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Rofipime
Cefepime hydrochloride for injections
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ROFIPIME:
COMPOSITION: |
ROFIPME - 1 gm
Each vial contains
Cefepime Hydrochloride Monohydrate
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equivalent to Cefepime |
1 gm
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Excipient |
L-arginine |
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ROFIPME - 2 gm
Each vial contains
Cefepime Hydrochloride Monohydrate
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equivalent to Cefepime |
2 gm
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Excipient |
L-arginine
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DOSAGE FORM
Powder for reconstitution (I.V/I.M)
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PHARMACOLOGY
Pharmacodynamics
Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall
synthesis. Cefepime has a broad spectrum of in vitro activity that encompasses a
wide range of gram-positive and gram-negative bacteria. Cefepime has a low affinity
for chromosomally-encoded beta-lactamases. Cefepime is highly resistant to hydrolysis
by most beta-lactamases and exhibits rapid penetration into gram-negative bacterial
cells. Within bacterial cells, the molecular targets of cefepime are the penicillin
binding proteins (PBP).
Cefepime has been shown to be active against most strains of the following microorganisms,
both in vitro and in clinical infections.
Aerobic Gram-Negative Microorganisms:
- Enterobacter
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- Pseudomonas aeruginosa
Aerobic Gram-Positive Microorganisms:
- Staphylococcus aureus ( methicillin-susceptible strains only )
- Streptococcus pneumoniae
- Streptococcus pyogenes ( Lancefield`s Group A streptococci)
- Viridans group streptococci
The following in vitro data are available, but their clinical significance is unknown.
Cefepime has been shown to have in vitro activity against most strains of the following
microorganisms; however, the safety and effectiveness of cefepime in treating clinical
infections due to these microorganisms have not been established in adequate and
well-controlled trials.
Aerobic Gram-Positive Microorganisms:
- Staphylococcusepidermidis(methicillin-susceptiblestrainsonly)
- Staphylococcussaprophyticus
- Streptococcusagalactiae(Lancefield`sGroupBstreptococci)
Note:
Most strains of enterococci, eg, Enterococcus faecalis , and methicillin-resistant
staphylococci are resistant to cefepime.
Aerobic Gram-Negative Microorganisms:
- Acinetobacter calcoaceticus subsp . lwoffi
- Citrobacter diversus
- Citrobacter freundii
- Enterobacter agglomerans
- Haemophilus influenzae ( including beta-lactamase producing strains )
- Hafnia alvei
- Klebsiella oxytoca
- Moraxella catarrhalis ( including beta-lactamase producing strains )
- Morganella morganii
- Proteus vulgaris
- Providencia rettgeri
- Providencia stuartii
- Serratia marcescens
Note:
Cefepime is inactive against many strains of Stenotrophomonas (formerly Xanthomonas
maltophilia and Pseudomonas maltophilia ).
Anaerobic Microorganisms:
Note:
Cefepime is inactive against most strains of Clostridium difficile .
Pharmacokinetics
Following IV and IM administration, cefepime is rapidly absorbed. Cefepime pharmacokinetics
are linear over the range 250 mg to 2 g. There is no evidence of accumulation in
healthy adult male volunteers receiving clinically relevant doses for a period of
9 days. The average plasma concentration achieved at 1hr after 1 and 2 gm IV administration
is 44.5 mcg/mL and 85.8 mcg/mL respectively. The average plasma concentration achieved
at 1hr after 1 and 2 gm IV administration is 25.9 mcg/mL and 49.9 respectively.
The average steady-state volume of distribution of cefepime is 18.0 (±2.0) L. The
serum protein binding of cefepime is approximately 20% and is independent of its
concentration in serum. Cefepime is excreted in human milk. A nursing infant consuming
approximately 1000 mL of human milk per day would receive approximately 0.5 mg of
cefepime per day. Data suggest that cefepime does cross the inflamed blood-brain
barrier. The clinical relevance of these data are uncertain at this time. Cefepime
is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide
(NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately
85% of the administered dose. Less than 1% of the administered dose is recovered
from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because
renal excretion is a significant pathway of elimination, patients with renal dysfunction
and patients undergoing haemodialysis require dosage adjustment.
