PRIMAXIN^® I.V.
(IMIPENEM AND CILASTATIN FOR INJECTION)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN I.V.

Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1987, 1994, 1998 MERCK & CO., Inc.
All rights reserved

For Intravenous Injection Only

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.

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.

PRIMAXIN I.V. is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions uled below:

• Lower respiratory tract infections. Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae

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

  , Klebsiella species, Serratia marcescens
• 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
• 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, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis, Fusobacterium species
• 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
• Bacterial septicemia. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species, Bacteroides species including B. fragilis
• Bone and joint infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa
• 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
• Endocarditis. Staphylococcus aureus (penicillinase-producing strains)
• 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.

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.

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

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.

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

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.

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. re-examined 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.

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.

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.

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.

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.

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.

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

Two patients were less than 3 months of age.

Based on studies of 135

One patient was greater than 3 months of age.

<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 µg/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.

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).

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.

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

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

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

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.

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.

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.

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.

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:

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

T_cc (Females)        =             0.85 x (above value)

To determine the dose for adults with impaired renal function and/or reduced body weight:

• Choose a total daily dose from Table I based on infection characteristics.
• 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.
• 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.

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.

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.)

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.

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

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 ul 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 spans to the infusion solution. The resulting mixture should be agitated until clear.

The dry powder should be stored at a temperature below 25°C (77°F).

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.

• 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.
• 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.
• 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 October 2006

Printed in USA

7882131

(Imipenem and Cilastatin for Injection)
(Formerly called Imipenem-Cilastatin Sodium for Injection)
IN ADD-Vantage^® VIALS

For IV Use Only.

INSTRUCTIONS FOR USE

To Open Diluent Container:

Peel overwrap from the corner and remove container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container:

(Use Aseptic Technique)

• Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:
  • To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening. (SEE FIGURE 1.) Pull the ring approximately half way around the cap and then pull straight up to remove the cap. (SEE FIGURE 2.) NOTE: DO NOT ACCESS VIAL WITH SYRINGE.
  • To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover. (SEE FIGURE 3.)
• Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately ½ turn (180°) after the first audible click. (SEE FIGURE 4.) The clicking sound does not assure a seal; the vial must be turned as far as it will go. NOTE: Once vial is seated, do not attempt to remove. (SEE FIGURE 4.)
• Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.
• Label appropriately.

To Prepare Admixture:

• Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.
• With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container. (SEE FIGURE 5.)
• Pull the inner cap from the drug vial. (SEE FIGURE 6.) Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.
• Mix container spans thoroughly and use within the specified time.

Preparation for Administration:

(Use Aseptic Technique)

• Confirm the activation and admixture of vial spans.
• Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
• Close flow control clamp of administration set.
• Remove cover from outlet port at bottom of container.
• Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.
• Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
• Squeeze and release drip chamber to establish proper fluid level in chamber.
• Open flow control clamp and clear air from set. Close clamp.
• Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
• Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

Stability

PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) 250 or 500 single dose ADD Vantage^® vials should be prepared with ADD Vantage^® diluent containers containing 100 mL of either 0.9 percent Sodium Chloride Injection or 5 percent Dextrose Injection. When prepared with either of these diluents, PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) maintains satisfactory potency for 4 hours at room temperature.

Before administering, see accompanying package circular for PRIMAXIN I.V. (Imipenem and Cilastatin for Injection).

Issued August 1996

Printed In USA

7482207

(Imipenem and Cilastatin for Injection)
IN MONOVIAL^® VIALS

For IV Use Only.

INSTRUCTIONS FOR USE

To Open Diluent Container:

Peel overwrap from the corner and remove container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container.

(Use Aseptic Technique)

	«Step 1. EXAMINE Examine the vial for any foreign material in the powder and make sure that the tamper-evident seal between the cap and the vial is intact.
	«Step 2. REMOVE CAP Remove the cap by first twisting it and then pulling it up to break the tamper-evident seal.
	«Step 3. CONNECT Insert the needle into the input port of the infusion bag. Push the needle-holder and vial together until they “click” into place.
	«Step 4. MIX Hold the vial in an upright position. Squeeze the infusion bag several times to transfer the diluent into the vial and shake the vial to constitute the powder, as needed.
	«Step 5. TRANSFER Reverse the connected I.V. assembly, holding the vial upside down. Squeeze and release the infusion bag several times to create an over-pressure in the vial and then allow the spans of the vial to transfer back into the bag. Repeat steps 4 and 5 to dissolve any powder remaining in the vial until the vial is completely empty.
	«Step 6. IDENTIFY Label the infusion bag with proper identification. Remove the vial from the bag. Mix spans of the infusion bag thoroughly before use within the specified time.

Preparation for Administration:

(Use Aseptic Technique)

• Check for leaks by squeezing infusion bag firmly. If leaks are found, discard unit as sterility may be compromised.
• Close flow control clamp of administration set.
• Remove cover from outlet port at bottom of infusion bag.
• Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full direction on administration set carton.
• Suspend infusion bag.
• Squeeze and release drip chamber to establish proper fluid level in chamber.
• Open flow control clamp and clear air for set. Close clamp.
• Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
• Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

Stability

PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) 500 mg single dose MONOVIAL^® vials should be prepared with diluent containers with a maximum port length of 14 mm. When prepared as directed in the accompanying package circular, PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C).

Before administering, see accompanying package circular for PRIMAXIN I.V. (Imipenem and Cilastatin for Injection).

Issued July 1988

Printed in USA

9177500