Standard Commodity Classification No. of Japan
Revised: May 2005 (11th version, Revision of Precautions, Revisions associated
with the amendment of the Pharmaceutical Affairs Law)
876131
- Synthetic penicillin product -
PENTCILLIN ® for Injection 1 g PENTCILLIN ® for Injection 2 g
<Piperacillin sodium for injection >
Designated drug/prescription drug note)
Storage
1 g
2 g Store at room temperature.
Approval No.
(54EM)940(54EM)941Date of listing in the NHI reimbursement price Feb 1980Feb 1980Expiration date
Date of initial marketing in Japan Feb 1980
Feb 1980
Date of latest reevaluation
Sep 2004Do not use after the expiration date indicated on the package and the label.
Date of latest approval of indications
Aug 1985
note)
Prescription drug: Caution -- Use only as directed by a physician.
CONTRAINDICATIONS (PENTCILLIN ® is contrain-dicated in the following patients.)
(1)Patients with a history of shock following exposure to
any of the ingredients in the product (2)Patients with infectious mononucleosis
[It has been reported that treatment with penicillin anti-biotics is more likely to develop rash.]RELATIVE CONTRAINDICATIONS (As a general rule, PENTCILLIN ® is contraindicated in the following patients. If the use of PENTCILLIN ® is considered es-sential, it should be administered with care.)
Patients with a history of hypersensitivity to any of the in-gredients in the product or other penicillin antibiotics
DESCRIPTION
Brand name PENTCILLIN ® for Injection 1 g
PENTCILLIN ® for Injection 2 g
Active ingredient Piperacillin sodium (JP)
Content (per vial) 1 g (Potency)
2 g (Potency)
Color/
dosage form
White freeze-dried product
The pH and osmotic pressure ratio of the injection solution re-constituted are shown in the following table.
Solvent Concentration pH Osmotic
pressure ratio note1)
Water for injection (JP) 1 g (Potency)/4 mL
5.0 − 7.0Approx. 2
Isotonic sodi-um chloride solution (JP)
2 g (Potency)/100 mL
5.0 − 7.0
Approx. 1
Isotonic sodi-um chloride solution (JP) 4 g (Potency)/100 mL 5.0 − 7.0Approx. 1
5% Glucose injection (JP)
4 g (Potency)/100 mL
5.0 − 7.0Approx. 1
note1)
: Osmotic pressure ratio to isotonic sodium chloride solution.
Na content:Each g (potency) of piperacillin sodium contains
1.93 mEq (44.42 mg) of Na.
INDICATIONS
<Indicated bacteria>
Piperacillin -susceptible bacteria; Staphylococcus spp ., Strep-tococcus spp., Streptococcus pneumoniae , Enterococcus spp.,Escherichia coli , Citrobacter spp., Klebsiella pneumoniae ,Enterobacter spp., Serratia spp., Proteus spp., Morganella morganii , Providencia spp., Haemophilus influenzae , Bacter-oides spp., and Prevotella spp. (excluding Prevotella bivia )<Indications>•Septicemia
•Acute bronchitis, pneumonia, lung abscess, pyothorax, and secondary infections in chronic respiratory lesion •Cystitis and pyelonephritis •Cholecystitis and cholangitis
•Bartholinitis, intrauterine infection, uterine adnexitis, and parametritis
•Pyogenic meningitis
DOSAGE AND ADMINISTRATION
For intravenous use, the usual adult dosage is 2 − 4 g (potency)of piperacillin sodium daily in 2 − 4 divided doses.Intramuscular administration is also possible.
For pediatric use, the usual dosage for intravenous administra-tion is 50 − 125 mg (potency)/kg of piperacillin sodium daily in 2 − 4 divided doses.
In patients with intractable or severe infections, intravenous piperacillin sodium is to be given at increased doses [up to 8 g (potency) daily in adults and 200 mg (potency)/kg daily in children] according to the patient’s condition.
