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.

Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya. Its chemical name is (5R,6S)-3-[[2-(formimidoylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate. It is an off-white, nonhygroscopic crystalline compound with a molecular weight of 317.37. It is sparingly soluble in water and slightly soluble in methanol. Its empirical formula is C₁₂H₁₇N₃O₄S•H₂O, and its structural formula is:

 

Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. Its chemical name is sodium (Z)-7[[(R)-2-amino-2-carboxyethyl]thio]-2-[(S)-2,2-dimethylcyclopropanecarboxamido]-2-heptenoate. It is an off-white to yellowish-white, hygroscopic, amorphous compound with a molecular weight of 380.43. It is very soluble in water and in methanol. Its empirical formula is C₁₆H₂₅N₂O₅SNa, and its structural formula is:

PRIMAXIN I.V. is buffered to provide solutions in the pH range of 6.5 to 8.5. There is no significant change in pH when solutions are prepared and used as directed. (See COMPATIBILITY AND STABILITY.) PRIMAXIN I.V. 250 contains 18.8 mg of sodium (0.8 mEq) and PRIMAXIN I.V. 500 contains 37.5 mg of sodium (1.6 mEq). Solutions of PRIMAXIN I.V. range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

Last updated on RxList: 8/20/2008

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 parainfluenzae^*, Klebsiella species, Serratia marcescens
2. Urinary tract infections (complicated and uncomplicated). Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)^*, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii^*, Proteus vulgaris^*, Providencia rettgeri^*, Pseudomonas aeruginosa
3. Intra-abdominal infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)^*, Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii^*, Proteus species, Pseudomonas aeruginosa, Bifidobacterium species,Clostridiumspecies, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species^*, Bacteroides species including B. fragilis, Fusobacterium species
4. Gynecologic infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)^*, Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species^*, Escherichia coli, Gardnerella vaginalis, Klebsiella species^*, Proteus species, Bifidobacterium species^*, Peptococcus species^*, Peptostreptococcus species, Propionibacterium species^*, Bacteroides species including B. fragilis^*
5. Bacterial septicemia. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species^*, Bacteroides species including B. fragilis^*
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 rettgeri^*, Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species^*
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 penicillinG.

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 ADMINISTRATIONsections.

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.

*Efficacy for this organism in this organ system was studied in fewer than 10 infections.

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:

Tcc (Males) =	(wt. in kg)(140-age)
	(72)(creatinine in mg/dL)

Tcc (Females) = 0.85 × above value

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:
   1. Select the body weight on the far left which is closest to the patient's body weight (kg).
   2. Select the patient's creatinine clearance category.
   3. 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

And Body Weight (kg)is:	If TOTAL DAILY DOSE from TABLE I is:
	1.0 g/day				1.5 g/day				2.0 g/day
	and creatinine clearance (mL/min/1.73m²) is:				and creatinine clearance (mL/min/1.73m²) is:				and creatinine clearance (mL/min/1.73m²) 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	250	250	250	500	250	250	250	500	500	250	250
	q6h	q8h	q12h	q12h	q8h	q6h	q8h	q12h	q6h	q8h	q6h	q12h
60	250	125	250	125	250	250	250	250	500	250	250	250
	q8h	q6h	q12h	q12h	q6h	q8h	q8h	q12h	q8h	q6h	q8h	q12h
50	125	125	125	125	250	250	250	250	250	250	250	250
	q6h	q6h	q8h	q12h	q6h	q8h	q12h	q12h	q6h	q6h	q8h	q12h
40	125	125	125	125	250	125	125	125	250	250	250	250
	q6h	q8h	q12h	q12h	q8h	q6h	q8h	q12h	q6h	q8h	q12h	q12h
30	125	125	125	125	125	125	125	125	250	125	125	125
	q8h	q8h	q12h	q12h	q6h	q8h	q8h	q12h	q8h	q6h	q8h	q12h