INDICATIONS
ROFIPIME is indicated in the treatment of the following infections caused
by susceptible strains of the designated microorganisms.
Pneumonia (moderate to severe) caused by Streptococcus pneumoniae , including cases
associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae
, or Enterobacter species.
Empiric Therapy for Febrile Neutropenic Patients. Cefepime as monotherapy
is indicated for empiric treatment of febrile neutropenic patients. In patients
at high risk for severe infection (including patients with a history of recent bone
marrow transplantation, with hypotension at presentation, with an underlying haematologic
malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy
may not be appropriate. Insufficient data exist to support the efficacy of cefepime
monotherapy in such patients.
Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis)
caused by Escherichia coli or Klebsiella pneumoniae , when the infection is severe,
or caused by Escherichia coli, Klebsiella pneumoniae , or Proteus mirabilis , when
the infection is mild to moderate, including cases associated with concurrent bacteremia
with these microorganisms.
Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus
aureus (methicillin-susceptible strains only) or Streptococcus pyogenes .
Complicated Intra-abdominal Infections (used in combination with metronidazole)
caused by Escherichia coli , viridans group streptococci, Pseudomonas aeruginosa,
Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis .
DOSAGE AND ADMINISTRATION
The recommended adult and paediatric dosages and routes of administration are outlined
in table 1. ROFIPIME should be administered intravenously over approximately 30
minutes.
Table 1: Recommended Dosage Schedule for ROFIPIME
|
Site and Type of Infection |
Dose |
Frequency |
Duration(days) |
Moderate to
Severe Pneumonia due to
S. pneumoniae * ,
P. aeruginosa,
K. pneumoniae,
or Enterobacter
species |
1-2 g IV |
q12h |
10 |
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Empiric therapy for febrile neutropenic patients |
2 g IV |
q8h |
7 ** |
Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including
pyelonephritis,
due to E. coli, K. pneumoniae, or P. mirabilis * |
0.5-1 g IV/IM*** |
q12h |
7-10 |
Severe
Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis,
due to E. coli or K. pneumoniae* |
2 g IV |
q12h |
10 |
Severe
Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis,
due to E. coli or K. pneumoniae* |
2 g IV |
q12h |
10 |
Moderate to Severe
Uncomplicated Skin and Skin Structure Infections due to S. aureus or S. pyogenes |
2 g IV |
q12h |
10 |
Complicated Intra-abdominal Infections
(used in combination with metronidazole) caused by E. coli, viridans group
streptococci, P. aeruginosa, K. pneumoniae, Enterobacter species, or B. fragilis |
2 g IV |
q12h |
7-10 |
*including cases associated with concurrent bacteremia
**or until resolution of neutropenia. In patients whose fever resolves but who remain
neutropenic for more than 7 days, the need for continued antimicrobial therapy should
be re-evaluated frequently.
***IM route of administration is indicated only for mild to moderate, uncomplicated
or complicated UTIs due to E. coli when the IM route is considered to be a more
appropriate route of drug administration .
Paediatric patients ( 2 months upto 16 months)
The maximum dose for paediatric patients should not exceed the recommended adult
dose. The usual recommended dosage in paediatric patients up to 40 kg in weight
for uncomplicated and complicated urinary tract infections (including pyelonephritis),
uncomplicated skin and skin structure infections, pneumonia and as empric therapy
for febrile neutropenic patients is 50 mg/kg/dose, administered q12 h ( q8h for
febrile neutropenic patients ) , for duration as given above.
Renal Impairment:
In patients with impaired renal function (creatinine clearance <=60 mL/min) the
dose of ROFIPIME should be adjusted to compensate for the slower rate of renal elimination.
