Generic: IMIPENEM AND CILASTATIN SODIUM
1 INDICATIONS AND USAGE Imipenem and Cilastatin for Injection, USP for intravenous use is a combination of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor, indicated for the treatment of the following serious infections caused by designated susceptible bacteria: Lower respiratory tract infections. ( 1.1 ) Urinary tract infections. ( 1.2 ) Intra-abdominal infections. ( 1.3 ) Gynecologic infections. ( 1.4 ) Bacterial septicemia. ( 1.5 ) Bone and joint infections...
1 INDICATIONS AND USAGE Imipenem and Cilastatin for Injection, USP for intravenous use is a combination of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor, indicated for the treatment of the following serious infections caused by designated susceptible bacteria: Lower respiratory tract infections. ( 1.1 ) Urinary tract infections. ( 1.2 ) Intra-abdominal infections. ( 1.3 ) Gynecologic infections. ( 1.4 ) Bacterial septicemia. ( 1.5 ) Bone and joint infections. ( 1.6 ) Skin and skin structure infections. ( 1.7 ) Endocarditis. ( 1.8 ) Limitations of Use : Imipenem and Cilastatin for Injection, USP (I.V.) is not indicated in patients with meningitis because safety and efficacy have not been established ( 1.9 ). Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures ( 1.9 ). Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients weighing less than 30 kg with impaired renal function ( 1.9 ). Usage : To reduce the development of drug resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection, USP (I.V.) and other antibacterial drugs, Imipenem and Cilastatin for Injection, USP (I.V.) should be used only to treat infections that are proven or strongly suspected to be caused by bacteria ( 1.10 ). 1.1 Lower Respiratory Tract Infections Imipenem and Cilastatin for Injection, USP (I.V.) for intravenous use is indicated for the treatment of lower respiratory tract infections caused by susceptible strains of Staphylococcus aureus (penicillinase-producing isolates), Acinetobacter species, Enterobacter species, Escherichia coli , Haemophilus influenzae , Haemophilus parainfluenzae , Klebsiella species, Serratia marcescens . 1.2 Urinary Tract Infections (complicated and uncomplicated) Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of urinary tract infections (complicated and uncomplicated) caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , Pseudomonas aeruginosa . 1.3 Intra-Abdominal Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of intra-abdominal infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), 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. 1.4 Gynecologic Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of gynecologic infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), 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 . 1.5 Bacterial Septicemia Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of bacterial septicemia caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Pseudomonas aeruginosa , Serratia species, Bacteroides species including B. fragilis . 1.6 Bone and Joint Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of bone and joint infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Enterobacter species, Pseudomonas aeruginosa . 1.7 Skin and Skin Structure Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of skin and skin structure infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), 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. 1.8 Endocarditis Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of endocarditis caused by susceptible strains of Staphylococcus aureus (penicillinase-producing isolates). 1.9 Limitations of Use Imipenem and Cilastatin for Injection, USP (I.V.) is not indicated in patients with meningitis because safety and efficacy have not been established. Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ), and Use in Specific Populations ( 8.4 )] . Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients less than 30 kg with impaired renal function, as no data are available [see Use in Specific Populations ( 8.4 ), and Dosage and Administration ( 2.2 )] . Periodic assessment of organ system functions, including renal, hepatic and hematopoietic, is advisable during prolonged therapy. 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection, USP (I.V.) and other antibacterial drugs, Imipenem and Cilastatin for Injection, USP (I.V.) should be used only to treat 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.
5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. If an allergic reaction to Imipenem and Cilastatin for Injection (I.V.) occurs, discontinue the drug immediately ( 5.1 ). Seizure Potential: Seizures and other CNS adverse reactions, such as confusional states and myoclonic activity, have been reported during treatment with Imipenem and Cilastatin for I...
