Primaxin IV

imipenem and cilastatin sodium

Dosage Form: injection, powder, for solution
PRIMAXIN® I.V.

(IMIPENEM AND CILASTATIN FOR INJECTION)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN I.V.1 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 bacteria.

For Intravenous Injection Only

1

Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Copyright © 1987, 1994, 1998 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved

Primaxin IV Description

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.

Primaxin IV - Clinical Pharmacology

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 µg/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 µg/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 µg/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 post dose)	—
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 (formerlyS. 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

Klebsiella spp.

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 µg/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 method{1} (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. coli ATCC 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 procedure{2} that has been recommended for use with disks to test the susceptibility of microorganisms to imipenem uses the 10-µg 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 (µg/mL)
B. thetaiotaomicron ATCC 29741	0.06–0.25
E. lentum ATCC 43055	0.12–0.5

Indications and Usage for Primaxin IV

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

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


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


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


4. Gynecologic infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)2, Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species2, Escherichia coli, Gardnerella vaginalis, Klebsiella species2, Proteus species, Bifidobacterium species2, Peptococcus species2, Peptostreptococcus species, Propionibacterium species2, Bacteroides species including B. fragilis2


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


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


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


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


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

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.

2

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

Contraindications

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

Warnings

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

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

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

Seizure Potential

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

Case reports in the literature have shown that co-administration of carbapenems, including imipenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of imipenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of PRIMAXIN I.V. is necessary, supplemental anti-convulsant therapy should be considered (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.

Precautions

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. 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.

Information for Patients

Patients should be counseled to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with PRIMAXIN I.V. If treatment with PRIMAXIN I.V. is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.

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.

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.

Drug Interactions

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.

Case reports in the literature have shown that co-administration of carbapenems, including imipenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid (see WARNINGS, Seizure Potential).

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 times3 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 times3 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 times3 (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 times3 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.

3

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

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 1784 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 µg/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 1355 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 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.

4

Two patients were less than 3 months of age.

5

One patient was greater than 3 months of age.

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).

Adverse React