3-Dimethyl-7-oxo6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (6R)-6-(2-Phenylacetamido)penicillanic acid.

C 16 H 18N 2 O 4 S = 334.4.
C AS 61-33-6.
ATC J01CE01; S01AA14.
ATC Vet QJ01CE01; QJ51CE01; QS01AA14.

H
S

N
H
N

CH3
CH3

O
COOH
Description. The name benzylpenicillin is commonly used to
describe either benzylpenicillin potassium or benzylpenicillin
sodium as these are the forms in which benzylpenicillin is used.
In Martindale, benzylpenicillin means either the potassium or
sodium salt.

Benzylpenicillin Potassium (BANM, rINNM)

Bencilpenicilina potsica; Bensylpenicillinkalium; Bentsyylipenisilliinikalium; Benzilpenicilino kalio druska; Benzilpenicillin-klium;
Benzylopenicylina potasowa; Benzylpenicilin draseln sl; Benzylpnicilline potassique; Benzylpenicillinum kalicum; Kalii Benzylpenicillinum; Penicillin G Potassium; Penisilin G Potasyum.

C 16 H 17KN 2 O 4 S = 372.5.
C AS 113-98-4.
ATC J01CE01; S01AA14.
ATC Vet QJ01CE01; QS01AA14.
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and
Viet.
Ph. Eur. 6.2 (Benzylpenicillin Potassium). The potassium salt of a
substance produced by growing certain strains of Penicillium notatum or related organisms or obtained by any other means. A
white or almost white crystalline powder. Very soluble in water;
practically insoluble in fatty oils and in liquid paraffin. A 10%
solution in water has a pH of 5.5 to 7.5. Store in airtight containers.
USP 31 (Penicillin G Potassium). Colourless or white crystals, or
white crystalline powder. It is odourless or practically so, and is
moderately hygroscopic. Very soluble in water, in sodium chloride 0.9%, and in glucose solutions; sparingly soluble in alcohol.
Its solutions retain substantially full potency for several days at
temperatures below 15, but are rapidly inactivated by acids, by
alkali hydroxides, by glycerol, and by oxidising agents. pH of a
6% solution in water is between 5.0 and 7.5. Store in airtight containers.
Incompatibility and stability. As for Benzylpenicillin Sodium, below.

Benzylpenicillin Sodium (BANM, rINNM)

Bencilpenicilina sdica; Bensylpenicillinnatrium; Bentsyylipenisilliininatrium; Benzilpenicilino natrio druska; Benzilpenicillin-ntrium;
Benzylopenicylina sodowa; Benzylpenicilin sodn sl; Benzylpnicilline sodique; Benzylpenicillinum natricum; Natrii Benzylpenicillinum; Penicillin G Sodium; Sodyum Penisilin G.

C 16 H 17N 2 NaO 4 S = 356.4.
C AS 69-57-8.
ATC J01CE01; S01AA14.
ATC Vet QJ01CE01; QS01AA14.
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., US, and Viet.
Ph. Eur. 6.2 (Benzylpenicillin Sodium). The sodium salt of a substance produced by growing certain strains of Penicillium notatum or related organisms or obtained by any other means. A
white or almost white crystalline powder. Very soluble in water;
practically insoluble in fatty oils and in liquid paraffin. A 10%
solution in water has a pH of 5.5 to 7.5. Store in airtight containers.
USP 31 (Penicillin G Sodium). Colourless or white crystals, or

white to slightly yellow crystalline powder. It is odourless or

practically so, and is moderately hygroscopic. Its solutions lose
potency fairly rapidly at room temperature, but retain substantially full potency for several days at temperatures below 15. Its
solutions are rapidly inactivated by acids, by alkali hydroxides,
by oxidising agents, and by penicillinase. pH of a 6% solution in
water is between 5.0 and 7.5. Store in airtight containers.
Incompatibility. Benzylpenicillin has been reported to be incompatible with metal ions and some rubber products. Its stability may be affected by ionic and nonionic surfactants, oxidising
and reducing agents, alcohols, glycerol, glycols, macrogols and
other hydroxy compounds, some paraffins and bases, some preservatives such as chlorocresol or thiomersal, carbohydrate solutions in an alkaline pH, fat emulsions, blood and blood products,
and viscosity modifiers. Benzylpenicillin is incompatible with a
wide range of acidic and basic drugs (see Stability, below) and
with a number of other antimicrobials, including amphotericin B,
some cephalosporins, and vancomycin. Benzylpenicillin and
aminoglycosides are mutually incompatible and injections
should be given at separate sites.
Stability. Benzylpenicillin is hydrolysed in aqueous solutions
by degradation of the beta-lactam ring and hydrolysis is accelerated by increased temperature or alkaline conditions; inactivation also occurs under acid conditions. Degradation products include penillic, penicillenic, and penicilloic acids which lower the
pH and cause a progressive increase in the rate of deterioration;
N-formylpenicillamine and very small amounts of penicillamine
have also been detected. Degradation is minimal at about pH 6.8
and deterioration of benzylpenicillin in solution may be retarded
by using a citrate buffer. Dilute solutions are more stable than
concentrated ones.
References.
1. Lynn B. The stability and administration of intravenous penicillins. Br J Intraven Ther 1981; 2 (Mar): 2239.
2. Bird AE, et al. N-Formylpenicillamine and penicillamine as degradation products of penicillins in solution. J Pharm Pharmacol
1986; 38: 91317.