5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. If an allergic reaction to Imipenem and Cilastatin for Injection (I.V.) occurs, discontinue the drug immediately ( 5.1 ). Seizure Potential: Seizures and other CNS adverse reactions, such as confusional states and myoclonic activity, have been reported during treatment with Imipenem and Cilastatin for Injection (I.V.). If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Imipenem and Cilastatin for Injection (I.V.) re-examined to determine whether it should be decreased, or the antibacterial drug discontinued ( 5.2 ). Increased Seizure Potential Due to Interaction with Valproic Acid: Co-administration of Imipenem and Cilastatin for Injection (I.V.), 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. The concomitant use of Imipenem and Cilastatin for Injection (I.V.) and valproic acid/divalproex sodium is generally not recommended ( 5.3 , 7.3 ). Clostridioides difficile-Associated Diarrhea (CDAD): has been reported with use of Imipenem and Cilastatin for Injection (I.V.) and may range in severity from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs ( 5.4 ). 5.1 Hypersensitivity Reactions 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 hypersensitivity reactions when treated with another beta-lactam. Before initiating therapy with Imipenem and Cilastatin for Injection (I.V.), careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to Imipenem and Cilastatin for Injection (I.V.) occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment as clinically indicated. 5.2 Seizure Potential Seizures and other CNS adverse experiences, such as confusional states and myoclonic activity, have been reported during treatment with Imipenem and Cilastatin for Injection (I.V.), especially when recommended dosages were exceeded [see Adverse Reactions ( 6.1 , 6.2 )]. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function [see Use in Specific Populations ( 8.6 )] . However, there have been reports of CNS adverse experiences in patients who had no recognized or documented underlying CNS disorder or compromised renal function. 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 Imipenem and Cilastatin for Injection (I.V.) re-examined to determine whether it should be decreased, or the antibacterial drug discontinued. 5.3 Increased Seizure Potential Due to Interaction with Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including Imipenem and Cilastatin for Injection (I.V.), 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 Cilastatin for Injection (I.V.) and valproic acid/divalproex sodium is generally not recommended. Antibacterials 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 Imipenem and Cilastatin for Injection (I.V.) is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions ( 7.3 )]. Close adherence to the recommended dosage and dosage schedules is urged, especially in patients with known factors that predispose to convulsive activity. 5.4 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Imipenem and Cilastatin for Injection (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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.5 Development of Drug-Resistant Bacteria As with other antibacterial drugs, prolonged use of Imipenem and Cilastatin for Injection (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 Imipenem and Cilastatin for Injection (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.
6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section. Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Seizure Potential [see Warnings and Precautions ( 5.2 )] Increased Seizure Potential Due to Interaction with Valproic Acid [see Warnings and Precautions ( 5.3 )] Clostridioides difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions ( 5.4 )] Development of Drug-Resistant Bacteria [see War...
6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section. Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Seizure Potential [see Warnings and Precautions ( 5.2 )] Increased Seizure Potential Due to Interaction with Valproic Acid [see Warnings and Precautions ( 5.3 )] Clostridioides difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions ( 5.4 )] Development of Drug-Resistant Bacteria [see Warnings and Precautions ( 5.5 )] The most frequently occurring adverse reactions (โฅ 0.2%) in adults were phlebitis, nausea, diarrhea, vomiting, rash, pain injection site, fever, hypotension, seizures, erythema at injection site, dizziness, pruritus, vein induration, urticaria, somnolence ( 6.1 ). The most frequently occurring adverse reactions (> 1%) in pediatric patients greater than or equal to 3 months of age were diarrhea, rash, phlebitis, gastroenteritis, vomiting, IV site irritation, urine discoloration ( 6.1 ). The most frequently occurring adverse reactions (> 1%) in neonates to 3 months of age were convulsions, diarrhea, oliguria/anuria, oral candidiasis, rash, tachycardia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients During clinical investigations 1,723 patients were treated with Imipenem and Cilastatin for Injection (I.V.). Table 4 shows the incidence of adverse reactions reported during the clinical investigations of adult patients treated with Imipenem and Cilastatin for Injection (I.V.). Table 