FORPAR XP Injection (Cefepime + Tazobactam)

Table of Content

Globally, the prevalence of drug-resistant Gram-negative bacteria is increasing and has become a major challenge for the clinicians. The last resort drugs, such as carbapenems or colistin, are also resistant to these bacteria. In view of this, it is necessary to judiciously use antibiotics that act as a carbapenem-sparer.

Cefepime/tazobactam (FORPAR XP) is a BL/BLI and is indicated for uncomplicated and complicated urinary tract infections, uncomplicated skin and skin structure infections, complicated intra-abdominal infections, LRTIs, including pneumonia and bronchitis, septicaemia and for empiric treatment in febrile neutropenic patients.

Cefepime, a fourth-generation cephalosporin, has the theoretical advantage of additional activity against AmpC and OXA enzymes over third-generation cephalosporins. Addition of tazobactam will help in inactivating extended-spectrum beta-lactamases (ESBLs), which are not covered by cefepime. Thus, the introduction of cefepime/tazobactam can tackle all three major mechanisms of resistance and act as a carbapenem-sparer in moderate-to-severe infections.

The recommended adult dosage of FORPAR XP is 0.5 gm to 2 gm every 12 hours. Cefepime/tazobactam should be administered via the I.V. route over 30 minutes. Maximum adult dose of cefepime should not exceed 6 gm a day.

January 2016

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

 

Qualitative and Quantitative Composition

FORPAR XP Injection 1.125 g

Each combipack contains:

  1. 1 vial of Cefepime &Tazobactam for Injection

Each vial contains:

Cefepime Hydrochloride, IP (sterile)

eq. to Cefepime ................... 1.0 g

(Buffered with L-arginine)

Tazobactam Sodium IP (sterile)

eq. to Tazobactam ......................... 125 mg

  1. 1 ampoule of Sterile Water for Injections IP

Each ampoule contains:

Sterile Water for Injections IP ......................10 mL

FORPAR XP Injection 2.25 g

Each combipack contains:

  1. 1 vial of Cefepime &Tazobactam for Injection

Each vial contains:

Cefepime Hydrochloride IP (sterile)

eq. to Cefepime ................... 2.0 g

(Buffered with L-arginine)

Tazobactam Sodium IP (sterile)

eq. to Tazobactam ......................... 250 mg

  1. 1 ampoule of Sterile Water for Injections IP

Each ampoule contains:

Sterile Water for Injections IP ......................10 mL

Dosage Form and Strength

Powder for injection for intravenous (IV) and intramuscular (IM) use only

Clinical Particulars

Therapeutic Indications

FORPAR XP Injection is indicated in the treatment of infections caused by bacteria that are cefepime-sensitive:

- Lower respiratory tract infections, including nosocomial pneumonia and community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis and secondary bacterial infection of acute bronchitis

- Uncomplicated and complicated urinary tract infections, including pyelonephritis

- Skin and subcutaneous infections

- Intra-abdominal infections, including peritonitis and biliary tract infections

- Gynaecological infections

- Bacterial meningitis in infants and children

- In combination with other antibacterial agents in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection

- Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology and Method of Administration

Dosage for Adults

The recommended adult dosages and routes of administration are outlined in Table 1below for patients with creatinine clearance >60 mL/min. Administer cefepime-tazobactam for injection by the IV route for approximately 30 minutes.

Table 1: Recommended Adult Dosages and Routes of Administration for Patients with Creatinine Clearance >60 mL/min

Site and Type of Infection in Adults

Dose

 IV/

 IM

Frequency

Duration (days)

Moderate-to-severe pneumonia

1–2 g IV

Every 8–12 hours

10

Empiric treatment in febrile neutropenic patients

2 g IV

Every 8 hours

7*

Mild-to-moderate uncomplicated or complicated urinary tract infections, including pyelonephritis

0.5–1g IV/IM**

Every 12 hours

7–10

Severe uncomplicated or complicated urinary tract infections (UTIs), including pyelonephritis

2 g IV

Every 12 hours

10

Moderate-to-severe skin and skin structure infections

2 g IV

Every 12 hours

10

Complicated intra-abdominal infections

2 g IV

Every 8–12 hours

7–10

* or until resolution of neutropoenia. In patients whose fever resolves but who remain neutropenic for more than 7days, 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 UTIsdue to Escherichia coli.

For Pseudomonas aeruginosa, use 2 g IV every 8 hours.