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

And Body Weight (kg) Is:	If TOTAL DAILY DOSE from TABLE I is:
	3.0 g/day				4.0 g/day
	and creatinine clearance (mL/min/1.73m²) 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	500	500	500	1000	750	500	500
	q8h	q6h	q8h	q12h	q6h	q8h	q6h	q12h
60	750	500	500	500	1000	750	500	500
	q8h	q8h	q8h	q12h	q8h	q8h	q8h	q12h
50	500	500	250	250	750	500	500	500
	q6h	q8h	q6h	q12h	q8h	q6h	q8h	q12h
40	500	250	250	250	500	500	250	250
	q8h	q6h	q8h	q12h	q6h	q8h	q6h	q12h
30	250	250	250	250	500	250	250	250
	q6h	q8h	q8h	q12h	q8h	q6h	q8h	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 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.

ADD-Vantage®^{† † †} Vials

See separate INSTRUCTIONS FOR USE OF 'PRIMAXIN I.V.' IN ADD-Vantage® VIALS. PRIMAXIN I.V. in ADD-Vantage® vials should be reconstituted with ADD-Vantage® diluent containers containing 100 mL of either 0.9% Sodium Chloride Injection or 100 mL 5% Dextrose Injection.

MONOVIAL^®‡ Vials

See separate INSTRUCTIONS FOR USE OF 'PRIMAXIN I.V.' IN MONOVIAL® VIALS. PRIMAXIN I.V. in MONOVIAL® vials should be reconstituted using an appropriate diluent in an infusion bag, with a maximum port length of 14 mm.

The MONOVIA®L vial is not compatible with the ADD-Vantage® diluent bags.

COMPATIBILITY AND STABILITY

Before Reconstitution

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.

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.

† † † Registered trademark of Abbott Laboratories, Inc.
‡ Registered trademark of Becton Dickinson and Company.

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Issued December 2007. FDA revision date: n/a

Last updated on RxList: 8/20/2008

Adults

PRIMAXIN I.V. is generally well tolerated. Many of the 1,723 patients treated in clinical trials were severely ill and had multiple background diseases and physiological impairments, making it difficult to determine causal relationship of adverse experiences to therapy with PRIMAXIN I.V.

Local Adverse Reactions

Adverse local clinical reactions that were reported as possibly, probably, or definitely related to therapy with PRIMAXIN I.V. were:

Phlebitis/thrombophlebitis - 3.1%
Pain at the injection site - 0.7%
Erythema at the injection site - 0.4%
Vein induration - 0.2%
Infused vein infection - 0.1%

Systemic Adverse Reactions

The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably, or definitely related to PRIMAXIN I.V. were nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%) (see PRECAUTIONS), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%).

Additional adverse systemic clinical reactions reported as possibly, probably, or definitely drug related occurring in less than 0.2% of the patients or reported since the drug was marketed are listed within each body system in order of decreasing severity: Gastrointestinal - pseudomembranous colitis (the onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment, see WARNINGS), hemorrhagic colitis, hepatitis (including fulminant hepatitis), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, staining of the teeth and/or tongue, heartburn, pharyngeal pain, increased salivation; Hematologic - pancytopenia, bone marrow depression, thrombocytopenia, neutropenia, leukopenia, hemolytic anemia; CNS - encephalopathy, tremor, confusion, myoclonus, paresthesia, vertigo, headache, psychic disturbances including hallucinations; Special Senses - hearing loss, tinnitus, taste perversion; Respiratory - chest discomfort, dyspnea, hyperventilation, thoracic spine pain; Cardiovascular - palpitations, tachycardia; Skin - Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, angioneurotic edema, flushing, cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae; Body as a whole - polyarthralgia, asthenia/weakness, drug fever; Renal - acute renal failure, oliguria/anuria, polyuria, urine discoloration. The role of PRIMAXIN I.V. in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotemia or to impaired renal function usually have been present.

