Cilastatin

12.1 Mechanism of Action Imipenem and Cilastatin for Injection (I.V.) is a combination of imipenem and cilastatin. Imipenem is a penem antibacterial drug [see Microbiology ( 12.4 )] . Cilastatin is a renal dehydropeptidase inhibitor that limits the renal metabolism of imipenem.

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 (

2 DOSAGE AND ADMINISTRATION The dosage of Imipenem and Cilastatin for Injection (I.V.) in adult patients should be based on suspected or confirmed pathogen susceptibility ( 2.1 ). For adult patients with normal renal function (creatinine clearance of greater than or equal to 90 mL/min), the recommended dosage regimens are: 500 mg every 6 hours OR 1,000 mg every 8 hours OR 1,000 mg every 6 hours ( 2.1 ). See full prescribing information for dosage recommendations in pediatric patients ( 2.2 ). A reduction in dose must be made for a patient with a creatinine clearance of less than 90 mL/min ( 2.3 ). Patients with creatinine clearances of less than 15 mL/min should not receive Imipenem and Cilastatin for Injection (I.V.) unless hemodialysis is instituted within 48 hours ( 2.4 ). Reconstitute Imipenem and Cilastatin for Injection, USP (I.V.) vial with appropriate diluent and dilute the reconstituted suspension with an appropriate infusion solution before administering by intravenous infusion ( 2.5 ). 2.1 Dosage in Adults For Intravenous Injection Only The dosage of Imipenem and Cilastatin for Injection (I.V.) in adult patients should be based on suspected or confirmed pathogen susceptibility as shown in Table 1 below. The dosage recommendations for Imipenem and Cilastatin for Injection (I.V.) represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. These doses should be used for patients with creatinine clearance of greater than or equal to 90 mL/min. A reduction in dose must be made for patients with creatinine clearance less than 90 mL/min as shown in Table 3 [see Dosage and Administration ( 2.3 )] . Recommend that the maximum total daily dosage not exceed 4 g/day. Administer 500 mg by intravenous infusion over 20 to 30 minutes. Administer 1,000 mg by intravenous infusion over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed. Table 1: Dosage of Imipenem and Cilastatin for Injection (I.V.) in Adult Patients with Creatinine Clearance Greater than or Equal to 90 mL/min Suspected or Proven Pathogen Susceptibility Dosage of Imipenem and Cilastatin for Injection (I.V.) If the infection is suspected or proven to be due to a susceptible bacterial species 500 mg every 6 hours OR 1,000 mg every 8 hours If the infection is suspected or proven to be due to bacterial species with intermediate susceptibility [see Microbiology ( 12.4 )] 1,000 mg every 6 hours 2.2 Dosage in Pediatric Patients Imipenem and Cilastatin for Injection (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures [see Use in Specific Populations ( 8.4 )] . Imipenem and Cilastatin for Injection (I.V.) is not recommended in pediatric patients < 30 kg with renal impairment, as no data are available [see Use in Specific Populations ( 8.4 )] . Based on studies in adults, the maximum total daily dose in pediatric patients should not exceed 4 g/day [see Dosage and Administration ( 2.1 )] . The recommended dosage for pediatric patients with non-CNS infections is shown in Table 2 below: Table 2: Recommended Imipenem and Cilastatin for Injection (I.V.) Dosage in Pediatric Patients for Non-CNS Infections * Doses less than or equal to 500 mg should be given by intravenous infusion over 20 to 30 minutes † Doses greater than 500 mg should be given by intravenous infusion over 40 to 60 minutes Age Dose (mg/kg) *, † Frequency (hours) Greater than or equal to 3 Months of Age 15-25 mg/kg Every 6 hours Less than or equal to 3 months of age (Greater than or equal to 1,500 g body weight) 4 weeks to 3 months of age 25 mg/kg Every 6 hours 1 to 4 weeks of age 25 mg/kg Every 8 hours Less than 1 week of age 25 mg/kg Every 12 hours Recommend that the maximum total daily dosage not exceed 4 g/day 2.3 Dosage in Adult Patients with Renal Impairment Patients with creatinine clearance less than 90 mL/min require dosage reduction of Imipenem and Cilastatin for Injection (I.V.) as indicated in Table 3 . The serum creatinine should represent a steady state of renal function. Use the Cockcroft-Gault method described below to calculate the creatinine clearance: Males: (weight in kg) x (140-age in years) (72) x serum creatinine (mg/100 mL) Females: (0.85) x (value calculated for males) Table 3: Dosage of Imipenem and Cilastatin for Injection (I.V.) for Adult Patients in Various Renal Function Groups Based on Estimated Creatinine Clearance (CLcr) * Administer doses less than or equal to 500 mg by intravenous infusion over 20 to 30 minutes. Discard unused portion of the infusion solution. † Administer doses greater than 500 mg by intravenous infusion over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed. Creatinine clearance (mL/min) Greater than or equal to 90 Less than 90 to greater than or equal to 60 Less than 60 to greater than or equal to 30 Less than 30 to greater tha

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 (≥ 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 ≥ 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 R

7 DRUG INTERACTIONS Ganciclovir: Generalized seizures have been reported in patients who received ganciclovir. Do not co-administer unless benefit outweighs risk ( 7.1 ). Probenecid: Concomitant administration of Imipenem and Cilastatin for Injection (I.V.) and probenecid results in increases in the plasma level and half-life of imipenem. Concomitant administration is not recommended ( 7.2 ). Valproic acid/divalproex sodium: Concomitant use with Imipenem and Cilastatin for Injection (I.V.) is generally not recommended. Consider other antibacterial drugs to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium ( 5.3 , 7.3 ). 7.1 Ganciclovir Generalized seizures have been reported in patients who received ganciclovir and Imipenem and Cilastatin for Injection (I.V.). These drugs should not be used concomitantly with Imipenem and Cilastatin for Injection (I.V.) unless the potential benefits outweigh the risks. 7.2 Probenecid Concomitant administration of Imipenem and Cilastatin for Injection (I.V.) and probenecid results in increases in the plasma level and half-life of imipenem. Therefore, it is not recommended that probenecid be given concomitantly with Imipenem and Cilastatin for Injection (I.V.). 7.3 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. 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 and Precautions ( 5.3 )]. 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.