Dosage for Paediatric Patients (2 months to 16 years of age)

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 duration as given above for adults is as follows:

  • For uncomplicated and complicated UTIs (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia (see below):50 mg per kg per dose, administered every 12 hours.
  • For moderate-to-severe pneumonia due to P. aeruginosa:50 mg per kg per dose, every 8 hours
  • For febrile neutropenic patients:50 mg per kg per dose, every 8 hours

Dosage Adjustment in Patients with Renal Impairment

Adult Patients

Adjust the dose of cefepime-tazobactam for injection in patients with creatinine clearance ≤60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of cefepime-tazobactam for injection should be the same as in patients with CrCL >60 mL/minexcept in patients undergoing haemodialysis. The recommended doses of cefepime-tazobactam for injection in patients with renal impairment are presented in Table 2 below.

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) x (140 – age)

                                                                     72 × serum creatinine (mg/dL)

Females: 0.85 × above value

Table 2: Recommended Dosing Schedule for Cefepime-Tazobactam for Injection in Adult Patients with Creatinine Clearance ≤60 mL/min

Creatinine Clearance (mL/min)

Recommended Maintenance Schedule

>60

500mg every 12 hours

1g every 12 hours

2g every 12 hours

 2g every 8 hours

30–60

500mg every 24 hours

1g every 24 hours

2g every 24 hours

 2g every 12 hours

11–29

500 mg every 24 hours

500 mg every 24 hours

1g every 24 hours

  2g every 24   hours

<11

250 mg every 24 hours

250 mg every 24 hours

500 mg every 24 hours

 1 g every 24 hours

CAPD

500mg every 48 hours

1g every 48 hours

2g every 48 hours

  2 g every 48 hours

Haemodialysis*

1 g on day 1, then 500 mg q24 h thereafter

 1 g every 24 hours

CAPD= continuous ambulatory peritoneal dialysis

*On haemodialysis days, cefepime and tazobactam should be administered following haemodialysis. Whenever possible, cefepime-tazobactam should be administered at the same time each day.

 

In patients undergoing CAPD, cefepime-tazobactam for injection may be administered at the recommended doses at a dosage interval of every 48 hours (see Table 2).

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. The dosage of cefepime-tazobactam for injection for haemodialysis patients is 1 g on day 1 followed by 500 mg every 24 hours for thetreatment of all infections except febrile neutropenia, which is 1 g every 24 hours.

Cefepime-tazobactam for injection should be administered at the same time each day and following the completion of haemodialysis on haemodialysis days (see Table 2).

Paediatric Patients

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 (see Tables 1 and 2) are recommended for paediatric patients.

Method of Preparation and Administration

For IV Administration (1.125 g and 2.25 g)

The contents of the vials should be reconstituted with 10 mL of sterile Water for Injections, IP, and further diluted with 50 or 100 mL of 0.9% Sodium Chloride solution or 5% Dextrose solution.  The appropriate dose of the drug should then be added to a compatible IV solution.  The resultant solutions are stable for 24 hours when stored at a temperature of 20–25o C. Intermittent IV infusion is given for approximately 30 minutes. 

For IM Administration (1.125 g)

The IM injection of cefepime and tazobactam is prepared by adding 2.4 mL of Sterile Water for Injections, IP.  The solution is stable for 1 hour when stored at 20–25ºC.

Compatible Diluents

For IV Use: Compatible diluents are 0.9% Sodium Chloride solution and 5% Dextrose solution.

For IM Use: Only sterile Water for Injectionsshould be used for reconstitution.

Solution of cefepime hydrochloride and tazobactam injection should not be frozen.

Contraindications

Cefepime-tazobactam for injection is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

Special Warnings and Precautions for Use

Hypersensitivity Reactions

Before therapy with cefepime-tazobactam 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 beta-lactams. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefepime-tazobactam for injection occurs, discontinue the drug and institute appropriate supportivemeasures.

Neurotoxicity

Serious adverse reactions have been reported, including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness, including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and non-convulsive status epilepticus. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after haemodialysis. If neurotoxicity associated with cefepime therapy occurs, discontinue cefepime and institute appropriate supportive measures.

Clostridium difficile-associated Diarrhoea

Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime for injection, and may range in severity from mild diarrhoea 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-producingstrains of C. difficile cause increased morbidity and mortality, as these infections can berefractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibacterial drug use.

Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug 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.