Adverse Laboratory Changes

Adverse laboratory changes without regard to drug relationship that were reported during clinical trials or reported since the drug was marketed were:

Hepatic: Increased ALT (SGPT), AST (SGOT), alkaline phosphatase, bilirubin, and LDH

Hemic: Increased eosinophils, positive Coombs test, increased WBC, increased platelets, decreased hemoglobin and hematocrit, agranulocytosis, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils

Electrolytes: Decreased serum sodium, increased potassium, increased chloride

Renal: Increased BUN, creatinine

Urinalysis: Presence of urine protein, urine red blood cells, urine white blood cells, urine casts, urine bilirubin, and urine urobilinogen.

Pediatric Patients

In studies of 178 pediatric patients ≥ 3 months of age, the following adverse events were noted:

The Most Common Clinical Adverse Experiences Without Regard to Drug Relationship (Patient Incidence > 1%)

Adverse Experience	No. of Patients (%)
Digestive System
Diarrhea	7*(3.9)
Gastroenteritis	2(1.1)
Vomiting	2*(1.1)
Skin
Rash	4(2.2)
Irritation, I.V. site	2(1.1)
Urogenital System
Urine discoloration	2(1.1)
Cardiovascular System
Phlebitis	4(2.2)
*One patient had both vomiting and diarrhea and is counted in each category.

In studies of 135 patients (newborn to 3 months of age), the following adverse events were noted:

The Most Common Clinical Adverse Experiences Without Regard to Drug Relationship (Patient Incidence > 1%)

Adverse Experience	No. of Patients (%)
Digestive System
Diarrhea	4 (3.0%)
Oral Candidiasis	2 (1.5%)
Skin
Rash	2 (1.5%)
Urogenital System
Oliguria/anuria	3 (2.2%)
Cardiovascular System
Tachycardia	2 (1.5%)
Nervous System
Convulsions	8 (5.9%)

Patients ( ≥ 3 Months of Age) With Normal Pretherapy but Abnormal During Therapy Laboratory Values

Laboratory Parameter	Abnormality	No. of Patients With Abnormalities/ No. of Patients With Lab Done (%)
Hemoglobin	Age < 5 mos.: < 10 gm % 6 mos.-12 yrs.: < 11.5 gm %	19/129	(14.7)
Hematocrit	Age < 5 mos.: < 30 vol % 6 mos.-12 yrs.: < 34.5 vol %	23/129	(17.8)
Neutrophils	≤ 1000/mm³(absolute)	4/123	(3.3)
Eosinophils	≥ 7%	15/117	(12.8)
Platelet Count	≥ 500 ths/mm³	16/119	(13.4)
Urine Protein	≥ 1	8/97	(8.2)
Serum Creatinine	> 1.2 mg/dL	0/105	(0)
BUN	> 22 mg/dL	0/108	(0)
AST (SGOT)	> 36 IU/L	14/78	(17.9)
ALT (SGPT)	> 30 IU/L	10/93	(10.8)

Patients ( < 3 Months of Age) With Normal Pretherapy but Abnormal During Therapy Laboratory Values

Laboratory Parameter	No. of Patients With Abnormalities* (%)
Eosinophil Count↑	11 (9.0%)
Hematocrit↓	3 (2.0%)
Hematocrit↑	1 (1.0%)
Platelet Count↑	5 (4.0%)
Platelet Count↓	2 (2.0%)
Serum Creatinine↑	5 (5.0%)
Bilirubin↑	3 (3.0%)
Bilirubin↓	1 (1.0%)
AST (SGOT)↑	5 (6.0%)
ALT (SGPT)↑	3 (3.0%)
Serum Alkaline Phosphate↑	2 (3.0%)
*The denominator used for percentages was the number of patients for whom the test was performed during or post-treatment and, therefore, varies by test.

Examination of published literature and spontaneous adverse event reports suggested a similar spectrum of adverse events in adult and pediatric patients.

