Imipenem/cilistatin (Primaxin ®)

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Usual Diluents

Standard Dilutions [Amount of drug] [Infusion volume] [Infusion rate]

[0 to 500 mg] [100 ml] [30 min]
[up to 1 gram] [250 ml] [60 min]

EXP: 4 HRS (RT) / 24 HRS (REF).
Label: Refrigerate.

Stability / Miscellaneous

WARNINGS
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS. THESE REACTIONS ARE MORE APT TO OCCUR IN PERSONS WITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS.

THERE HAVE BEEN REPORTS OF PATIENTS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS WHEN TREATED WITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY WITH PRIMAXIN I.V., CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS, AND OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PRIMAXIN SHOULD BE DISCONTINUED.

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, MAY ALSO BE ADMINISTERED AS INDICATED.

Seizure Potential
Seizures and other CNS adverse experiences, such as confusional states and myoclonic activity, have been reported during treatment with PRIMAXIN I.V. (See PRECAUTIONS and ADVERSE REACTIONS)

Carbapenems, including imipenem, may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop below the therapeutic range or a seizure occurs (See PRECAUTIONS, Drug Interactions).

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

PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) is a sterile formulation of imipenem (a thienamycin antibiotic) and cilastatin sodium (the inhibitor of the renal dipeptidase, dehydropeptidase l), with sodium bicarbonate added as a buffer. PRIMAXIN I.V. is a potent broad spectrum antibacterial agent for intravenous administration.

Usually restricted to one of the following:
(1) Serious nosocomial infections, especially those involving resistant organisms; polymicrobial infections (mixed gram pos/negative + anaerobes).
(2) As an alternative to combination therapy for serious intra-abdominal infections. It is used alone, thus avoiding the ototoxic & nephrotoxic effects of amino-glycosides.
(3) Pseudomonas infections caused by organisms resistant to both piperacillin & Fortaz.

IM injection: 500 mg/ 2ml (1% lidocaine) forms a suspension-shake well.

Dosing: Mild to moderate infection: 250-500mg ivpb q6-8h. Severe infection: 500mg to 1g ivpb q6-8h. Max dose/day= 50mg/kg/day or 4g/day.
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INDICATIONS AND USAGE
PRIMAXIN I.V. is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

1. Lower respiratory tract infections. Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae2, Klebsiella species, Serratia marcescens

2. Urinary tract infections (complicated and uncomplicated). Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)2 , Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii2 , Proteus vulgaris2 , Providencia rettgeri2 , Pseudomonas aeruginosa

3. Intra-abdominal infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)2 , Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii2 , Proteus species, Pseudomonas aeruginosa, Bifidobacterium species, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species2 , Bacteroides species including B. fragilis, Fusobacterium species

4. Gynecologic infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)2 , Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species2 , Escherichia coli, Gardnerella vaginalis, Klebsiella species2 , Proteus species, Bifidobacterium species2 , Peptococcus species2 , Peptostreptococcus species, Propionibacterium species2 , Bacteroides species including B. fragilis

5. Bacterial septicemia. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species2 , Bacteroides species including B. fragilis2

6. Bone and joint infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa

7. Skin and skin structure infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri2 , Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species2

8. Endocarditis. Staphylococcus aureus (penicillinase-producing strains)

9. Polymicrobic infections. PRIMAXIN I.V. is indicated for polymicrobic infections including those in which S. pneumoniae (pneumonia, septicemia), S. pyogenes (skin and skin structure), or nonpenicillinase-producing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillin G.

[². Efficacy for this organism in this organ system was studied in fewer than 10 infections.]

PRIMAXIN I.V. is not indicated in patients with meningitis because safety and efficacy have not been established.

For Pediatric Use information, see PRECAUTIONS, Pediatric Use, and DOSAGE AND ADMINISTRATION sections.

Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, PRIMAXIN I.V. is useful for the treatment of mixed infections and as presumptive therapy prior to the identification of the causative organisms.

Although clinical improvement has been observed in patients with cystic fibrosis, chronic pulmonary disease, and lower respiratory tract infections caused by Pseudomonas aeruginosa, bacterial eradication may not necessarily be achieved.

As with other beta-lactam antibiotics, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with PRIMAXIN I.V. During therapy of Pseudomonas aeruginosa infections, periodic susceptibility testing should be done when clinically appropriate.