Development of Drug-resistant Bacteria

Prescribing cefepime-tazobactam for injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. As with other antimicrobials, prolonged use of cefepime for injection may result in overgrowth of non-susceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

Drug/Laboratory Test Interactions

Urinary Glucose

The administration of cefepime may result in a false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest tablets).

Coombs' Test

A positive direct Coombs' test has been reported during treatment with cefepime for injection. In patients who develop haemolytic anaemia, discontinue the drug and institute appropriate therapy. Positive Coombs' test may be observed in newborns whose mothers have received cephalosporin antibiotics before parturition.

Prothrombin Time

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 TM patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

Drug Interactions

Drug/Laboratory Test Interactions

The administration of cefepime may result in a false-positive reaction for glucose in the urine withcertain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Aminoglycosides

Monitor renal function if aminoglycosides are to be administered with cefepime-tazobactam for injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.

Diuretics

Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function when cefepime is concomitantly administered with potent diuretics.

Use in Special Populations

Pregnancy

PREGNANCY CATEGORY B

There are no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1,000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a body surface area basis) or to mice at doses up to 1,200 mg/kg (approximately equal to the recommendedmaximum human dose calculated on a body surface area basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a body surface area basis).

Labour and Delivery

Cefepime has not been studied for use during labour and delivery. Treatment should only be given if clearly indicated.

Lactating Women

Cefepime is excreted in human breast milk. Caution should be exercised when cefepime is administered to a nursing mother.

Paediatric Use

The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated UTIs (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age group of 2 months to 16 years. Use of cefepime-tazobactam for injection in this age group is supported by evidence from adequate and well-controlled studies of cefepime in adults with additional pharmacokinetic and safety data from paediatric trials. Safety and effectiveness in paediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of cefepime for injection in paediatric patients for the treatment of serious infections in the paediatric population where the suspected or proven pathogen is Haemophilus influenzae type B. 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

Of the more than 6,400 adults treated with cefepime-tazobactam for injection in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable with clinical efficacy and safety in non-geriatricadult patients. Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures.This drug is known to be substantially excreted by the kidneys, 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 renal function should be monitored

Renal Impairment

Adjust the dose of cefepime-tazobactam for injection in patients with creatinine clearance ≤60 mL/min to compensate for the slower rate of renal elimination.

Effects on Ability to Drive and Use Machines

The effects of the medicinal product on the ability to drive and use machines have not been studied. However, possible adverse reactions like altered state of consciousness, dizziness, confusional state or hallucinations may alter the ability to drive and use machines.

Undesirable Effects

The following adverse reactions are discussed in the Special Warnings and Precautions for Use section:

  • Hypersensitivity Reactions
  • Neurotoxicity
  • Clostridium difficile-associated Diarrhoea

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials using multiple doses of cefepime, 4,137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g IV every 12 hours). There were no deaths or permanent disabilities that were thought to be related to drug toxicity. Due to adverse reactions, 64 (1.5%) patients discontinued medication. Of these 64 patients who discontinued therapy, 33 (51%) did so because of rash. The percentage of cefepime-treated patients who discontinued the study drug because of drug-relatedadverse reactions was similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses.

Incidence ≥1%

Local adverse reactions (3%), including phlebitis (1.3%), pain and/or inflammation (0.6%)*; rash (1.1%)

Incidence <1% but >0.1%

Colitis (including pseudomembranous colitis), diarrhoea, erythema, fever, headache, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting,

anaemia

Adverse Reactions in Cefepime Multiple-Dose Regimens – Clinical Trials in North America(n=3,125 cefepime-treated patients)

At the higher dose of 2 g every 8 hours, the incidence of adverse reactions was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhoea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%).

Adverse Laboratory Changes in Cefepime Multiple-Dose Regimens – Clinical Trials in North America

Table 3

Incidence ≥1%

Positive Coombs' test (without haemolysis) (16.2%); decreased phosphorus (2.8%); increased

alanine transaminase (ALT) (2.8%), aspartate transaminase (AST) (2.4%) and eosinophils (1.7%); abnormal PTT (1.6%) andprothrombin time (PT) (1.4%)

Incidence <1% but >0.1%

Increased alkaline phosphatase, blood urea nitrogen (BUN), calcium, creatinine, phosphorus,potassium, total bilirubin; decreased calcium*, haematocrit, neutrophils, platelets, white blood cells (WBCs)

* Hypocalcaemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported.