Prior to intravenous injection, dissolve the product in water for injection (JP), isotonic sodium chloride solution (JP), or gluco-se injection (JP), and inject the solution slowly. In the case of intravenous drip infusion, 1 − 2 g (potency) of the product should usually be added to 100 to 500 mL of fluid replacement, and infuse over 1 to 2 hours. In the case of intramuscular in-jection, dissolve 1 g (potency) of the product in 3 mL of lido-caine injection (JP; 0.5W/V%).
•Precautions for dissolution at the intravenous drip infusion
In the case of intravenous drip infusion, do not use water for injection. (Because an isotonic solution will not be obtained.)
<Precautions>
1.The drug must be used with care, and the dose or dosing
interval should be adjusted in patients with severe
renal dysfunction. [See ″PHARMACOKINETICS″
section.]
2.As a general rule, the duration of administration of the
drug should be limited to the minimum period required
for the treatment of the patient’s condition, after
susceptibility of the microorganism to the drug has been
confirmed, in order to prevent the emergence of drug-
resistant microorganisms.
PRECAUTIONS
1.Careful Administration (PENTCILLIN® should be
administered with care in the following patients.)
(1)Patients with a history of hypersensitivity to cephem
antibiotics
[Patients should be interviewed carefully because
shock may develop.]
(2)Patients who or whose parents or siblings have a pre-
disposition to develop allergic reactions such as bron-
chial asthma, rash and urticaria.
[The patient with allergic predisposition should be
carefully interviewed because he/she is more likely to
develop hypersensitivity.]
(3)Patients with severe renal dysfunction
[Persistently elevated blood concentrations may de-
velop. (See ″PHARMACOKINETICS″section.)]
(4)Patients with poor oral food intake or who are receiving
parenteral alimentation, and patients in poor general
health
[Patients who are unable to take vitamin K through
food should be observed carefully because vitamin K
deficiency may develop.]
(5)Patients with hemorrhagic diathesis
[A bleeding tendency may be exacerbated.]
(6)Patients with hepatic dysfunction [Persistently elevated
blood concentrations may develop.]
(7)Elderly patients [See ″5. Use in the Elderly″ section.]2.Important Precautions
Because there are no ways to know beforehand occurrence of shock or anaphylactoid reaction, the following steps should be taken.
(1)Adequate inquiry about previous history, etc., is made
before treatment with this drug, particularly confirming
the history of allergic reaction to antibiotics, etc.
(2)Emergency care is prepared for treatment of shock,
etc., whenever to use this drug.
(3) The patient is kept resting under careful observation
during a period from initiation until completion of the
treatment, paying special attention immediately after
administration.
3.Drug Interactions
Precautions for coadministration (PENTCILLIN®should be administered with care when coadministered with the following drugs.)
Drugs Signs, Symptoms, and
Treatment
Mechanism and
Risk Factors Methotrexate 1)Delay in methotrexate
elimination may develop,
resulting in its
increased toxicity. It is
recommended to take
precautions such as
monitoring plasma
methotrexate
concentrations
It is considered that
PENTCILLIN®
prolongs the renal
elimination of
methotrexate by
inhibiting the
tubular secretion in
the kidney.
4.Adverse Reactions
In investigations conducted before approval, adverse reac-tions (including abnormal laboratory data) to the drug were reported in 148 (6.09%) of 2,432 patients. Adverse reac-tions were reported in 396 (1.99%) of 19,884 patients who were observed in the clinical experience investigation dur-ing the 4 years after approval (May 1979 to August 1983).
Adverse reactions to the drug were reported in 544 (2.44%) of 22,316 patients who had been observed at time of ap-proval and during the 4 years after approval. A total of 1,119 cases of adverse reactions were reported. The major adverse reactions were rash in 175 cases (0.78%), increased AST (GOT) in 152 cases (0.68%), increased ALT (GPT) in 143 cases (0.64%), fever in 120 cases (0.54%) and a de-crease in white blood cell count in 66 cases (0.30%).
Adverse reactions with unknown incidence developed after approval are also included in the data pr
esented in this sec-tion.
(1)Clinically significant adverse reactions
1)Shock and anaphylactoid reactions (including
dyspnoea and pruritus, etc.) (incidence: less than
0.1%) may develop. The patients should be carefully
monitored. If any signs of shock or anaphylactoid re-
actions are observed, administration should be dis-
continued and appropriate therapeutic measures
should be taken.