Infections resistant to other antibiotics, for example, cephalosporins, penicillin, and aminoglycosides, have been shown to respond to treatment with PRIMAXIN I.V.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN I.V. and other antibacterial drugs, PRIMAXIN I.V. should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION
Adults
The dosage recommendations for PRIMAXIN I.V. represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 125 mg, 250 mg, or 500 mg dose should be given by intravenous administration over 20 to 30 minutes. Each 750 mg or 1000 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

The total daily dosage for PRIMAXIN I.V. should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function, and body weight. Adult patients with impaired renal function, as judged by creatinine clearance

70 mL/min/1.73 m2, require adjustment of dosage as described in the succeeding section of these guidelines.

Intravenous Dosage Schedule for Adults with Normal Renal Function and Body Weight

70 kg
Doses cited in Table I are based on a patient with normal renal function and a body weight of 70 kg. These doses should be used for a patient with a creatinine clearance of

71 mL/min/1.73 m2 and a body weight of

70 kg. A reduction in dose must be made for a patient with a creatinine clearance of

70 mL/min/1.73 m2 and/or a body weight less than 70 kg. (See Tables II and III.)

Dosage regimens in column A of Table I are recommended for infections caused by fully susceptible organisms which represent the majority of pathogenic species. Dosage regimens in column B of Table I are recommended for infections caused by organisms with moderate susceptibility to imipenem, primarily some strains of P. aeruginosa.

TABLE I: INTRAVENOUS DOSAGE SCHEDULE FOR ADULTS WITH NORMAL RENAL FUNCTION AND BODY WEIGHT

70 kg

Type or Severity of Infection	A Fully susceptible organisms including gram-positive and gram-negative aerobes and anaerobes	B MODERATELY SUSCEPTIBLE ORGANISMS, PRIMARILY SOME STRAINS OF P. aeruginosa
Mild	250 mg q6h (TOTAL DAILY DOSE = 1.0g)	500 mg q6h (TOTAL DAILY DOSE = 2.0g)
Moderate	500 mg q8h (TOTAL DAILY DOSE = 1.5g) or 500 mg q6h (TOTAL DAILY DOSE = 2.0g)	500 mg q6h (TOTAL DAILY DOSE = 2.0g) or 1 g q8h (TOTAL DAILY DOSE = 3.0g)
Severe, life threatening only	500 mg q6h (TOTAL DAILY DOSE = 2.0g)	1 g q8h (TOTAL DAILY DOSE = 3.0g) or 1 g q6h (TOTAL DAILY DOSE = 4.0g)
Uncomplicated urinary tract infection	250 mg q6h (TOTAL DAILY DOSE = 1.0g)	250 mg q6h (TOTAL DAILY DOSE = 1.0g)
Complicated urinary tract infection	500 mg q6h (TOTAL DAILY DOSE = 2.0g)	500 mg q6h (TOTAL DAILY DOSE = 2.0g)

Due to the high antimicrobial activity of PRIMAXIN I.V., it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4.0 g/day, whichever is lower. There is no evidence that higher doses provide greater efficacy. However, patients over twelve years of age with cystic fibrosis and normal renal function have been treated with PRIMAXIN I.V. at doses up to 90 mg/kg/day in divided doses, not exceeding 4.0 g/day.

Reduced Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight <70 kg

Patients with creatinine clearance of

70 mL/min/1.73 m2 and/or body weight less than 70 kg require dosage reduction of PRIMAXIN I.V. as indicated in the tables below. Creatinine clearance may be calculated from serum creatinine concentration by the following equation:

Creatinine clearance for males =	[140-age (years)]× [body wt (kg)] 72 × [serum creatinine (mg/dL)]
Creatinine clearance for females =	[140-age (years)]× [body wt (kg)]× 0.85 72 × [serum creatinine (mg/dL)]

To determine the dose for adults with impaired renal function and/or reduced body weight:
1. Choose a total daily dose from Table I based on infection characteristics.
2. a) If the total daily dose is 1.0 g, 1.5 g, or 2.0 g, use the appropriate subsection of Table II and continue with step 3.
b) If the total daily dose is 3.0 g or 4.0 g, use the appropriate subsection of Table III and continue with step 3.
3. From Table II or III:
a) Select the body weight on the far left which is closest to the patient's body weight (kg).
b) Select the patient's creatinine clearance category.
c) Where the row and column intersect is the reduced dosage regimen.