The recommended initial dose of cefepime should be the same as in patients with
normal renal function. The recommended maintenance doses of cefepime in patients
with renal insufficiency are presented in the table below.
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Recommended Maintenance Schedule in Adults patients with Renal Impairment Relative
to Normal recommended Dosing Schedule |
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Creatinine Clearance (mL/min) |
Recommended Maintenance Schedule |
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>60 Normal recommended dosing schedule |
500 mg q12h |
1 g q12h |
2 g q12h |
2 g q8h |
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30-60 |
500 mg q24h |
1 g q24h |
2 g q24h |
2 g q12h |
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11-29 |
500 mg q24h |
500 mg q24h |
1 g q24h |
2 g q24h |
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<11 |
250 mg q24h |
250 mg q24h |
500 mg q24h |
1 g q24h |
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CAPD |
500 mg q48h |
1 g q48h |
2 g q48h |
2 g q48h |
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Haemodialysis * |
1 g on day 1, then 500 mg q24h thereafter |
1 g q24h |
* On haemodialysis days, cefepime should be administered following haemodialysis.
Whenever possible, cefepime should be administered at the same time each day.
When only serum creatinine is available, the following formula (Cockcroft and Gault
equation) may be used to estimate creatinine clearance. The serum creatinine should
represent a steady state of renal function:
Males: Creatinine Clearance (mL/min) = Weight (kg) × (140 - age) 72 × serum creatinine
(mg/dL) Females: 0.85 × above value
In patients undergoing haemodialysis, approximately 68% of the total amount of cefepime
present in the body at the start of dialysis will be removed during a 3-hour dialysis
period. A repeat dose, equivalent to the initial dose, should be given at the completion
of each dialysis session.
In patients undergoing continuous ambulatory peritoneal dialysis, cefepime may be
administered at normally recommended doses at a dosage interval of every 48 hours.
Data in paediatric patients with impaired renal function are not available; however,
since cefepime pharmacokinetics are similar in adults and paediatric patients, changes
in the dosing regimen proportional to those in adults are recommended for paediatric
patients.
Administration
For Intravenous Infusion: Constitute the 1 g or 2 g with 50 or 100 mL of
a compatible IV fluid listed in the Compatibility and Stability subsection.
Alternatively, constitute the 1 g or 2 g vial, and add an appropriate quantity of
the resulting solution to an IV container with one of the compatible IV fluids. The
resulting solution should be administered over approximately 30 minutes.
Intermittent IV infusion with a Y-type administration set can be accomplished with
compatible solutions. However, during infusion of a solution containing cefepime,
it is desirable to discontinue the other solution.
For Intramuscular Administration: For IM administration cefepime hydrochloride
should be constituted with one of the following diluents: Sterile Water for Injection,
0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1.0% Lidocaine Hydrochloride,
or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol
Preparation of cefepime solutions is summarized in the following table.