¹Based on patient body surface area of 1.6 m² (weight of 60 kg).
**Two patients were less than 3 months of age.
*** One patient was greater than 3 months of age.

Generalized seizures have been reported in patients who received ganciclovir and PRIMAXIN. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.

Since concomitant administration of PRIMAXIN and probenecid results in only minimal increases in plasma levels of imipenem and plasma half-life, it is not recommended that probenecid be given with PRIMAXIN.

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

A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics and may result in loss of seizure control. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that carbapenem antibiotics may inhibit valproic acid glucuronide hydrolysis. 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 WARNINGS, Seizure Potential).

Last updated on RxList: 8/20/2008

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.

General

CNS adverse experiences such as confusional states, myoclonic activity, and seizures have been reported during treatment with PRIMAXIN I.V., especially when recommended dosages were exceeded. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. However, there have been reports of CNS adverse experiences in patients who had no recognized or documented underlying CNS disorder or compromised renal function.

When recommended doses were exceeded, adult patients with creatinine clearances of ≤ 20 mL/min/1.73 m², whether or not undergoing hemodialysis, had a higher risk of seizure activity than those without impairment of renal function. Therefore, close adherence to the dosing guidelines for these patients is recommended. (See DOSAGE AND ADMINISTRATION.)

Patients with creatinine clearances of ≤ 5 mL/min/1.73 m² should not receive PRIMAXIN I.V. unless hemodialysis is instituted within 48 hours.

For patients on hemodialysis, PRIMAXIN I.V. is recommended only when the benefit outweighs the potential risk of seizures.

Close adherence to the recommended dosage and dosage schedules is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of PRIMAXIN I.V. reexamined to determine whether it should be decreased or the antibiotic discontinued.

As with other antibiotics, prolonged use of PRIMAXIN I.V. may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing PRIMAXIN I.V. in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Laboratory Tests

While PRIMAXIN I.V. possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem-cilastatin. Genetic toxicity studies were performed in a variety of bacterial and mammalian tests in vivo and in vitro. The tests used were: V79 mammalian cell mutagenesis assay (imipenem-cilastatin sodium alone and imipenem alone), Ames test (cilastatin sodium alone and imipenem alone), unscheduled DNA synthesis assay (imipenem-cilastatin sodium) and in vivo mouse cytogenetics test (imipenem-cilastatin sodium). None of these tests showed any evidence of genetic alterations.

Reproductive tests in male and female rats were performed with imipenem-cilastatin sodium at intravenous doses up to 80 mg/kg/day and at a subcutaneous dose of 320 mg/kg/day, approximately equal to the highest recommended human dose of the intravenous formulation (on a mg/m² body surface area basis). Slight decreases in live fetal body weight were restricted to the highest dosage level. No other adverse effects were observed on fertility, reproductive performance, fetal viability, growth or postnatal development of pups.

Pregnancy: Teratogenic Effects

Pregnancy Category C: Teratology studies with cilastatin sodium at doses of 30, 100, and 300 mg/kg/day administered intravenously to rabbits and 40, 200, and 1000 mg/kg/day administered subcutaneously to rats, up to approximately 1.9 and 3.2 times¹ the maximum recommended daily human dose (on a mg/m² body surface area basis) of the intravenous formulation of imipenem-cilastatin sodium (50 mg/kg/day) in the two species, respectively, showed no evidence of adverse effect on the fetus. No evidence of teratogenicity was observed in rabbits given imipenem at intravenous doses of 15, 30 or 60 mg/kg/day and rats given imipenem at intravenous doses of 225, 450, or 900 mg/kg/day, up to approximately 0.4 and 2.9 times^{† †} the maximum recommended daily human dose (on a mg/m² body surface area basis) in the two species, respectively.

Teratology studies with imipenem-cilastatin sodium at intravenous doses of 20 and 80, and a subcutaneous dose of 320 mg/kg/day, up to 0.5 times^{† †} (mice) to approximately equal to (rats) the highest recommended daily intravenous human dose (on a mg/m² body surface area basis) in pregnant rodents during the period of major organogenesis, revealed no evidence of teratogenicity.

