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

Composition

FORPAR XP 1.125 g

Each combipack contains:

(a) 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 (Sterile) eq. to Tazobactam ......................... 125 mg

(b) 1 Ampoule of Sterile Water for Injections IP

Each ampoule contains:

Sterile Water for Injections IP ......................10 ml

FORPAR XP 2.25 g

Each combipack contains:

(a) 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 (Sterile) eq. to Tazobactam ......................... 250 mg

(b) 1 Ampoule of Sterile Water for Injections IP

Each ampoule contains:

Sterile Water for Injections IP ......................10 ml

Dosage Form

Powder for injection for IV and IM use only

Description

FORPAR XP is a combination of cefepime hydrochloride, a semisynthetic fourth-generation cephalosporin, and a beta-lactamase inhibitor, tazobactam sodium, in an 8:1 ratio.

Pharmacology

Pharmacodynamics

Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents. Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis.  Cefepime has a low affinity for chromosomally-encoded beta-lactamases penetration into Gram-negative bacterial cells.  Within bacterial cells, the molecular targets of cefepime are the penicillin-binding proteins (PBP).

Zwitterions of cefepime enhance its movement across the cell membrane, resulting in high concentrations in the periplasmic space and relatively net resistance to drug hydrolysis, and cefepime exhibits only modest inactivation.

Emergence of drug resistance to cefepime was considered as less of a problem till recently.  ESBLs are capable of hydrolysing penicillin, and broad- and extended-spectrum cephalosporins. ESBLs can be found in a variety of Enterobacteriaceae species such as K. pneumoniae, K. oxytoca and E. coli.  Other organisms that harbour ESBLs are Enterobacter spp., Salmonella spp., Morganella morganii, Proteus mirabilis, Serratia marcescens and P. aeruginosa. Use of cefepime alone has been associated with selection of ESBL-producing organisms and outbreaks of infection.

Tazobactam generally acts as an irreversible inhibitor and inactivates both plasmid- and chromosomally-mediated beta-lactamases.

The combination of cefepime with tazobactam is useful for the treatment of infections due to ESBL-producing organisms.  Tazobactam augments and protects the action of cefepime.

Cefepime and Tazobactam is usually effective against following micro-organisms:

Aerobic Gram-negative Micro-organisms

Enterobacter, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Pseudomonas aeruginosa

Aerobic Gram-positive Micro-organisms

Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pneumoniae, Streptococcus pyogenes (Lancefield’s Group A streptococci), Viridans Group streptococci

Cefepime has been shown to have in vitro activity against most strains of the following micro-organisms, however the safety and effectiveness of cefepime in treating clinical infections due to the microorganisms have not been established in adequate and well controlled trials.

Aerobic Gram-positive Micro-organisms

Staphylococcus epidermidis (methicillin-susceptible isolates only), Staphylococcus saprophyticus, Streptococcus agalactiae (Lancefield’s Group B streptococci)

NOTE: Most strains of enterococci, e.g., Enterococcus faecalis and methicillin-resistant staphylococci are resistant to cefepime.

Aerobic Gram-negative Micro-organisms

Acinetobacter calcoaceticus, Citrobacter diversus , Citrobacter freundii, Enterobacter agglomerans, Haemophilus influenza, Halfnia alvei, Klebsiella oxytoca, Moraxella catarrhalis, 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 Micro-organisms

NOTE: Cefepime is inactive against most strains of Clostridium difficile.

Pharmacokinetics

Absorption

Cefepime exhibits linear dose-dependent pharmacokinetics over the dosage range of 250 mg to 2 g, and there is no evidence of drug accumulation following multiple doses in healthy adults with normal renal function.

Cefepime is almost completely absorbed following intramuscular (I.M.) administration.  The single 500 mg, 1 g or 2 g I.M. doses of cefepime attain peak plasma concentrations of 13.9, 29.6 or 57.5 mcg/ml, respectively.  Plasma concentration is attained within 1.4–1.6 hours.  After 8 hours, the plasma concentration averaged 1.9, 4.5 or 8.7 mcg/ml, respectively.

Following I.V. infusion over 30 minutes of a single 500 mg , 1 g or 2 g dose of cefepime peak plasma concentration of the drug averaged 31.6–39.1, 65.9–81.7 or 126–139.9 mcg/ml, respectively. Plasma concentrations at 8 hours after the dose averaged 1.4, 2.4 and 3.9 mcg/ml, respectively.

Distribution

Following parenteral administration, cefepime is widely distributed into tissues and fluids, including blister fluid, bronchial mucosa, sputum bile, peritoneal fluid, appendix and gall bladder. Cefepime is distributed into the CSF following parenteral administration.  It is also excreted in human milk. 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. Plasma half-life of cefepime averages 2–2.3 hours.

Metabolism and Excretion

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. Cefepime is eliminated principally unchanged in urine by glomerular filtration, 80-82% of a single dose cefepime is excreted unchanged in urine. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment. Cefepime is removed by haemodialysis and peritoneal dialysis.