TABLE II: REDUCED INTRAVENOUS DOSAGE OF PRIMAXIN I.V. IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT <70 kg

	If TOTAL DAILY DOSE from TABLE I is:
	1.0 g/day				1.5 g/day				2.0 g/day
And Body Weight (kg) is:	and creatinine clearance (mL/min/1.73 m2) is:				and creatinine clearance (mL/min/1.73 m2) is:				and creatinine clearance (mL/min/1.73 m2) is:
	71	41-70	21-40	6-20	71	41-70	21-40	6-20	71	41-70	21-40	6-20
	then the reduced dosage regimen (mg) is:				then the reduced dosage regimen (mg) is:				then the reduced dosage regimen (mg) is:
70	250 q6h	250 q8h	250 q12h	250 q12h	500 q8h	250 q6h	250 q8h	250 q12h	500 q6h	500 q8h	250 q6h	250 q12h
60	250 q8h	125 q6h	250 q12h	125 q12h	250 q6h	250 q8h	250 q8h	250 q12h	500 q8h	250 q6h	250 q8h	250 q12h
50	125 q6h	125 q6h	125 q8h	125 q12h	250 q6h	250 q8h	250 q12h	250 q12h	250 q6h	250 q6h	250 q8h	250 q12h
40	125 q6h	125 q8h	125 q12h	125 q12h	250 q8h	125 q6h	125 q8h	125 q12h	250 q6h	250 q8h	250 q12h	250 q12h
30	125 q8h	125 q8h	125 q12h	125 q12h	125 q6h	125 q8h	125 q8h	125 q12h	250 q8h	125 q6h	125 q8h	125 q12h

TABLE III: REDUCED INTRAVENOUS DOSAGE OF PRIMAXIN I.V. IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT <70 kg

If TOTAL DAILY DOSE from TABLE I is:
	3.0 g/day				4.0 g/day
And Body Weight (kg) is:	and creatinine clearance (mL/min/1.73 m2) is:				and creatinine clearance (mL/min/1.73 m2) is:
	71	41-70	21-40	6-20	71	41-70	21-40	6-20
	then the reduced dosage regimen (mg) is:				then the reduced dosage regimen (mg) is:
70	1000 q8h	500 q6h	500 q8h	500 q12h	1000 q6h	750 q8h	500 q6h	500 q12h
60	750 q8h	500 q8h	500 q8h	500 q12h	1000 q8h	750 q8h	500 q8h	500 q12h
50	500 q6h	500 q8h	250 q6h	250 q12h	750 q8h	500 q6h	500 q8h	500 q12h
40	500 q8h	250 q6h	250 q8h	250 q12h	500 q6h	500 q8h	250 q6h	250 q12h
30	250 q6h	250 q8h	250 q8h	250 q12h	500 q8h	250 q6h	250 q8h	250 q12h

Patients with creatinine clearances of 6 to 20 mL/min/1.73 m2 should be treated with PRIMAXIN I.V. 125 mg or 250 mg every 12 hours for most pathogens. There may be an increased risk of seizures when doses of 500 mg every 12 hours are administered to these patients.

Patients with creatinine clearance

5 mL/min/1.73 m2 should not receive PRIMAXIN I.V. unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of PRIMAXIN I.V. for patients undergoing peritoneal dialysis.

Hemodialysis
When treating patients with creatinine clearances of

5 mL/min/1.73 m2 who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of 6-20 mL/min/1.73 m2. (See Reduced Intravenous Dosage Schedule for Adults with Impaired Renal Function and/or Body Weight <70 kg.) Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive PRIMAXIN I.V. after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, PRIMAXIN I.V. is recommended only when the benefit outweighs the potential risk of seizures. (See PRECAUTIONS.)

Pediatric Patients
See package insert for PRECAUTIONS, Pediatric Patients.

For pediatric patients

3 months of age, the recommended dose for non-CNS infections is 15–25 mg/kg/dose administered every six hours. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.

