Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2408
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Penicillin G Potassium (Injection, Solution)
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Penicillin G Potassium
Injection, USP should be administered by intravenous infusion. The usual dose
recommendations are as follows: Adult patients *Because of its short half-life,
Penicillin G is administered in divided doses,usuallyevery 4-6 hours with the
exception of meningococcal meningitis/septicemia, i.e., every 2 hours. Pediatric patients This product should not be
administered to patients requiring less than one million units per dose (see PRECAUTIONS-Pediatric
Use). Renal
Impairment: Penicillin G is relatively nontoxic, and dosage adjustments
are generally required only in cases of severe renal impairment. The recommended
dosage regimens are as follows: Creatinine clearance less than
10 mL/min/1.73m; administer a full loading dose (see recommended dosages in the
tables above) followed by one-half of the loading dose every 8-10 hours. Uremic patients with a
creatinine clearance greater than 10 mL/min/1.73m; administer a full loading dose
(see recommended dosages in the tables above) followed by one-half of the loading dose
every 4-5 hours. Additional dosage modifications should be made in patients with
hepatic disease and renal impairment. For most acute infections,
treatment should be continued for at least 48 to 72 hours after the patient becomes
asymptomatic. Antibiotic therapy for Group A��-hemolytic streptococcal
infections should be maintained for at least 10 days to reduce the risk of rheumatic
fever. Parenteral drug products should
be inspected visually for particulate matter and discoloration prior to administration
whenever solution and container permit.
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Penicillin G Potassium, USP is
a natural penicillin. It is chemically designated
4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic
acid,3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, monopotassium salt,
[2S-(2��, 5��, 6��)]. It is crystalline. It is freely soluble
in water, in isotonic sodium chloride solution and in dextrose solutions. The
structural formula is as shown below. Penicillin G Potassium
Injection, USP (equivalent to 1, 2, or 3 million units of penicillin G) is a 50 mL
premixed, iso-osmotic, sterile, nonpyrogenic, frozen solution for intravenous
administration. Dextrose, USP has been added to the above dosages to adjust osmolality
(approximately 2 g, 1.2 g, and 350 mg as dextrose hydrous, respectively). Sodium
Citrate, USP has been added as a buffer. The pH has been adjusted with hydrochloric
acid and may have been adjusted with sodium hydroxide. The pH is 6.5 (5.5 to 8.0). The
solution is contained in a single dose GALAXY container (PL 2040 Plastic) and is
intended for intravenous use after thawing to room temperature. This GALAXY container is
fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in
contact with the polyethylene layer of this container and can leach out certain
chemical components of the plastic in very small amounts within the expiration period.
The suitability of the plastic has been confirmed in tests in animals according to the
USP biological tests for plastic containers as well as by tissue culture toxicity
studies.
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After an intravenous infusion
of penicillin G, peak serum concentrations are attained immediately after completion
of the infusion. In a study of ten patients administered a single 5 million unit dose
of penicillin G intravenously over 3-5 minutes, the mean serum concentrations were 400
mcg/mL, 273 mcg/mL and 3.0 mcg/mL at 5-6 minutes, 10 minutes and 4 hours after
completion of the injection, respectively. In a separate study, five healthy adults
were administered one million units of penicillin Gintravenously, either as a bolus
over 4 minutes or as an infusion over 60 minutes. The mean serum concentration eight
minutes after completion of the bolus was 45 mcg/mL and eight minutes after completion
of the infusion was 14.4 mcg/mL. The mean��-phase serum
half-life of penicillin G administered by the intravenous route in ten patients with
normal renal function was 42 minutes, with a range of 31-50 minutes. The clearance of penicillin G
in normal individuals is predominantly via the kidney. The renal clearance, which is
extremely rapid, is the result of glomerular filtration and active tubular transport,
with the latter route predominating. Urinary recovery is reported to be 58-85% of the
administered dose. Renal clearance of penicillin is delayed in premature infants,
neonates and in the elderly due to decreased renal function. The serum half-life of
penicillin G correlates inversely with age and clearance of creatinine and ranges from
3.2 hours in infants 0 to 6 days of age to 1.4 hours in infants 14 days of age or
older. Nonrenal clearance includes
hepatic metabolism and, to a lesser extent, biliary excretion. The latter routes
become more important with renal impairment. Probenecid blocks the renal
tubular secretion of penicillin. Therefore, the concurrent administration of
probenecid prolongs the elimination of penicillin G and, consequently, increases the
serum concentrations. Penicillin G is distributed to
most areas of the body including lung, liver, kidney, muscle, bone and placenta. In
the presence of inflammation, levels of penicillin in abscesses, middle ear, pleural,
peritoneal and synovial fluids are sufficient to inhibit most susceptible bacteria.