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Preparation of Solutions of Cefepime |
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Single Dose Vials for Intravenous/Intramuscular Administration |
Amount of Diluent to be added (mL) |
Approximate Available Volume (mL) |
Approximate Cefepime Concentration (mg/mL) |
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Cefepime vial content |
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1 g (IV) |
10.0 |
11.3 |
100 |
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1 g (IM) |
2.4 |
3.6 |
280 |
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2 g (IV) |
10.0 |
12.5 |
160 |
Compatibility and Stability
Intravenous cefepime is compatible at concentrations between 1 and 40 mg/mL with
the following IV infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose
Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection,
Lactated Ringers and 5% Dextrose Injection. These solutions may be stored up to
24 hours at controlled room temperature 20°-25° C (68°-77° F) or 7 days in a refrigerator
2°-8° C (36°-46° F). Cefepime admixture compatibility information is summarized
in the table below:
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Cefepime Admixture Stability |
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Cefepime Concentration |
Admixture and Concentration |
IV Infusion Solutions |
Stability Time for |
RT/L
(20°-25° C) |
Refrigeration
(2°-8° C) |
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40 mg/mL |
Amikacin
6 mg/mL |
NS or D5W |
24 hours |
7 days |
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40 mg/mL |
Ampicillin
1 mg/mL |
D5W |
8 hours |
8 hours |
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40 mg/mL |
Ampicillin
10 mg/mL |
D5W |
2 hours |
8 hours |
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40 mg/mL |
Ampicillin
1 mg/mL |
NS |
24 hours |
48 hours |
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40 mg/mL |
Ampicillin
10 mg/mL |
NS |
8 hours |
48 hours |
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4 mg/mL |
Ampicillin
40 mg/mL |
NS |
8 hours |
8 hours |
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4-40 mg/mL |
Clindamycin Phosphate
0.25-6 mg/mL |
NS or D5W |
24 hours |
7 days |
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4 mg/mL |
Heparin
10-50 units/mL |
NS or D5W |
24 hours |
7 days |
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4 mg/mL |
Potassium Chloride
10-40 mEq/L |
NS or D5W |
24 hours |
7 days |
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4 mg/mL |
Theophylline
0.8 mg/mL |
D5W |
24 hours |
7 days |
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1-4 mg/mL |
na |
Aminosyn® II
4.25% with electrolytes and calcium |
8 hours |
3 days |
0.125-0.25
mg/mL |
na |
Inpersol™ with
4.25% dextrose |
24 hours |
7 days |
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NS = 0.9% Sodium Chloride Injection. |
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D5W = 5% Dextrose Injection. |
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na = not applicable. |
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RT/L = Ambient room temperature and light. |
Intramuscular cefepime hydrochloride constituted as directed is stable for 24 hours
at controlled room temperature 20°-25° C (68°-77° F) or for 7 days in a refrigerator
2°-8° C (36°-46° F) with the following diluents: Sterile Water for Injection, 0.9%
Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for
Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.
NOTE :
Parenteral drugs should be inspected visually for particulate matter before administration.
As with other cephalosporins, the colour of cefepime powder, as well as its solutions,
tends to darken depending on storage conditions; however, when stored as recommended,
the product potency is not adversely affected.
CONTRAINDICATIONS
ROFIPIME is contraindicated in patients who have shown immediate hypersensitivity
reactions to cefepime or the cephalosporin class of antibiotics, penicillins or
other beta-lactam antibiotics.
WARNINGS AND PRECAUTIONS
Before therapy with ROFIPIME for injection is instituted, careful inquiry
should be made to determine whether the patient has had previous immediate hypersensitivity
reactions to cefepime, cephalosporins, penicillins, or other drugs. If this product
is to be given to penicillin-sensitive patients, caution should be exercised because
cross-hypersensitivity among beta-lactam antibiotics has been clearly documented
and may occur in up to 10% of patients with a history of penicillin allergy. If
an allergic reaction to ROFIPIME occurs, discontinue the drug. Serious acute
hypersensitivity reactions may require treatment with epinephrine and other emergency
measures including oxygen, corticosteroids, intravenous fluids, intravenous antihistamines,
pressor amines, and airway management, as clinically indicated.
In patients with impaired renal function (creatinine clearance <= 60 mL/min), the
dose of ROFIPIME should be adjusted to compensate for the slower rate of renal elimination.
Because high and prolonged serum antibiotic concentrations can occur from usual
dosages in patients with renal insufficiency or other conditions that may compromise
renal function, the maintenance dosage should be reduced when cefepime is administered
to such patients. Continued dosage should be determined by degree of renal impairment,
severity of infection, and susceptibility of the causative organisms.
Pseudomembranous colitis has been reported with nearly all antibacterial agents,
including ROFIPIME , and may range in severity from mild to life-threatening. Therefore,
it is important to consider this diagnosis in patients who present with diarrhoea
subsequent to the administration of antibacterial agents.