For pediatric patients

3 months of age (weighing

1,500 gms), the following dosage schedule is recommended for non-CNS infections:
<1 wk of age: 25 mg/kg every 12 hrs
1-4 wks of age: 25 mg/kg every 8 hrs
4 wks-3 mos. of age: 25 mg/kg every 6 hrs.

Doses less than or equal to 500 mg should be given by intravenous infusion over 15 to 30 minutes. Doses greater than 500 mg should be given by intravenous infusion over 40 to 60 minutes.

PRIMAXIN I.V. is not recommended in pediatric patients with CNS infections because of the risk of seizures.

PRIMAXIN I.V. is not recommended in pediatric patients<30 kg with impaired renal function, as no data are available.

PREPARATION OF SOLUTION
Infusion Bottles

Contents of the infusion bottles of PRIMAXIN I.V. Powder should be restored with 100 mL of diluent (see list of diluents under COMPATIBILITY AND STABILITY) and shaken until a clear solution is obtained.

Vials
Contents of the vials must be suspended and transferred to 100 mL of an appropriate infusion solution. A suggested procedure is to add approximately 10 mL from the appropriate infusion solution (see list of diluents under COMPATIBILITY AND STABILITY) to the vial. Shake well and transfer the resulting suspension to the infusion solution container.

Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Therefore, diluents containing benzyl alcohol should not be used when PRIMAXIN I.V. is constituted for administration to pediatric patients in this age range.

CAUTION: THE SUSPENSION IS NOT FOR DIRECT INFUSION.

Repeat with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution. The resulting mixture should be agitated until clear.

COMPATIBILITY AND STABILITY
Before Reconstruction:
The dry powder should be stored at a temperature below 25°C (77°F).

Reconstituted Solutions:
Solutions of PRIMAXIN I.V. range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

PRIMAXIN I.V., as supplied in single use infusion bottles, vials and MONOVIAL® vials and reconstituted with the following diluents (see PREPARATION OF SOLUTION), maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C). Solutions of PRIMAXIN I.V. should not be frozen.

0.9% Sodium Chloride Injection
5% or 10% Dextrose Injection
5% Dextrose and 0.9% Sodium Chloride Injection
5% Dextrose Injection with 0.225% or 0.45% saline solution
5% Dextrose Injection with 0.15% potassium chloride solution
Mannitol 5% and 10%

PRIMAXIN I.V., as supplied in single dose ADD-Vantage® vials and reconstituted with the following diluents (see PREPARATION OF SOLUTION), maintains satisfactory potency for 4 hours at room temperature.
0.9% Sodium Chloride Injection
5% Dextrose Injection

PRIMAXIN I.V. should not be mixed with or physically added to other antibiotics. However, PRIMAXIN I.V. may be administered concomitantly with other antibiotics, such as aminoglycosides.

HOW SUPPLIED
PRIMAXIN I.V. is supplied as a sterile powder mixture in single dose containers including vials, infusion bottles, ADD-Vantage® vials, and MONOVIAL® vials containing imipenem (anhydrous equivalent) and cilastatin sodium as follows:

No. 3514 — 250 mg imipenem equivalent and 250 mg cilastatin equivalent and 10 mg sodium bicarbonate as a buffer

NDC 0006-3514-58 in trays of 25 vials.

No. 3516— 500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer

NDC 0006-3516-59 in trays of 25 vials.

No. 3517 — 500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer

NDC 0006-3517-75 in trays of 10 infusion bottles.

No. 3551 — 250 mg imipenem equivalent and 250 mg cilastatin equivalent and 10 mg sodium bicarbonate as a buffer

NDC 0006-3551-58 in trays of 25 ADD-Vantage® vials.

No. 3552 — 500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer

NDC 0006-3552-59 in trays of 25 ADD-Vantage® vials.

No. 3666 — 500 mg imipenem equivalent and 500 mg cilastatin equivalent and 20 mg sodium bicarbonate as a buffer

NDC 0006-3666-59 in trays of 25 MONOVIAL® vials.

REFERENCES
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2 NCCLS, Villanova, PA, 1997.
2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests-Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1 NCCLS, Villanova, PA, 1997.
3. National Committee for Clinical Laboratory Standards, Method for Antimicrobial Susceptibility Testing of Anaerobic Bacteria-Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26 NCCLS, Villanova, PA, 1993.

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
Issued December 2007
9813933

Source: [package insert]

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