Imipenem-cilastatin sodium, when administered subcutaneously to pregnant rabbits at dosages equivalent to the usual human dose of the intravenous formulation and higher (1000-4000 mg/day), caused body weight loss, diarrhea, and maternal deaths. When comparable doses of imipenem-cilastatin sodium were given to non-pregnant rabbits, body weight loss, diarrhea, and deaths were also observed. This intolerance is not unlike that seen with other beta-lactam antibiotics in this species and is probably due to alteration of gut flora.

A teratology study in pregnant cynomolgus monkeys given imipenem-cilastatin sodium at doses of 40 mg/kg/day (bolus intravenous injection) or 160 mg/kg/day (subcutaneous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhea, abortion, and death in some cases. In contrast, no significant toxicity was observed when non-pregnant cynomolgus monkeys were given doses of imipenem-cilastatin sodium up to 180 mg/kg/day (subcutaneous injection). When doses of imipenem-cilastatin sodium (approximately 100 mg/kg/day or approximately 0.6 times^{† †} the maximum recommended daily human dose of the intravenous formulation) were administered to pregnant cynomolgus monkeys at an intravenous infusion rate which mimics human clinical use, there was minimal maternal intolerance (occasional emesis), no maternal deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to control groups.

No adverse effects on the fetus or on lactation were observed when imipenem-cilastatin sodium was administered subcutaneously to rats late in gestation at dosages up to 320 mg/kg/day, approximately equal to the highest recommended human dose (on a mg/m² body surface area basis).

There are, however, no adequate and well-controlled studies in pregnant women. PRIMAXIN I.V. should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers

It is not known whether imipenem-cilastatin sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRIMAXIN I.V. is administered to a nursing woman.

Pediatric Use

Use of PRIMAXIN I.V. in pediatric patients, neonates to 16 years of age, is supported by evidence from adequate and well-controlled studies of PRIMAXIN I.V. in adults and by the following clinical studies and published literature in pediatric patients: Based on published studies of 178^** pediatric patients ≥ 3 months of age (with non-CNS infections), the recommended dose of PRIMAXIN I.V. is 15-25 mg/kg/dose administered every six hours. Doses of 25 mg/kg/dose in patients 3 months to < 3 years of age, and 15 mg/kg/dose in patients 3-12 years of age were associated with mean trough plasma concentrations of imipenem of 1.1±0.4 g/mL and 0.6±0.2 μg/mL following multiple 60-minute infusions, respectively; trough urinary concentrations of imipenem were in excess of 10 μg/mL for both doses. These doses have provided adequate plasma and urine concentrations for the treatment of non-CNS infections. 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. (See Table 1, DOSAGE AND ADMINISTRATION.) Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis. (See DOSAGE AND ADMINISTRATION.)

Based on studies of 135^*** 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.

In a published dose-ranging study of smaller premature infants (670-1,890 gms) in the first week of life, a dose of 20 mg/kg q12h by 15-30 minutes infusion was associated with mean peak and trough plasma imipenem concentrations of 43 g/mL and 1.7 μg/mL after multiple doses, respectively. However, moderate accumulation of cilastatin in neonates may occur following multiple doses of PRIMAXIN I.V. The safety of this accumulation is unknown.

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.

Geriatric Use

Of the approximately 3600 subjects ≥ 18 years of age in clinical studies of PRIMAXIN I.V., including postmarketing studies, approximately 2800 received PRIMAXIN I.V. Of the subjects who received PRIMAXIN I.V., data are available on approximately 800 subjects who were 65 and over, including approximately 300 subjects who were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, 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 it may be useful to monitor renal function.

No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY, Adults). Dosage adjustment in the case of renal impairment is necessary (see DOSAGE AND ADMINISTRATION, Reduced Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg).