A similar safety profile was seen in clinical trials of paediatric patients.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of cefepime-tazobactam for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In addition to the adverse reactions reported during the North American clinical trials with cefepime, the following adverse reactions have been reported during worldwide postmarketing experience. Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor and coma), aphasia, myoclonus, seizures, and non-convulsive status epilepticus have been reported . Anaphylaxis (including anaphylactic shock, transient leucopenia, neutropenia, agranulocytosis and thrombocytopaenia)has been reported.

Cephalosporin-class Adverse Reactions

In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibacterial drugs:

  • Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anaemia, haemolytic anaemia, haemorrhage, hepatic dysfunction (including cholestasis), and pancytopaenia.

Reporting of suspected adverse reactions

If you experience any sideeffects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India (PvPI) by calling on 18002677779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting sideeffects, you can help provide more information on the safety of this product.

Overdose

Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal insufficiency, haemodialysis (not peritoneal dialysis) is recommended to aid in the removal of cefepime from the body. Symptoms of overdose include encephalopathy (disturbance of consciousness, including confusion, hallucinations, stupor and coma), myoclonus, seizures, neuromuscular excitability, and non-convulsive status epilepticus.

Pharmacological Properties

Mechanism of Action

Cefepime is a bactericidal drug 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-negativebacteria. Within bacterial cells, the molecular targets of cefepime are the penicillin-binding proteins (PBPs).

Antimicrobial Activity

Cefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Gram-negative Bacteria

Enterobacter spp.

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

Gram-positive Bacteria

Staphylococcus aureus (methicillin-susceptible isolates only)

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group streptococci

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefepime against isolates of similar genus or organism group. However, the efficacy of cefepime in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Staphylococcus saprophyticus

Streptococcus agalactiae

NOTE: Most isolates of enterococci, e.g. Enterococcus faecalis, and methicillin-resistant staphylococciare resistant to cefepime.

Gram-negative Bacteria

Acinetobacter calcoaceticus subsp. lwoffii

Citrobacter diversus

Citrobacter freundii

Enterobacter agglomerans

Haemophilus influenzae

Hafnia alvei

Klebsiella oxytoca

Moraxella catarrhalis

Morganella morganii

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Serratia marcescens

NOTE: Cefepime is inactive against many isolates of Stenotrophomonas maltophilia.

Susceptibility Testing: For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by the US FDA for this drug, please see: https://www.fda.gov/STIC.

Pharmacodynamic Properties

Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of cefepime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamic relationship for cefepime has not been evaluated in patients.

Pharmacokinetic Properties

Pharmacokinetic parameters for cefepime in healthy adult male volunteers (n=9) following single 30-minute infusions (IV) of cefepime 500 mg, 1 g and 2 g are summarised in Table 4 below. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Cefepime pharmacokinetics is linear over the range of 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.

Table 4: Mean Pharmacokinetic Parameters for Cefepime (±SD), IV Administration

Cefepime for Injection

Parameter

500 mg IV

1 g IV

2 g IV

Cmax mcg/mL

39.1 (3.5)

81.7 (5.1)

163.9 (25.3)

AUC, h•mcg/mL

70.8 (6.7)

148.5 (15.1)

284.8 (30.6)

Number of subjects (male)

9

9

9

Pharmacokinetic parameters for cefepime following a single IM injection are summarised in Table 5. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 g given by the IM route and do not vary with respect to treatment duration.

Table 5: Mean Pharmacokinetic Parameters for Cefepime (±SD), IM Administration

Cefepime for Injection

Parameter

500 mg IM

1 g IM

2 g IM

Cmax mcg/mL

13.9 (3.4)

29.6 (4.4)

57.5 (9.5)

Tmax,h

1.4 (0.9)

1.6 (0.4)

1.5 (0.4)

AUC, h•mcg/mL

60 (8)

137 (11)

262 (23)

Number of subjects (male)

6

6

12

Absorption

Following IM administration, cefepime is completely absorbed.

Distribution

The average steady-state volume of distribution of cefepime is 18 (±2) L. The serum protein-binding of cefepime is approximately 20% and is independent of its concentration in serum.

Cefepime is excreted in human milk at a concentration of 0.5 mcg/mL. A nursing infant consuming approximately 1,000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day.

Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 6.