2)Toxic epidermal necrolysis (Lyell syndrome) and
muco-cutaneo-ocular syndrome (Stevens-Johnson
syndrome) (incidence unknown) may develop. The
patients should be carefully monitored. If any signs of these syndromes are observed, administration should be discontinued and appropriate therapeutic measures should be taken.
3)Serious nephropathy such as acute renal failure
and interstitial nephritis (incidence unknown) may develop. The patients should be carefully monitored and periodic renal function tests should be per-formed. If any abnormal findings are observed, ad-ministration should be discontinued and appropriate therapeutic measures should be taken.
4)Pancytopenia (incidence unknown), agranulocyto-
西元
国际广场sis and thrombocytopenia (incidence: less than0.1%), and hemolytic anaemia (incidence unknown)
may develop. The patients should be carefully moni-
tored. If any abnormal findings are observed, admin-
istration should be discontinued and appropriate therapeutic measures should be taken.
5)Serious colitis with bloody stool, such as pseudo-
membranous colitis(incidence unknown), may de-velop. If abdominal pain or frequent diarrhoea is ob-served, administration should be immediately dis-continued and appropriate therapeutic measures
should be taken.
6)Interstitial pneumonia and PIE syndrome with fe-
ver, cough, dyspnoea, chest X-ray abnormalities, and eosinophilia (incidence unknown), may develop.
If such symptoms are observed, administration should be discontinued and appropriate therapeutic measures, such as administration of adrenocortical hormone, should be taken.
7)Rhabdomyolysis (incidence unknown) may develop.
If myalgia, weakness, increased CK (CPK), and in-creased blood or urine myoglobin are observed, ad-ministration should be discontinued, and appropriate
therapeutic measures should be taken. Also, special attention should be paid to the development of acute renal failure based on Rhabdomyolysis.
8)Hepatic function disorder and jaundice (inci-
dence:less than 0.1%) may develop. The patients should be carefully monitored. If any abnormal findings are observed, administration should be dis-continued and appropriate therapeutic measures
should be taken.
(2)Other adverse reactions
If the following adverse reactions are observed, appro-priate therapeutic measures should be taken according to the patient′s condition.
Type 1.0% > ≥ 0.1% or
incidence unknown
< 0.1%
Hypersensitiv-ity Fever, rash, pruritus Edema, urticaria
swollen lymph nodes
Hematologic Granulocytopenia,
eosinophilia Thrombocytopenia, anaemia
Hepatic Increased AST (GOT),
increased ALT (GPT),
increased Al-P,
increased LDH Jaundice
Type 1.0% > ≥ 0.1% or
incidence unknown
病因学
< 0.1%
Gastrointesti-
nal
Nausea/vomiting Diarrhoea, anorexia,
abdominal pain
Central nerv-
ous system
Neurological symp-
toms such as convul-
sions after the drug is
given in a large dose to
patients with renal
failure note2)
-
Microbial
Substitution
-Stomatitis,
candidiasis
Vitamin
Deficiency
Vitamin K deficiency
symptoms
(hypoprothrombine-
mia, bleeding ten-
dency, etc.) note2)
Vitamin B deficiency
symptoms
(glossitis, stomatitis,
anorexia, neuritis, etc.)
Others-Headache, myalgia,
numbness
note2) : incidence unknown
5.Use in the Elderly
Special attention should be paid to the following points
when the drug is used in elderly patients. The drug should
be used with caution and the dose and dosing interval must
be adjusted based on careful clinical observation of the pa-
tient′s condition.
(1)Elderly patients often have reduced physiological
function, which may increase the risk of adverse reac-
tions.刘易斯模型
(2)In elderly patients, use of the drug may be associated
with the development of a bleeding tendency due to
vitamin K deficiency.
6.Use during Pregnancy, Delivery or Lactation
The safety of the drug in pregnant women has not been es-
tablished. Therefore, the drug should be used in pregnant
women and women who may possibly be pregnant only if
the expected therapeutic benefits outweigh the possible
risks associated with treatment.