Last updated on RxList: 8/20/2008

The acute intravenous toxicity of imipenem-cilastatin sodium in a ratio of 1:1 was studied in mice at doses of 751 to 1359 mg/kg. Following drug administration, ataxia was rapidly produced and clonic convulsions were noted in about 45 minutes. Deaths occurred within 4-56 minutes at all doses.

The acute intravenous toxicity of imipenem-cilastatin sodium was produced within 5-10 minutes in rats at doses of 771 to 1583 mg/kg. In all dosage groups, females had decreased activity, bradypnea, and ptosis with clonic convulsions preceding death; in males, ptosis was seen at all dose levels while tremors and clonic convulsions were seen at all but the lowest dose (771 mg/kg). In another rat study, female rats showed ataxia, bradypnea, and decreased activity in all but the lowest dose (550 mg/kg); deaths were preceded by clonic convulsions. Male rats showed tremors at all doses and clonic convulsions and ptosis were seen at the two highest doses (1130 and 1734 mg/kg). Deaths occurred between 6 and 88 minutes with doses of 771 to 1734 mg/kg.

In the case of overdosage, discontinue PRIMAXIN I.V., treat symptomatically, and institute supportive measures as required. Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable.

PRIMAXIN I.V. is contraindicated in patients who have shown hypersensitivity to any component of this product.

Last updated on RxList: 8/20/2008

Adults

Intravenous Administration

Intravenous infusion of PRIMAXIN I.V. over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 24 μg/mL for the 250 mg dose, from 21 to 58 g/mL for the 500 mg dose, and from 41 to 83 μg/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 μg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute intravenous infusion of PRIMAXIN I.V. range from 15 to 25 μg/mL for the 250 mg dose, from 31 to 49 g/mL for the 500 mg dose, and from 56 to 88 μg/mL for the 1000 mg dose.

The plasma half-life of each component is approximately 1 hour. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%. Approximately 70% of the administered imipenem is recovered in the urine within 10 hours after which no further urinary excretion is detectable. Urine concentrations of imipenem in excess of 10 μg/mL can be maintained for up to 8 hours with PRIMAXIN I.V. at the 500-mg dose. Approximately 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of PRIMAXIN I.V.

No accumulation of imipenem/cilastatin in plasma or urine is observed with regimens administered as frequently as every 6 hours in patients with normal renal function.

In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin are 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed.

Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I resulting in relatively low levels in urine. Cilastatin sodium, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, fully adequate antibacterial levels of imipenem are achieved in the urine.

After a 1 gram dose of PRIMAXIN I.V., the following average levels of imipenem were measured (usually at 1 hour post dose except where indicated) in the tissues and fluids listed:

Tissue or Fluid	N	Imipenem Level μg/mL or g/g	Range
Vitreous Humor	3	3.4 (3.5 hours post dose)	2.88-3.6
Aqueous Humor	5	2.99 (2 hours post dose)	2.4-3.9
Lung Tissue	8	5.6 (median)	3.5-15.5
Sputum	1	2.1	-
Pleural	1	22.0	-
Peritoneal	12	23.9 S.D.± 5.3 (2 hours postdose)	-
Bile	2	5.3 (2.25 hours post dose)	4.6-6.0
CSF (uninflamed)	5	1.0 (4 hours post dose)	0.26-2.0
CSF (inflamed)	7	2.6 (2 hours post dose)	0.5-5.5
Fallopian Tubes	1	13.6	-
Endometrium	1	11.1	-
Myometrium	1	5.0	-
Bone	10	2.6	0.4-5.4
Interstitial Fluid	12	16.4	10.0-22.6
Skin	12	4.4	NA
Fascia	12	4.4	NA

Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable. (See OVERDOSAGE.)

Microbiology

The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1B.

Imipenem has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of beta-lactamases from certain gram-negative bacteria which are inherently resistant to most beta-lactam antibiotics, e.g., Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.