Many cephalosporins, including cefepime, have been associated with a fall in prothrombin
activity. Those at risk include patients with renal or hepatic impairment, or poor
nutritional state, as well as patients receiving a protracted course of antimicrobial
therapy. Prothrombin time should be monitored in patients at risk, and exogenous
vitamin K administered as indicated.
Positive direct Coombs` tests have been reported during treatment with cefepime
hydrochloride. In haematologic studies or in transfusion cross-matching procedures
when antiglobulin tests are performed on the minor side or in Coombs` testing of
newborns whose mothers have received cephalosporin antibiotics before parturition,
it should be recognized that a positive Coombs` test may be due to the drug.
Cefepime hydrochloride should be prescribed with caution in individuals with a history
of gastrointestinal disease, particularly colitis.
Arginine has been shown to alter glucose metabolism and elevate serum potassium
transiently when administered at 33 times the amount provided by the maximum recommended
human dose of cefepime hydrochloride. The effect of lower doses is not presently
known.
Drug interactions
Renal function should be monitored carefully if high doses of aminoglycosides are
to be administered with ROFIPIME because of the increased potential of nephrotoxicity
and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported
following concomitant administration of other cephalosporins with potent diuretics
such as furosemide.
Renal impairment
Please see under DOSAGE AND ADMINSITRATION.
Hepatic impairment
No adjustment is necessary for patients with impaired hepatic function.
Pregnancy
This drug should be used during pregnancy only if clearly needed.
Lactation
Cefepime is excreted in human breast milk in very low concentrations [0.5 µg/mL].
Caution should be exercised when cefepime is administered to a nursing woman.
Paediatric use
The safety and efficacy of cefepime have been established in the age group 2 months
upto 16 years. Safety and effectiveness in paediatric patients below the age of
2 months have not been established. In those patients in whom meningeal seeding
from a distant infection site or in whom meningitis is suspected or documented,
an alternate agent with demonstrated clinical efficacy in this setting should be
used.
Geriatric Use
In elderly patients, dosage and administration of cefepime should be adjusted in
the presence of renal insufficiency.
UNDESIRABLE EFFECTS
Adverse events thought to be probably related to cefepime were Incidence equal to
or greater than 1%: Local reactions (3.0%), including phlebitis (1.3%), pain and/or
inflammation (0.6%) ; rash (1.1%).
Incidence less than 1% but greater than 0.1%: Colitis (including pseudomembranous
colitis), diarrhoea, fever, headache, nausea, oral moniliasis, pruritus, urticaria,
vaginitis, vomiting.
At the higher dose of 2 g q8h, the incidence of probably-related adverse events
onsisted of rash (4%), diarrhoea (3%), nausea (2%), vomiting (1%), pruritus (1%),
fever (1%), and headache (1%).
OVERDOSAGE
Patients who receive an overdose should be carefully observed and given supportive
treatment. In the presence of renal insufficiency, hemodialysis, not peritoneal
dialysis, is recommended to aid in the removal of cefepime from the body. Accidental
overdosing has occurred when large doses were given to patients with impaired renal
function. Symptoms of overdose include encephalopathy (disturbance of consciousness
including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and
neuromuscular excitability.
INCOMPATIBILITY
Solutions of ROFIPIME , like those of most beta-lactam antibiotics, should not be
added to solutions of ampicillin at a concentration greater than 40 mg/mL, and should
not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate
or aminophylline because of potential interaction. However, if concurrent therapy
with ROFIPIME is indicated, each of these antibiotics can be administered separately.
SHELF-LIFE
See on pack
STORAGE AND HANDLING INSTRUCTIONS
Store in a cool dry place
Protect from light
PACKAGING INFORMATION
ROFIPIME - 1 gm is available in a vial of 15 ml with 10 ml Sterile water for injection
IP
ROFIPIME - 2 gm is available in a vial of 20 ml with 10 ml Sterile water for injection
IP
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