7.Pediatric Use
The safety of this drug in low birth weight infants and neo-
nates has not been established.
8.Effects on Laboratory Tests
(1)False-positive results may develop in urine glucose
tests using reduction such as those with Clinitest and
Benedict’s solution, etc.
(2)False-positive results may develop in serum aspergil-
lus antigen (galactomannan) tests used for diagnosis
of invasive aspergillosis.
9.Precautions concerning Use
(1)<Following reconstitution>
1)Use promptly after reconstitution. If the reconstituted
solution must be stored, use the solution within 24
hours if stored in a refrigerator (at about 5°C).
2)Because the effect of aminoglycoside antibiotics
(such as tobramycin) is decreased by combination of
this drug, each drug should be administered with dif-ferent routes.
卵黄磷蛋白(2)<Intravenous injection>
Intravenous injection may cause vascular pain, throm-bus, or phlebitis. Inject the agent as slowly as possible and take special care with respect to the injection site,the method of injection, etc.(3)<Intramuscular injection>
With regard to intramuscular injection, pay special at-tention to the following points to avoid injuring tissues and nerves.
1)Inject the agent carefully to avoid contact with nerves.
2)If repeated injection is required, change the injection site (e.g., alternate between the right and left arms).3)Intramuscular injection should not be employed in neonates, low birth weight infants, nursing infants,infants and children.
4)If insertion of the injection needle induces intense pain or if blood flows back into the syringe, withdraw the needle immediately and perform injection at a different site.
5)Never intravenously inject the product dissolved in lidocaine injection (JP; 0.5W/V %).
10.Other Precautions
(1)Periodic testing of hematological parameters and
hepatic function during treatment is recommended.(2)A high incidence of hypersensitivity reactions to the
drug has been reported among the patients with cystic fibrosis outside of Japan.
(3)Concomitant use of the drug with vecuronium has been
reported to prolong the muscle-relaxing action of vecu-ronium.
PHARMACOKINETICS
1.Blood concentration
Blood concentration after 1 or 2 g of PENTCILLIN ® was administered intravenously to the healthy adults is shown below 2).
Dosage Blood concentration (15-min interval; µg/mL)
Blood Half-life T1/2
(hr)1g 59.10.7 (mean)2g
130.0
0.7 (mean)
B l o o d c o n c e n t r a t i o n (µg /m L )
Time (hr)
2g (n=3) 1g (n=4)
2.Transfer to tissues
High biliary concentrations (mean: 795.6 µg/mL) of PENTCILLIN ® in the gallbladder were observed 90 min after an intravenous administration at a dosage of 2 g given to patients with cholelithiasis or biliary infection. The mean drug concentration in the tissues of the gallbladder was 31.2 µg/g 3).
PENTCILLIN ® concentrations in the tissues of each uteri-ne part (endometrium, myometrium, uterine cervix, vaginal portion of uterus, uterine tube, and ovary) peaked (25.0 to 40.8 µg/g) 15 to 40 min after intravenous administration.The concentration in the fluid of the pelvic dead space reached the highest level (41.9 µg/mL) 105 min after intra-venous administration 4).
The transition of the drug into cord blood and amniotic fluid was favorable, whereas the drug was little excreted into the breast milk 5).
In addition, the transition of the drug into pleural effusion 6),expectoration 7), saliva 8), spinal fluid 6), etc. was also fa-vorable.3.Protein-bound forms
PENTCILLIN ® is 21.2% bound to human serum proteins (drug concentration: 25 µg/mL, using centrifugal ultrafil-tration). The binding to serum proteins is reversible 9).4.Metabolism
After PENTCILLIN ® was administered to subjects, DEt-PIPC as an active metabolite of the parent compound (PIPC) was excreted in plasma and urine 10).5. Excretion
PENTCILLIN ® was administered to subjects as a single intravenous drip infusion dose of 1g for 30 min. The cu-mulative excretion rate of PENTCILLIN ® as unchanged compound for the first 24 hours
after administration was 56.2% in healthy non-elderly adults (20 to 40 years old,n=7), and 57.7% in elderly adults (≥65 years old, Ccr ≥40mL/min, n=7) 11).6.Blood concentration in patients with renal impairment
In patients with renal impairment, the blood half-life in-creased with decreasing renal function. In patients with severe renal impairment (Ccr ≤ 10), the half-life increased to 4.12 hours, which was approximately 4 times that ob-tained from patients with normal renal function 12) (Data from outside of Japan).