Imipenem has in vitro activity against a wide range of gram-positive and gram-negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections treated with the intravenous formulation of imipenem-cilastatin sodium as described in the INDICATIONS AND USAGE section.

Gram-positive aerobes

Enterococcus faecalis (formerly S. faecalis)
(NOTE: Imipenem is inactive in vitro against Enterococcus faecium [formerly S. faecium].)
Staphylococcus aureus including penicillinase-producing strains
Staphylococcus epidermidis including penicillinase-producing strains
(NOTE: Methicillin-resistant staphylococci should be reported as resistant to imipenem.)
Streptococcus agalactiae (Group B streptococci)
Streptococcus pneumoniae
Streptococcus pyogenes

Gram-negative aerobes

Acinetobacter spp.
Citrobacter spp.
Enterobacter spp.
Escherichia coli
Gardnerella vaginalis
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiellaspp.
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Pseudomonas aeruginosa
(NOTE: Imipenem is inactive in vitro against Xanthomonas (Pseudomonas) maltophilia and some strains of P. cepacia.)
Serratia spp., including
S. marcescens

Gram-positive anaerobes

Bifidobacterium spp.
Clostridium spp.
Eubacterium spp.
Peptococcus spp.
Peptostreptococcus spp.
Propionibacterium spp.

Gram-negative anaerobes

Bacteroides spp., including B. fragilis
Fusobacterium spp.

The following in vitro data are available, but their clinical significance is unknown.

Imipenem exhibits in vitro minimum inhibitory concentrations (MICs) of 4 g/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive aerobes

Bacillus spp.
Listeria monocytogenes
Nocardia spp.
Staphylococcus saprophyticus
Group C streptococci
Group G streptococci
Viridans group streptococci

Gram-negative aerobes

Aeromonas hydrophila
Alcaligenes spp.
Capnocytophaga spp.
Haemophilus ducreyi
Neisseria gonorrhoeae including penicillinase-producing strains
Pasteurella spp.
Providencia stuartii

Gram-negative anaerobes

Prevotella bivia
Prevotella disiens
Prevotella melaninogenica
Veillonella spp.

In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

Susceptibility Tests

Measurement of MIC or minimum bactericidal concentration (MBC) and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.)

Dilution Techniques

Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such procedure uses a standardized dilution method¹ (broth, agar, or microdilution) or equivalent with imipenem powder.

The MIC values obtained should be interpreted according to the following criteria:

MIC (μg/mL)	Interpretation
≤ 4	Susceptible (S)
8	Intermediate (I)
≥ 16	Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard imipenem powder should provide the following MIC values:

Microorganism	MIC (μg/mL)
E. coliATCC 25922	0.06-0.25
S. aureus ATCC 29213	0.015-0.06
E. faecalis ATCC 29212	0.5-2.0
P. aeruginosa ATCC 27853	1.0-4.0

Diffusion Techniques

Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure² that has been recommended for use with disks to test the susceptibility of microorganisms to imipenem uses the 10- g imipenem disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for imipenem.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-μg imipenem disk should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥ 16	Susceptible (S)
14-15	Intermediate (I)
≤ 13	Resistant (R)

Interpretation should be as stated above for results using dilution techniques.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. The 10-μg imipenem disk should provide the following diameters in these laboratory test quality control strains:

Microorganism	Zone Diameter (mm)
E. coli ATCC 25922	26-32
P. aeruginosa ATCC 27853	20-28

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to imipenem can be determined by the reference agar dilution method or by alternate standardized test methods.³

The MIC values obtained should be interpreted according to the following criteria:

MIC (μg/mL)	Interpretation
≤ 4	Susceptible (S)
8	Intermediate (I)
≥ 16	Resistant (R)

As with other susceptibility techniques, the use of laboratory control microorganisms is required. Standard imipenem powder should provide the following MIC values: Reference Agar Dilution Testing:

Microorganism	MIC (μg/mL)
B. fragilis ATCC 25285	0.03-0.12
B. thetaiotaomicron ATCC 29741	0.06-0.25
E. lentum ATCC 43055	0.25-1.0

Broth Microdilution Testing:

Microorganism	MIC ( g/mL)
B. thetaiotaomicron ATCC 29741	0.06-0.25
E. lentum ATCC 43055	0.12-0.5

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.

