PRIMAXIN^® I.M.
(IMIPENEM AND CILASTATIN FOR INJECTABLE SUSPENSION)

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

Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1985, 1998 MERCK & CO., Inc.
All rights reserved

PRIMAXIN I.M. (Imipenem and Cilastatin for Injectable Suspension) is a formulation of imipenem (a thienamycin antibiotic) and cilastatin sodium (the inhibitor of the renal dipeptidase, dehydropeptidase I). PRIMAXIN I.M. is a potent broad spectrum antibacterial agent for intramuscular administration.

Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya. Its chemical name is [5R-[5α, 6α (R *)]]-6-(1-hydroxyethyl) -3-[[2-[(iminomethyl) amino] ethyl]thio]-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 [R-[R*, S*-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid, monosodium salt. 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.M. 500 contains 32 mg of sodium (1.4 mEq) and PRIMAXIN I.M. 750 contains 48 mg of sodium (2.1 mEq). Prepared PRIMAXIN I.M. suspensions are white to light tan in color. Variations of color within this range do not affect the potency of the product.

Following intramuscular administrations of 500 or 750 mg doses of imipenem-cilastatin sodium in a 1:1 ratio with 1% lidocaine, peak plasma levels of imipenem antimicrobial activity occur within 2 hours and average 10 and 12 μg/mL, respectively. For cilastatin, peak plasma levels average 24 and 33 μg/mL, respectively, and occur within 1 hour. When compared to intravenous administration of imipenem-cilastatin sodium, imipenem is approximately 75% bioavailable following intramuscular administration while cilastatin is approximately 95% bioavailable. The absorption of imipenem from the IM injection site continues for 6 to 8 hours while that for cilastatin is essentially complete within 4 hours. This prolonged absorption of imipenem following the administration of the intramuscular formulation of imipenem-cilastatin sodium results in an effective plasma half-life of imipenem of approximately 2 to 3 hours and plasma levels of the antibiotic which remain above 2 μg/mL for at least 6 or 8 hours, following a 500 mg or 750 mg dose, respectively. This plasma profile for imipenem permits IM administration of the intramuscular formulation of imipenem-cilastatin sodium every 12 hours with no accumulation of cilastatin and only slight accumulation of imipenem.

A comparison of plasma levels of imipenem after a single dose of 500 mg or 750 mg of imipenem-cilastatin sodium (intravenous formulation) administered intravenously or of imipenem-cilastatin sodium (intramuscular formulation) diluted with 1% lidocaine and administered intramuscularly is as follows:

Imipenem urine levels remain above 10 μg/mL for the 12-hour dosing interval following the administration of 500 mg or 750 mg doses of the intramuscular formulation of imipenem-cilastatin sodium. Total urinary excretion of imipenem averages 50% while that for cilastatin averages 75% following either dose of the intramuscular formulation of imipenem-cilastatin sodium.

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, increased levels of imipenem are achieved in the urine. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%.

In a clinical study in which a 500-mg dose of the intramuscular formulation of imipenem-cilastatin sodium was administered to healthy subjects, the average peak level of imipenem in interstitial fluid (skin buler fluid) was approximately 5.0 μg/mL within 3.5 hours after administration.

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

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, including 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 many 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 intramuscular formulation of imipenem-cilastatin sodium as described in the INDICATIONS AND USAGE section.

PRIMAXIN I.M. is indicated for the treatment of serious infections (uled below) of mild to moderate severity for which intramuscular therapy is appropriate. PRIMAXIN I.M. is not intended for the therapy of severe or life-threatening infections, including bacterial sepsis or endocarditis, or in instances of major physiological impairments such as shock.

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

• Lower respiratory tract infections, including pneumonia and bronchitis as an exacerbation of COPD (chronic obstructive pulmonary disease), caused by Streptococcus pneumoniae and Haemophilus influenzae .
• Intra-abdominal infections, including acute gangrenous or perforated appendicitis and appendicitis with peritonitis, caused by Group D streptococcus including Enterococcus faecalis

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

  ; Streptococcus viridans group, Escherichia coli; Klebsiella pneumoniae; Pseudomonas aeruginosa; Bacteroides species including B. fragilis, B. distasonis, B. intermedius and B. thetaiotaomicron; Fusobacterium species and Peptostreptococcus species.
• Skin and skin structure infections, including abscesses, cellulitis, infected skin ulcers and wound infections caused by Staphylococcus aureus including penicillinase-producing strains; Streptococcus pyogenes; Group D streptococcus including Enterococcus faecalis; Acinetobacter species including A. calcoaceticus; Citrobacter species; Escherichia coli; Enterobacter cloacae; Klebsiella pneumoniae; Pseudomonas aeruginosa ; and Bacteroides species including B. fragilis.
• Gynecologic infections, including postpartum endomyometritis, caused by Group D streptococcus including Enterococcus faecalis; Escherichia coli; Klebsiella pneumoniae; Bacteroides intermedius; and Peptostreptococcus species.