Penetration into the eye, brain, cerebrospinal fluid (CSF) or prostate is poor in the
absence of inflammation. With inflamed meninges, the penetration of penicillin G into
the CSF improves, such that the CSF/serum ratio is 2-6%. Inflammation also enhances
its penetration into the pericardial fluid. Penicillin G is actively secreted into the
bile resulting in levels at least 10 times those achieved simultaneously in serum.
Penicillin G penetrates poorly into human polymorphonuclear leukocytes. In the presence of impaired
renal function, the��-phase serum half-life of penicillin G is prolonged.��-phase serum half-lives of one to two hours were observed in azotemic
patients with serum creatinine concentrations<3 mg/100 mL and ranged as high
as 20 hours in anuric patients. A linear relationship, including the lowest range of
renal function, is found between the serum elimination rate constant and renal
function as measured by creatinine clearance. In patients with altered renal
function, the presence of hepatic insufficiency further alters the elimination of
penicillin G. In one study, the serum half-lives in two anuric patients (excreting<400 mL urine/day) were 7.2 and 10.1 hours. A totally anuric patient with
terminal hepatic cirrhosis had a penicillin half-life of 30.5 hours, while another
patient with anuria and liver disease had a serum half-life of 16.4 hours. The dosage
of penicillin G should be reduced in patients with severe renal impairment, with
additional modifications when hepatic disease accompanies the renal impairment.
Hemodialysis has been shown to reduce penicillin G serum levels.<br/>Microbiology: Penicillin G is
bactericidal against penicillin-susceptible microorganisms during the stage of
active multiplication. It acts by inhibiting biosynthesis of cell-wall
mucopeptide. It is not active against the penicillinase-producing bacteria, which
include many strains of staphylococci. Penicillin G is highly active in vitro against staphylococci (except
penicillinase-producing strains), streptococci (groups A, B, C, G, H, L and M),
pneumococci and Neisseria
meningitidis. Other organisms susceptible
in vitro to penicillin G are Neisseria gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, clostridia,
Actinomyces species, Spirillum minus, Streptobacillus
moniliformis, Listeria
monocytogenes, and leptospira; Treponema
pallidum is extremely susceptible. Some species of gram-negative
bacilli were previously considered susceptible to very high intravenous doses of
penicillin G (up to 80 million units/day) including some strains of Escherichia coli, Proteus mirabilis, salmonella,
shigella, Enterobacter aerogenes (formerly
Aerobacter aerogenes) and Alcaligenes faecalis. Penicillin G is no longer
considered a drug of choice for infections caused by these organisms.<br/>Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide the results of in vitro
susceptibility test results for antimicrobial drugs used in local hospitals and
practice areas to the physician as periodic reports that describe the
susceptibility profile of nosocomial and community-acquired pathogens. These
reports should aid the physician in selecting the most effective
antimicrobial.<br/>Dilution Techniques: Quantitative methods
are used to determine antimicrobial minimum inhibitory concentrations (MICs).
These MICs provide estimates of the susceptibility of bacteria to
antimicrobial compounds. The MICs should be determined using a standardized
procedure. Standardized procedures are based on dilution method(broth, agar or microdilution) or equivalent using standardized inoculum and
concentrations of pencillin. The MIC values should be interpreted according to
the criteria in Table 1.<br/>Diffusion Techniques: Quantitative methods
that require measurement of zone diameters also provide reproducible estimates
of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedurerequires the use of standardized inoculum
concentrations. This procedure uses paper disks impregnated with 10 units of
penicillin to test the susceptibility of microorganisms to penicillin.
Interpretation involves correlation of the diameter obtained in the disk test
with the MIC for penicillin. Reports from the laboratory providing results of
the standard single-disk susceptibility test with a 10 unit penicillin disk
should be interpreted according to the following criteria in Table 1.<br/>Quality Control: Standardized
susceptibility test procedures require the use of laboratory control
microorganisms to monitor and ensure the accuracy and precision of the
supplies and reagents used in the assay, and the techniques of the individuals
performing the test. Standard penicillin powder should provide MIC values
provided below. For the diffusion technique, the 10 unit penicillindisk
should provide the following zone diameters with the quality control strains:
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A history of a hypersensitivity
(anaphylactic) reaction to any penicillin is a contraindication. Solutions containing
dextrose may be contraindicated in patients with known allergy to corn or corn
products.
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Penicillin G Potassium
Injection, USP is supplied as a premixed frozen iso-osmotic solution in 50 mL single
dose GALAXY containers (PL 2040 Plastic) as follows: Store at or below
-20��C/-4��F. [See Directions for Use of GALAXY
Container (PL 2040 Plastic).]