Units
The second International Standard Preparation (1952)
of benzylpenicillin sodium contained 1670 units of
penicillin per mg but was withdrawn in 1968 since
penicillin can now be characterised completely by
chemical tests. Despite this, doses of benzylpenicillin
are still expressed in units in some countries.
Benzylpenicillin potassium 600 mg or benzylpenicillin sodium 600 mg have generally been considered to
be equivalent to about 1 million units (1 mega unit).

Adverse Effects
The most common adverse effects of benzylpenicillin
are hypersensitivity reactions, especially skin rashes;
anaphylaxis occasionally occurs and has sometimes
been fatal.
Gastrointestinal effects such as diarrhoea and nausea
are the most common adverse effects after oral use of
benzylpenicillin; a sore mouth or tongue or a black
hairy tongue have occasionally been reported. Pseudomembranous colitis has been associated with the use
of most antibiotics; ampicillin or amoxicillin are the
most frequently implicated penicillins (see Antibioticassociated Colitis, p.171).
Other adverse effects have generally been associated
with large intravenous doses of benzylpenicillin; patients with renal impairment are also at increased risk.
These adverse effects include haemolytic anaemia and
neutropenia, both of which might have some immunological basis; prolongation of bleeding time and defective platelet function; convulsions and other signs of
CNS toxicity (encephalopathy has followed intrathecal
dosage and can be fatal); and electrolyte disturbances
because of the large amounts of potassium or sodium
given when benzylpenicillin potassium or sodium, respectively, are used.
Hepatitis and cholestatic jaundice have been reported
rarely with some penicillins, notably penicillinase-resistant penicillins such as flucloxacillin and oxacillin,
and also combinations of amoxicillin or ticarcillin with
clavulanic acid.
Nephropathy and interstitial nephritis, which may have
some immunological basis, have been especially associated with meticillin, but may be produced by other
penicillins.

The symbol denotes a preparation no longer actively marketed

Some patients with syphilis and other spirochaete infections may experience a Jarisch-Herxheimer reaction
shortly after starting treatment with penicillin, which is
probably due to the release of endotoxins from the
killed treponemes and should not be mistaken for a hypersensitivity reaction. Symptoms include fever, chills,
headache, and reactions at the site of the lesions. The
reaction can be dangerous in cardiovascular syphilis,
or where there is a serious risk of increased local damage, such as with optic atrophy.
Hypersensitivity. The overall incidence of allergic reactions to penicillin has been reported to vary from
about 1 to 10% although some patients may have been
incorrectly labelled allergic to penicillin. Anaphylactic reactions occur in about 0.05% of patients, usually
after parenteral use, but they have also been reported
after taking oral penicillin.
Hypersensitivity to penicillin gives rise to immediate
reactions including anaphylaxis, angioedema, urticaria, and some maculopapular rashes. Late reactions may
include serum sickness-like reactions and haemolytic
anaemia. Reactions are considered to be due mainly to
breakdown products produced in vitro before use or to
metabolites of penicillin, and possibly penicillin itself.
These act as haptens which, when combined with proteins and other macromolecules, produce potential antigens. As the hypersensitivity is related to the basic
penicillin structure, patients who are genuinely allergic
to benzylpenicillin must be assumed to be allergic to all
penicillins; sensitised patients may also react to the cephalosporins and other beta-lactam antibiotics.
Tests for hypersensitivity may be used to determine
those patients most likely to develop serious allergic
reactions to penicillins. Skin tests are used to evaluate
the current risk of immediate or accelerated IgE-mediated reactions, the most serious being anaphylaxis.
Both the major and minor determinants of penicillin
hypersensitivity should be used; the major determinant
is available as penicilloyl-polylysine (p.2364) and a
minor-determinant mixture consisting of benzylpenicillin and its derivatives, including penicilloic acid and
benzylpenicilloylamine, can be used, although if this is
not available a solution of benzylpenicillin may be substituted. Adrenaline should be available in case an anaphylactic reaction develops. The results of skin tests
are unreliable if a significant time has elapsed before
beginning therapy. A number of in-vitro tests including
the radioallergosorbent test (RAST) have been developed.
Desensitisation may be attempted in patients allergic to
penicillin when treatment with penicillin is considered
essential. It involves very small doses of penicillin given at relatively short intervals of 15 minutes or more,
and gradually increased to therapeutic concentrations.
However, desensitisation may be hazardous and
should only be carried out if the patient can be monitored continuously and adrenaline and resuscitation
equipment are immediately available. Desensitisation
should be regarded as temporary, and allergic reactions
may recur during the next exposure to penicillin.
Neutropenia. Neutropenia has been widely reported in
patients given high doses of beta lactams and an incidence of from 5 to more than 15% has been reported in
patients treated for 10 days or more. Warning signs include fever, rash, and eosinophilia. Monitoring of the
leucocyte count is recommended during long-term
treatment with high doses. Some have proposed a direct toxic effect whereas others have postulated an immune mechanism.
Effects on the blood. References to neutropenia associated
with penicillins.
1. Anonymous. Antibiotic-induced neutropenia. Lancet 1985; ii:
814.
2. Neftel KA, et al. Inhibition of granulopoiesis in vivo and in vitro
by -lactam antibiotics. J Infect Dis 1985; 152: 908.
3. Olaison L, Alestig K. A prospective study of neutropenia induced by high doses of -lactam antibiotics. J Antimicrob Chemother 1990; 25: 44953.
4. Scheetz MH, et al. Systematic review of piperacillin-induced
neutropenia. Drug Safety 2007; 30: 295306.

The symbol denotes a substance whose use may be restricted in certain sports (see p.vii)