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

To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN I.M. and other antibacterial drugs, PRIMAXIN I.M. 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.M. is contraindicated in patients who have shown hypersensitivity to any component of this product. Due to the use of lidocaine hydrochloride diluent, this product is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type and in patients with severe shock or heart block. (Refer to the package circular for lidocaine hydrochloride.)

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (anaphylactic) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY WITH PRIMAXIN^® I.M., 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 myoclonic activity, have been reported during treatment with PRIMAXIN I.M. (See PRECAUTIONS.)

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

Lidocaine HCl — Refer to the package circular for lidocaine HCl.

CNS adverse experiences such as myoclonic activity, or seizures have been reported with PRIMAXIN I.M. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) who also have compromised renal function. However, there were reports in which there was no recognized or documented underlying CNS disorder. Anticonvulsant therapy should be continued in patients with a known seizure disorder.

As with other antibiotics, prolonged use of PRIMAXIN I.M. 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.M. 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.

Caution should be taken to avoid inadvertent injection into a blood vessel. (See DOSAGE AND ADMINISTRATION.) For additional precautions, refer to the package circular for lidocaine HCl.

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

Since concomitant administration of PRIMAXIN (Imipenem-Cilastatin Sodium) 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 I.M.

PRIMAXIN I.M. should not be mixed with or physically added to other antibiotics. However, PRIMAXIN I.M. 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, 2.1 times

Based on patient body surface area of 1.6 m² (weight of 60 kg).

It is not known whether imipenem-cilastatin sodium or lidocaine HCl (diluent) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRIMAXIN I.M. is administered to a nursing woman.

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Clinical studies of PRIMAXIN I.M. did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects; however, clinical studies of PRIMAXIN I.V. in a sufficient number of subjects aged 65 and over have not revealed overall differences in safety or effectiveness between these subjects and younger subjects (refer to the package circular for PRIMAXIN I.V.). Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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. Dosage adjustment in the case of renal impairment is necessary (see DOSAGE AND ADMINISTRATION, ADULTS WITH IMPAIRED RENAL FUNCTION).

In 686 patients in multiple dose clinical trials of PRIMAXIN I.M., the following adverse reactions were reported:

In addition, a variety of adverse effects, not observed in clinical trials with PRIMAXIN I.M., have been reported with intravenous administration of PRIMAXIN I.V. (Imipenem and Cilastatin for Injection). Those uled below are to serve as alerting information to physicians.

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.M., 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.M. is for intramuscular use only.

The dosage recommendations for PRIMAXIN I.M. represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present.

Patients with lower respiratory tract infections, skin and skin structure infections, and gynecologic infections of mild to moderate severity may be treated with 500 mg or 750 mg administered every 12 hours depending on the severity of the infection.

Intra-abdominal infection may be treated with 750 mg every 12 hours. [See table below.]

Total daily IM dosages greater than 1500 mg per day are not recommended.

The dosage for any particular patient should be based on the location of and severity of the infection, the susceptibility of the infecting pathogen(s), and renal function.

The duration of therapy depends upon the type and severity of the infection. Generally, PRIMAXIN I.M. should be continued for at least two days after the signs and symptoms of infection have resolved. Safety and efficacy of treatment beyond fourteen days have not been established.

PRIMAXIN I.M. should be administered by deep intramuscular injection into a large muscle mass (such as the gluteal muscles or lateral part of the thigh) with a 21 gauge 2” needle. Aspiration is necessary to avoid inadvertent injection into a blood vessel.

The safety and efficacy of PRIMAXIN I.M. have not been studied in patients with creatinine clearance of less than 20 mL/min/1.73 m². Serum creatinine alone may not be a sufficiently accurate measure of renal function. Creatinine clearance (T_cc) may be estimated from the following equation:

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

T_cc (Females)        =             0.85 x (above value)

PRIMAXIN I.M. should be prepared for use with 1.0% lidocaine HCl solution

Refer to the package circular for lidocaine HCl for detailed information concerning CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS.

PRIMAXIN I.M. is supplied as a sterile powder mixture in vials for IM administration as follows:

No. 3582 — 500 mg imipenem equivalent and 500 mg cilastatin equivalent

NDC 0006-3582-75 in trays of 10 vials.

No. 3583 — 750 mg imipenem equivalent and 750 mg cilastatin equivalent

NDC 0006-3583-76 in trays of 10 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

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