Table 6: Mean Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g)

Tissue or Fluid

Dose/Route

Number of Patients

 

Mean Time of

Sample Post-

Dose (h)

 

Mean

Concentration

Blister fluid

2 g IV

6

1.5

81.4 mcg/mL

Bronchial mucosa

2 g IV

20

4.8

24.1 mcg/g

Sputum

2 g IV

5

4

7.4 mcg/mL

 

Urine

 

 

Bile

 

500 mg IV

1 g IV

2 g IV

2 g IV

 

8

12

12

26

0 to 4

0 to 4

0 to 4

9.4

292 mcg/mL

926 mcg/mL

3120 mcg/mL

17.8 mcg/mL

Peritoneal fluid

2 g IV

19

4.4

18.3 mcg/mL

Appendix

2 g IV

31

5.7

5.2 mcg/g

 

Gallbladder

2 g IV

38

8.9

11.9 mcg/g

 

Prostate

2 g IV

5

1

31.5 mcg/g

Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.

Metabolism and Excretion

Cefepime is metabolised 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.

Specific Populations

Patients with Renal Impairment

Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring haemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (±2) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients.

Patients with Hepatic Impairment

The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).

Geriatric Patients

Cefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74 (±15) mL/min. There appeared to be a decrease in cefepime total body clearance as a function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patient's creatinine clearance is ≤60 mL/min.

Paediatric Patients

Cefepime pharmacokinetics have been evaluated in paediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules.

Following a single IV dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The urinary recovery of unchanged cefepime was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2 (±1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen whencefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and t1/2were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to cefepime following a 50mg per kg IV dose in a paediatric patient is comparable with that in an adult treated with a 2g IV dose. The absolute bioavailability of cefepime after an IM dose of 50 mg per kg was 82.3 (±15)% in 8 patients.

Non-Clinical Properties

Animal Toxicology or Pharmacology

No animal carcinogenicity studies have been conducted with cefepime. In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (two chromosomalaberration and two micronucleus studies) were negative for clastogenicity. No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1,000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a body surface area basis).

Description

Cefepime-tazobactam for injection, USP, is a semi-synthetic, cephalosporin antibacterial for parenteral administration. The chemical name is 1--2-carboxy-8-oxo-5-thia-1-azabyciclo oct-2-enyl]methyl]-1-methylpyrrolidinum chloride,7 -(Z)-Omethyloxime), monohydrochloride, monohydrate, which corresponds to the following structuralformula:

Pharmaceutical Particulars

Incompatibilities

Cefepime must not be mixed with other medicinal products or solutions except those mentioned. There is a physical-chemical incompatibility with metronidazole, vancomycin, gentamicin, tobramycin, netilmicin and aminophylline. In the cases where a concomitant IV administration is indicated, these active substances should not be administered together with cefepime or through the same IV route.

Shelf-Life

Refer Pack for Expiry Date

Packaging Information

FORPAR XP 1.125gAvailable in a vail of 15 ml with 10 ml Sterile water for injection IP

FORPAR XP 2. 25gAvailable in a vail of 30 ml with 10 ml Sterile water for injection IP

Storage and Handling Instructions

Store in a dry & dark place at temperature not exceeding 30C. Do not freeze.

Patient Counselling Information

  • Counsel patients that antibacterial drugs, including cefepime-tazobactam for injection, should only be used to treat bacterial infections. They do not treat viral infections (e.g. the common cold). When cefepime-tazobactam for injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or 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 cefepime-tazobactam for injection or other antibacterial drugs in the future.
  • Diarrhoea is a common problem caused by antibacterial drugs, which usually ends when the antibiotic is discontinued. Inform patient that they may develop watery and bloody stools (with or without stomach cramps and fever) during treatment and as late as 2 or more months after having taken the last dose of the antibiotic. Inform patients that they should contact their physician as soon as possible if this occurs.
  • Advise patients of neurological adverse events that could occur with the use of cefepime-tazobactam for injection. Instruct patients or their carers to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness, including confusion, hallucinations, stupor and coma), aphasia (disturbance of speaking and understanding spoken and written language), myoclonus, seizures and non-convulsive status epilepticus, for immediate treatment, dosage adjustment, or discontinuation of cefepime-tazobactam for injection.

Details of The Manufacturer

Akums Drugs and Pharmaceuticals Ltd.

2,3,4 and 5 Sec-6B, IIE, SIDCUL,

Ranipur, Haridwar – 249403 (Uttarakhand)

Details of Permission or Licence Number with Date

29\UA\SC/P-2007

Date of Revision

29thAugust 2019