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General: 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. Penicillin G Potassium, USP by the intravenous route in
high doses (above 10 million units) should be administered slowly because of the
potential adverse effects of electrolyte imbalance from the potassium content of
the penicillin. Penicillin G Potassium Injection, USP contains 1.7 mEq potassium
and 1.02 mEq of sodium per million units. The use of antibiotics may promote
overgrowth of nonsusceptible organisms, including fungi. Indwelling intravenous
catheters encourage superinfections. Should superinfection occur, appropriate
measures should be taken. When indicated, incision and drainage or other surgical
procedures should be performed in conjunction with antibiotic therapy. Prescribing Penicillin G
Potassium Injection, USP 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 the development of drug-resistant
bacteria.<br/>Laboratory Tests: Periodic assessment of
organ system function, including frequent evaluation of electrolyte balance,
hepatic, renal and hematopoietic systems, and cardiac and vascular status should
be performed during prolonged therapy with high doses of intravenous penicillin G
.
If any impairment of function is suspected or known to exist, a reduction in the
total dosage should be considered (see DOSAGE AND
ADMINISTRATION). In suspected staphylococcal
infections, proper laboratory studies, including susceptibility tests should be
performed. All infections due to Group A beta-hemolytic streptococci should be
treated for at least 10 days. Patients being treated for
gonococcal infection should have a serologic test for syphilis before receiving
penicillin. All cases of penicillin treated syphilis should receive adequate
follow-up including clinical and serological examinations. The recommended
follow-up varies with the stage of syphilis being treated.<br/>Drug Interactions: Bacteriostatic
antibacterials (i.e., chloramphenicol, erythromycins, sulfonamides or
tetracyclines) may antagonize the bactericidal effect of penicillin, and
concurrent use of these drugs should be avoided. This has been documented in vitro; however, the clinical significance of
this interaction is not well-documented. Penicillin blood levels may
be prolonged by concurrent administration of probenecid which blocks the renal
tubular secretion of penicillins. Other drugs may compete
with penicillin G for renal tubular secretion and thus prolong the serum half-life
of penicillin. These drugs include: aspirin, phenylbutazone, sulfonamides,
indomethacin, thiazide diuretics, furosemide and ethacrynic acid.<br/>Drug/Laboratory Test Interactions: After treatment with
penicillin G, a false-positive reaction for glucose in the urine may occur with
Benedict's solution, Fehling's solution or
Clinitest tablet, but not with the enzyme-based tests, such
as Clinistix and Tes-Tape. Penicillin G has been
associated with pseudoproteinuria by certain test methods.<br/>Carcinogenesis and Mutagenesis
and Impairment of Fertility: No long term animal studies
have been conducted with this drug.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Penicillins are excreted in
human milk. Caution should be exercised when penicillins are administered to a
nursing woman.<br/>Pediatric Use: Incompletely developed
renal function in newborns may delay elimination of penicillin; therefore,
appropriate reductions in the dosage and frequency of administration should be
made in these patients. All newborns treated with penicillins should be monitored
closely for clinical and laboratory evidence of toxic or adverse effects (see
PRECAUTIONS). Pediatric doses are
generally determined on a weight basis and should be calculated for each patient
individually. Recommended guidelines for pediatric dosages are presented in
DOSAGE AND
ADMINISTRATION. The potential for toxic
effects in children from chemicals that may leach from the single dose premixed
intravenous preparation in plastic containers has not been evaluated.<br/>Geriatric Use: Clinical studies of
Penicillin G Injection 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. 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. Penicillin G Injection
contains 23.5 mg (1.02 mEq) of sodium per million units. At the usual recommended
doses, patients would receive between 23.5 and 564 mg/day (1.02 and 24.5 mEq) of
sodium. The geriatric population may respond with a blunted natriuresis to salt
loading. This may be clinically importantwith regard to such diseases as
congestive heart failure.<br/>Information for Patients: Patients should be
counseled that antibacterial drugs including Penicillin G Potassium Injection, USP
should only be used to treat bacterial infections. They do not treat viral
infections (e.g., the common cold). When Penicillin G Potassium Injection, USP 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 dosesor 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 Penicillin G Potassium Injection, USP or other antibacterial drugs in
the future. 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.
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Dose related toxicity may arise
with the use of massive doses of intravenous penicillins (40 to 100 million units per
day), particularly in patients with severe renal impairment . The
manifestations may include agitation, confusion, asterixis, hallucinations, stupor,
coma, multifocal myoclonus, seizures and encephalopathy. Hyperkalemia is also possible
(see ADVERSE
REACTIONS-Metabolic). In case of overdosage,
discontinue penicillin, treat symptomatically and institute supportive measures as
required. If necessary, hemodialysis may be used to reduce blood levels of Penicillin
G, although the degree of effectiveness of this procedure is questionable.