4: Incidence (%)* of Adverse Reactions Reported During Clinical Investigations of Adult Patients Treated with Imipenem and Cilastatin for Injection (I.V.) * Adverse reactions with an incidence โฅ 0.2% of Imipenem and Cilastatin for Injection (I.V.) -treated adult patients. Body System Adverse Reactions Frequency (%) Local Administration site Phlebitis/ thrombophlebitis 3.1% Pain at the injection site 0.7% Erythema at the injection site 0.4% Vein induration 0.2% Gastrointestinal Nausea 2% Diarrhea 1.8% Vomiting 1.5% Skin Rash 0.9% Pruritus 0.3% Urticaria 0.2% Vascular Hypotension 0.4% Body as a Whole Fever 0.5% Nervous system Seizures 0.4% Dizziness 0.3% Somnolence 0.2% Additional adverse reactions reported in less than 0.2% of the patients or reported since the drug was marketed are listed within each body system in order of decreasing severity [see Table 5 ]. Table 5: Additional Adverse Reactions Occurring in Less than 0.2% of Adult Patients Listed within Each Body System in Order of Decreasing Severity Body System Adverse Reactions Gastrointestinal Pseudomembranous Colitis (the onset of Pseudomembranous colitis symptoms), Hemorrhagic Colitis Gastroenteritis Abdominal Pain Glossitis Tongue Papillar Hypertrophy Heartburn Pharyngeal Pain Increased Salivation CNS Encephalopathy Confusion Myoclonus Paresthesia Vertigo Headache Special Senses Hearing Loss Tinnitus Respiratory Chest Discomfort Dyspnea Hyperventilation Thoracic Spine Pain Cardiovascular Palpitations Tachycardia Skin Erythema Multiforme Angioneurotic Edema Flushing Cyanosis Hyperhidrosis Skin Texture Changes Candidiasis Pruritus Vulvae Local Administration site Infused vein infection Body as a Whole Polyarthralgia Asthenia/Weakness Renal Oliguria/Anuria Polyuria Adverse Laboratory Changes The following adverse laboratory changes were reported during clinical trials: Hepatic: Increased alanine aminotransferase (ALT or SGPT), aspartate aminotransferase (AST or SGOT), alkaline phosphatase, bilirubin, and lactate dehydrogenase (LDH) Hemic: Increased eosinophils, positive Coombs test, increased WBC, increased platelets, decreased hemoglobin and hematocrit, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils Electrolytes: Decreased serum sodium, increased potassium, increased chloride Renal: Increased BUN, creatinine Urinalysis: Presence of urine protein, urine red blood cells, urine white blood cells, urine casts, urine bilirubin, and urine urobilinogen. Pediatric Patients Table 6: Incidence (%)* of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Greater Than or Equal to 3 Months of Age Treated with Imipenem and Cilastatin for Injection (I.V.) * Adverse reactions that occurred in > 1 % of Imipenem and Cilastatin for Injection (I.V.)-treated pediatric patients (greater than or equal to 3 months of age) Body System Adverse Reactions Frequency (%) Local Administration Site Phlebitis 2.2% Intravenous Site Irritation 1.1% Gastrointestinal Diarrhea 3.9% Gastroenteritis 1.1% Vomiting 1.1% Skin Rash 2.2% Renal Urine Discoloration 1.1% Table 7: Incidence (%)* of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Neonates to 3 Months of Age Treated with Imipenem and Cilastatin for Injection (I.V.) * Adverse reactions that occurred in > 1 % of Imipenem and Cilastatin for Injection (I.V.)-treated pediatric patients (neonates to 3 months of age) Body System Adverse Reactions Frequency (%) Gastrointestinal Diarrhea 3% CNS Convulsions 5.9% Cardiovascular Tachycardia 1.5% Skin Rash 1.5% Body as a Whole Oral Candidiasis 1.5% Renal Oliguria/Anuria 2.2% Adverse Laboratory Changes The following adverse laboratory changes were reported in studies of 178 pediatric patients 3 months of age: increased AST (SGOT), decreased hemoglobin/hematocrit, increased platelets, increased eosinophils, increased ALT (SGPT), increased urine protein, decreased neutrophils. The following adverse laboratory changes were reported in studies of 135 patients (neonates to 3 months of age): increased eosinophils, increased AST (SGPT), increased serum creatinine, increased/decreased platelet count, increased/decreased bilirubin, increased ALT (SGPT), increased alkaline phosphatase, increased/decreased hematocrit. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Imipenem and Cilastatin for Injection (I.V.). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 8: Adverse Reactions Identified During Post Approval Use of Imipenem and Cilastatin for Injection (I.V.) Body System Adverse Reactions Gastrointestinal Hepatitis (including fulminant hepatitis) Hepatic failure Jaundice Staining of the teeth and/or tongue Hematologic Pancytopenia Bone marrow depression Thrombocytopenia Neutropenia Leukopenia Hemolytic anemia CNS Tremor Psychic disturbances including hallucinations Dyskinesia Agitation Special Senses Taste perversion Skin Stevens-Johnson syndrome Toxic epidermal necrolysis Body as a whole Drug fever Renal Acute renal failure Urine discoloration Adverse Laboratory Changes Adverse laboratory changes reported since the drug was marketed were: Hematologic: agranulocytosis. Examination of published literature and spontaneous adverse reactions reports suggested a similar spectrum of adverse reactions in adult and pediatric patients.
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