Severity of renal impairment
(Ccr: mL/min)
Number of
patients Blood Half-life T1/2 (hr)Healthy Ccr > 8018 1.0480 ≥ Ccr > 40
13 1.70Mild 40 ≥ Ccr > 20
11 2.45Moderate 20 ≥ Ccr > 107 2.77Severe Ccr ≤ 10
18
4.12
7.
Blood concentration in patients on dialysis
The following shows the time-course profile of blood con-centrations of PENTCILLIN ® administered intravenously at a dosage of 2 g to patients with chronic renal failure on hemodialysis 13).
concentration (100%) obtained 1 hour after administration.
n=8
P e r c e n t r e m a i n i n g o f d r u g i n t h e b l o o d (%)
Time (hr)
Non-dialysis Dialysis
Hemodialysis
8.
Blood concentration in elderly adults
PENTCILLIN ® was administered to elderly adults (≥65years old, Ccr ≥40 mL/min, n=7) and healthy non-elderly adults (20 to 40 years old, n=7) as a single intravenous drip infusion dose of 1g for 30 min. In elderly adults, as compared with non-elderly adults, total clearance fell to about 70% and blood half life was extended for about 0.3
11)CLINICAL STUDIES
The open clinical studies of PENTCILLIN ® (intravenous ad-ministration, intravenous drip infusion, intramuscular admini-stration) in 1,005 patients are summarized below. The daily dosage for adult ranged between 2 − 6 g in most of the patients.The usefulness of PENTCILLIN ® was confirmed in two dou-ble-blind comparative studies in patients with respiratory in-
fection (PIPC 2g × twice daily, intravenous drip infusion over
2 hours) 14)
, and with chronic complex urinary tract infection (PIPC 1g × twice daily, intravenous administration) 15).
libsvm
Type of infection Disease
Efficacy (%)Systemic infections Septicemia
75.0 ( 27/ 36)Acute bronchitis and Secondary infections in chronic respiratory lesion 61.1 ( 33/ 54)
Pneumonia
80.5 (140/174)Respiratory infections
Lung abscess, Pyothorax
65.0 ( 13/ 20)Cystitis 70.2 (179/255)Urinary tract infections Pyelonephritis 73.6 (192/261)Biliary infections Cholecystitis, Cholangitis 76.5 ( 62/ 81)Bartholinitis 90.9 ( 10/ 11)Intrauterine infection
98.2 ( 55/ 56)Uterine adnexitis 96.0 ( 24/ 25)Gynecological infections Parametritis
90.5 ( 19/ 21)Suppurative meningitis
90.9( 10/ 11)
PHARMACOLOGY
1.Antibacterial activity
Piperacillin possesses a broad antibacterial spectrum again-st aerobic Gram negative bacteria, Pseudomonas aerugi-nosa , Gram positive bacteria, Enterococcus spp. anaerobic bacteria and Bacteroides spp .
The MIC90 for Gram negative clinical isolates, Haemo-philus influenzae was 2 µg/mL, while it was 2 µg/mL for Gram negative clinical isolates, Streptococcus pneumoniae.It possesses a more potent antibacterial activity than flo-moxef sodium 16) (in vitro ).2.Mechanism of action
Piperacillin possesses a potent bactericidal effect by in-hibiting cell wall synthesis of bacteria 17).
PHYSICOCHEMISTRY
Nonproprietary name:
Piperacillin Sodium (JAN), piperacillin (INN)Abbreviation:PIPC Chemical name:
Monosodium(2S ,5R ,6R )-6-{(2R )-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetylamino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
Molecular formula: C 23H 26N 5NaO 7S Molecular weight: 539.54Structural formula:
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