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Penicillin G
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Penicillin G Potassium (Injection, Solution)
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Body as a whole:: The Jarisch-Herxheimer
reaction is a systemic reaction, that may occur after the initiation of penicillin
therapy in patients with syphilis or other spirochetal infections (i.e., Lyme
disease and Relapsing fever). The reaction begins one to two hours after
initiation of therapy and disappears within 12 to 24 hours. It is characterized by
fever, chills, myalgias, headache, exacerbation of cutaneous lesions, tachycardia,
hyperventilation, vasodilation with flushing and mild hypotension. The
pathogenesis of the Herxheimer reaction may be due to the release from the
spirochetes of heat-stable pyrogen.<br/>Hypersensitivity reactions: The reported incidence of
allergic reactions to all penicillins ranges from 0.7 to 10 percent in different
studies .
Sensitization is usually the result of previous treatment with a penicillin, but
some individuals have had immediate reactions when first treated. In such cases,
it is postulated that prior exposure to penicillin may have occurred via trace
amounts present in milk or vaccines. Two types of allergic
reactions to penicillin are noted clinically - immediate and delayed. Immediate reactions usually
occur within 20 minutes of administration and range in severity from urticaria and
pruritus to angioneurotic edema, laryngospasm, bronchospasm, hypotension, vascular
collapse and death . Such
immediate anaphylactic reactions are very rare and usually occur after parenteral
therapy, but afew cases of anaphylaxis have been reported following oral therapy.
Another type of immediate reaction, an accelerated reaction, may occur between 20
minutes and 48 hours after administration and may include urticaria, pruritus,
fever and, occasionally, laryngeal edema. Delayed reactions to
penicillin therapy usually occur within 1-2 weeks after initiation of therapy.
Manifestations include serum sickness-like symptoms, i.e., fever, malaise,
urticaria, myalgia, arthralgia, abdominal pain and various skin rashes, ranging
from maculopapular eruptions to exfoliative dermatitis. Contact dermatitis has been
observed in individuals who prepare penicillin solutions.<br/>Gastrointestinal system: Pseudomembranous colitis
has been reported with the onset occurring during or after penicillin G treatment.
Nausea, vomiting, stomatitis, black or hairy tongue, and other symptoms of
gastrointestinal irritation may occur, especially during oral therapy.<br/>Hematologic system: Reactions include
neutropenia, which resolves after penicillin therapy is discontinued;
Coombs-positive hemolytic anemia, an uncommon reaction, occurs in patients treated
with intravenous penicillin G in doses greater than 10 million units/day and who
have previously received large doses of the drug; and with large doses of
penicillin, a bleeding diathesis can occur secondary to platelet
dysfunction.<br/>Metabolic: Penicillin G Potassium, USP
(1 million units contains 1.7 mEq of potassium ion) may cause serious and even
fatal electrolyte disturbances, i.e., hyperkalemia, when given intravenously in
large doses.<br/>Nervous system: Neurotoxic reactions
including hyperreflexia, myoclonic twitches, seizures and coma have been reported
following the administration of massive intravenous doses, and are more likely in
patients with impaired renal function.<br/>Urogenital system: Renal tubular damage and
interstitial nephritis have been associated with large intravenous doses of
penicillin G. Manifestations of this reaction may include fever, rash,
eosinophilia, proteinuria, eosinophiluria, hematuria and a rise in serum urea
nitrogen. Discontinuation of penicillin G results in resolution in the majority of
patients.<br/>Local reactions: Phlebitis and
thrombophlebitis may occur, and pain at the injection site has been reported with
intravenous administration.
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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 penicillin G, careful inquiry should be made concerning
previous hypersensitivity reactions to penicillins, cephalosporins, or other
allergens. If an allergic reaction occurs, penicillin G 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 diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including Penicillin G Potassium Injection,
USP, 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.
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Therapy: Penicillin G Potassium
Injection, USP is indicated in the treatment of serious infections caused by
susceptible strains of the designated microorganisms in the conditions listed
below. Appropriate culture and susceptibility tests should be done before
treatment in order to isolate and identify organisms causing infection and to
determine their susceptibility to penicillin G.Therapy with Penicillin G
Potassium Injection, USP may be initiated before results of such tests are known
when there is reason to believe the infection may involve any of the organisms
listed below; however, once these results become available, appropriate therapy
should be continued. To reduce the development
of drug-resistant bacteria and maintain the effectiveness of Penicillin G
Potassium Injection, USP and other antibacterial drugs, Penicillin G Potassium
Injection, USP should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible 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.
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Penicillin G Potassium
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