When tazobactam 0.5 g is infused over 30 minutes as a single dose, the peak serum level averages 27.1 mcg/ml, the half-life is 0.67 hour, and its renal clearance is 268 ml per min. Tazobactam is metabolized to a single metabolite, which has been found to be microbiologically inactive.  Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the administered dose appearing as unchanged drug and the remainder as the single metabolite.

Indications

FORPAR XP is used parenterally for the treatment of moderate-to-severe infections caused by or suspected of being caused by susceptible BL-producing bacteria when cefepime alone would be ineffective.

Cefepime and tazobactam combination is used for the treatment of the following indications:

  • Uncomplicated and complicated urinary tract infections
  • Uncomplicated skin and skin structure infections
  • Complicated intra-abdominal infections
  • LRTI including pneumonia & bronchitis
  • Septicemia
  • Empiric treatment in febrile neutropenic patients

Dosage and Administration

Dosage

Cefepime and tazobactam is administered, preferably, by I.V. infusion, but also can be given by deep I.M. injection when indicated.

Cefepime and tazobactam should be administered via the I.V. route over 30 minutes.

Adults

Recommended dosage schedule for cefepime and tazobactam for injection in patients with CrCl (creatinine clearance) >60ml/min (expressed as cefepime)

Site and type of infection in adults

Dose

Frequency

Duration (days)

Moderate to severe pneumonia

1-2 g I.V.

12-hourly

10

Empiric treatment in febrile neutropenic patients

2 g I.V.

8-hourly

7

Mild-to-moderate uncomplicated or complicated urinary tract infections

0.5–1g I.V./I.M.**

12-hourly

7–10

Severe uncomplicated or complicated  urinary tract infections

2 g I.V.

12-hourly

10

Moderate-to-severe skin and skin structure infections

2 g I.V.

12-hourly

10

Complicated Intra-abdominal infections

2 g I.V.

12-hourly

7–10

**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. 

Maximum adult dose of cefepime should not exceed 6 g a day.

Pediatric (2 months to 16 years of age)

The maximum dose for pediatric patients should not exceed the recommended adult dose. The usual recommended dosage in pediatric patients up to 40 kg in weight for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia is 50 mg per kg per dose, administered every 12 hours (50 mg per kg per dose, every 8 hours for febrile neutropenic patients), for durations as given above.

Hepatic Impairment

No adjustment is necessary for patients with impaired hepatic function.

Renal Impairment

In patients with impaired renal function (creatinine clearance <60 ml/min), the dose of cefepime/tazobactam injection should be adjusted to compensate for the slower rate of renal elimination of cefepime and tazobactam. The recommended initial dose of cefepime should be the same in patients with normal renal function except in patients undergoing hemodialysis. The half-life of tazobactam increases with decreased creatinine clearance. At creatinine clearance below 20ml/min, the increase in half life is fourfold for tazobactam compared to subjects with normal renal function. The recommended doses of cefepime in patients with renal insufficiency are presented in the table 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) × (140 – age in years)

                                                                  72 × serum creatinine in (mg/dL)

Females (ml/min) = 0.85 × above value

Table: Recommended Dosing Schedule for cefepime and tazobactam for injection in Adult Patients (Normal Renal Function, Renal Insufficiency and Hemodialysis)

Creatinine clearance (ml/min)

Recommended Maintenance Schedule

>60 Normal recommended dosing schedule

500mg q12 h

1g q12 h

2g q12 h

30–60

500mg q24 h

1g q24 h

2g q24 h

11–29

500 mg q24 h

500 mg q24 h

1g q24 h

<11

250 mg q24 h

250 mg q24 h

500 mg q24 h

CAPD

500mg q48 h

1g q48 h

2g q48 h

Haemodialysis*

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

CAPD= Continuous Ambulatory Peritoneal Dialysis

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

In patients undergoing haemodialysis, approximately 58% of total amount of cefepime present in the body at the start of dialysis will be removed during a 3 h dialysis period.

Cefepime and tazobactam for injection should not be given to pediatric patients with impaired renal function.

Method of Preparation and Administration

For I.V. Administration 1.125 g and 2.25 g

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

For I.M. Administration 1.125 g

I.M. injection of cefepime and tazobactam is prepared by adding 2.4 ml of Sterile Water for Injection IP.  The solution is stable for 1 hour when stored at 20ºC to 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 Injection to be used for reconstitution.

Solution of Cefepime Hydrochloride and Tazobactam Injection should not be frozen.

Contraindications

Cefepime and tazobactam combination is contraindicated in patients who are hypersensitive to the drugs or other cephalosporins and should be used with caution in patients with a history of hypersensitivity to penicillins.  Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins or other beta lactam antibiotics. If a hypersensitivity reaction occurs during cefepime and tazobactam therapy, the drug should be discontinued and the patient treated with appropriate therapy, e.g. epinephrine, corticosteroids and maintenance of an adequate airway and oxygen as indicated.