Last updated on RxList: 8/20/2008

Patients should be counseled that antibacterial drugs including PRIMAXIN I.V. should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When PRIMAXIN I.V. 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 PRIMAXIN I.V. 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.

Last updated on RxList: 8/20/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

IMIPENEM/CILASTATIN - INJECTION

(imm-eh-PEN-um/sye-luh-STAT-in)

COMMON BRAND NAME(S): Primaxin

USES: This medication is used to treat a wide variety of bacterial infections. This medication is known as a carbapenem-type antibiotic. It works by stopping the growth of bacteria.

This antibiotic treats only bacterial infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or misuse of any antibiotic can lead to its decreased effectiveness.

HOW TO USE: This medication is given by injection into a muscle or vein, usually every 6 to 8 hours or as directed by your doctor.

Read and learn all preparation and usage instructions supplied by the manufacturer. If your product needs to be mixed, follow all instructions for proper mixing with the correct IV fluids. Consult your pharmacist for details. Before using, check the product visually for particles or discoloration. If either is present, do not use the liquid.

Antibiotics work best when the amount of medicine in your body is kept at a constant level. Therefore, use this drug at evenly spaced intervals. The dosage is based on your medical condition and response to treatment.

Continue to use this medication until the full prescribed treatment period is finished, even if symptoms disappear after a few days. Stopping the medication too early may result in a return of the infection.

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist for details.

SIDE EFFECTS: Swelling, redness, pain, or soreness at the injection site may occur. This medication may also infrequently cause upset stomach, nausea, vomiting, or diarrhea. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: dark urine, easy bruising/bleeding, hearing changes (e.g., decreased hearing, ringing in the ears), mental/mood changes (e.g., confusion, hallucinations), persistent sore throat/fever, swollen tongue, tingling hands/feet, yellowing eyes/skin, muscle twitching/spasms.

Seek immediate medical attention if any of these rare but very serious side effects occur: seizures, unusual weakness.

This medication may rarely cause a severe intestinal condition (pseudomembranous colitis) due to a type of resistant bacteria. This condition may occur during treatment or weeks to months after treatment has stopped. Do not use anti-diarrhea products or narcotic pain medications if you have any of the following symptoms because these products may make them worse. Tell your doctor immediately if you develop: persistent diarrhea, abdominal or stomach pain/cramping, blood/mucus in your stool.

Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection. Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge, or other new symptoms.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using imipenem with cilastatin, tell your doctor or pharmacist if you are allergic to either of its ingredients; or to penicillins or cephalosporins; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: brain disorders (e.g., seizures, head injury, tumor), kidney disease, liver disease, stomach/intestinal diseases (e.g., colitis).

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for side effects while using this drug.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This medication passes into breast milk. Though there have been no reports of harm to nursing infants, consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: live bacterial vaccines, ganciclovir, probenecid, other antibiotics, divalproate/valproic acid.

This medication may decrease the effectiveness of combination-type birth control pills. This can result in pregnancy. Ask your doctor or pharmacist for details. Discuss whether you should use additional reliable birth control methods while using this medication.

This medication may interfere with certain laboratory tests (e.g., urine glucose), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: seizures.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in that case.

Laboratory and/or medical tests (e.g., complete blood count, kidney/liver function tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Before mixing, store the dry powder at room temperature below 77 degrees F (25 degrees C) away from light and moisture. After mixing, store at room temperature or in the refrigerator at or below 41 degrees F (5 degrees C). Do not freeze mixed solutions. If stored at room temperature, use/discard the mixed solution within 4 hours.

Consult the package instructions or your pharmacist for other storage details. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.