Warnings and Precautions

General

Before therapy with cefepime and tazobactam for infection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reaction to cefepime, cephalosporins, penicillins or other drugs.

During postmarketing surveillance, serious adverse events have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules. However, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime, 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.

Drug Interactions

Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with cefepime/tazobactam 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

In patients with impaired renal function (creatinine clearance <60 ml/min), the dose of cefepime/tazobactam injection should be adjusted to compensate for the slower rate of renal elimination of cefepime and tazobactam. Dose adjustment is required in patients with renal failure with creatinine clearance <60 ml/min. In patients with creatinine clearance less than or equal to 60 mL/min, the dose of cefepime hydrochloride 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 impairment 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.

Hepatic Impairment

No adjustment is necessary for patients with impaired hepatic function

Pregnancy

Pregnancy Category B. There are no adequate or controlled studies using cefepime and tazobactam in pregnant women or during labour and delivery and the drug should be used during pregnancy only when clearly indicated.

Lactation

Cefepime is excreted in human breast milk in very low concentration following parenteral administration and the drug should be used with caution in nursing mothers.

Pediatric

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

Geriatrics

When geriatric patients received the usual recommended adult dose of cefepime, clinical efficacy and safety were comparable to clinical efficacy and safety in non-geriatric adult 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. Cefepime and tazobactam are known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater to 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.

Information to patients

Patients should be counseled that antibacterial drugs including cefepime and tazobactam for injection should only be used to treat bacterial infections. They do not treat viral infections (eg, the common cold). When cefepime and tazobactam for injection 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 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 and tazobactam for injection 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.

Patients should be advised of neurological adverse events that could occur with cefepime use. Patients should be instructed to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures, for immediate treatment, dosage adjustment, or discontinuation of cefepime.

Undesirable Effects

Adverse effects with cefepime and tazobactam are similar to those reported with cefepime alone and generally are transient and mild-to-moderate in severity.

Adverse events reported with cefepime are as follows:

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), diarrhea, headache, fever, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting.

At the higher dose of 2 g q8h, the incidence of probably-related adverse events was higher.  They consisted of rash (4%), diarrhoea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%) and headache (1%).

The following adverse laboratory changes, irrespective of a relationship to therapy with cefepime, were reported:

Incidence equal to or greater than 1%:  Positive Coombs test (without haemolysis) (16.2%), decreased phosphorus (2.8%), increased ALT/SGPT (2.8%), AST/SGOT (2.4%), eosinophils (1.7%), abnormal PTT (1.6%), PT (1.4%).

Incidence less than 1% but greater than 0.1%:  Increased alkaline phosphatase, BUN, calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calcium, haematocrit, neutrophils, platelets, WBC.

Postmarketing Experience

In addition to the events reported above with cefepime, the following adverse experiences have been reported during worldwide postmarketing experience.

As with some other drugs in this class, encephalopathy (disturbance of consciousness including confusion hallucinations, stupor and coma, myoclonus, and seizures have been reported.  Although most cases occurred in patients with renal impairment who received doses of cefepime that exceeded recommended dosage schedules, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.

As with other cephalosporins, anaphylaxis including anaphylactic shock, transient leucopenia, neutropenia, agranulocytosis and thrombocytopenia have 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 antibiotics:  Stevens-Johnson syndrome, erythema, multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anaemia, haemolytic anaemia, haemorrhage, hepatic dysfunction, including cholestasis, and pancytopenia.

Overdosage

Patients who receive an over dosage 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. Overdose with tazobactam has been reported in combination with piperacillin. Majority of the events reported such as nausea, vomiting and diarrhoea have also been reported with usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended I.V. doses are given.

Treatment should be supportive and symptomatic according to the patient’s clinical presentation. Excessive serum concentration of tazobactam may be reduced by haemodialysis following a single 0.375gm dose of tazobactam; the percentage of tazobactam dose removed by haemodialysis was approximately 39%.

Incompatibility

Do not use any other solution other than those mentioned in “Method of Preparation”. Solutions of cefepime/tazobactam 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 cefepime/tazobactam is indicated each of these antibiotics can be administered separately. Cefepime/tazobactam should not be used with other drugs in a syringe &/or infusion bottle since compatibility has not been established. Cefepime/tazobactam should not be added to blood or blood products &/or albumin hydrolysates.

Storage and Handling Instructions

Before Opening

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

Reconstituted Solutions

The resultant I.V. solution should be used immediately after preparation. When further diluted for intravenous use, dilution of fixed dose combination of cefepime hydrochloride and tazobacatm injection with the appropriate diluents maintains satisfactory potency for up to 24 h when kept below 25°C. For I.M. solution, it is stable for 1 hour when stored at 20ºC to 25ºC.

Keep medicine out of reach of children.

Packaging Information

FORPAR XP 1.125 g ……….  Available in a vial of 15 ml with 10 ml Water for Injection

FORPAR XP 2.25 g …………. Available in a vial of 30 ml with 10 ml Water for Injection

Last Updated: Jan 2016
Last Reviewed: Jan 2016