PRIMAXIN IV

PRIMAXIN (imipenem and cilastatin) for Injection is a sterile formulation of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor with sodium bicarbonate added as a buffer. PRIMAXIN is an antibacterial drug for intravenous administration. Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya . Its chemical name is (5 R ,6 S )-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 C 12 H 17 N 3 O 4 S∙H 2 O, 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 C 16 H 25 N 2 O 5 SNa, and its structural formula is: Each single-dose vial of PRIMAXIN contains 500 mg imipenem (equivalent to 530 mg imipenem monohydrate), 500 mg cilastatin (equivalent to 531 mg cilastatin sodium), and 20 mg sodium bicarbonate (used as a buffer). PRIMAXIN 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 How Supplied/Storage and Handling (16.1) ]. PRIMAXIN 500 contains 37.5 mg of sodium (1.6 mEq). Solutions of PRIMAXIN range from colorless to yellow. Variations of color within this range do not affect the potency of the product. Chemical Structure Chemical Structure

PRIMAXIN 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: PRIMAXIN is not indicated in patients with meningitis because safety and efficacy have not been established ( 1.9 ). PRIMAXIN is not recommended in pediatric patients with CNS infections because of the risk of seizures ( 1.9 ). PRIMAXIN 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 PRIMAXIN and other antibacterial drugs, PRIMAXIN 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 PRIMAXIN 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) PRIMAXIN 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 PRIMAXIN 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 PRIMAXIN 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 PRIMAXIN 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 PRIMAXIN 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 PRIMAXIN 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 PRIMAXIN is indicated for the treatment of endocarditis caused by susceptible strains of Staphylococcus aureus (penicillinase-producing isolates). 1.9 Limitations of Use PRIMAXIN is not indicated in patients with meningitis because safety and efficacy have not been established. PRIMAXIN 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) ]. PRIMAXIN 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 PRIMAXIN and other antibacterial drugs, PRIMAXIN 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.

The dosage of PRIMAXIN 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 1000 mg every 8 hours OR 1000 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 PRIMAXIN unless hemodialysis is instituted within 48 hours ( 2.4 ). Reconstitute PRIMAXIN 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 PRIMAXIN in adult patients should be based on suspected or confirmed pathogen susceptibility as shown in Table 1 below. The dosage recommendations for PRIMAXIN 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 1000 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 PRIMAXIN in Adult Patients with Creatinine Clearance Greater than or Equal to 90 mL/min Suspected or Proven Pathogen Susceptibility Dosage of PRIMAXIN If the infection is suspected or proven to be due to a susceptible bacterial species 500 mg every 6 hours OR 1000 mg every 8 hours If the infection is suspected or proven to be due to bacterial species with intermediate susceptibility [see Microbiology (12.4) ] 1000 mg every 6 hours 2.2 Dosage in Pediatric Patients PRIMAXIN is not recommended in pediatric patients with CNS infections because of the risk of seizures [see Use in Specific Populations (8.4) ]. PRIMAXIN 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 PRIMAXIN Dosage in Pediatric Patients for Non-CNS Infections Age Dose (mg/kg) 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 Recommend that the maximum total daily dosage not exceed 4g/day 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 2.3 Dosage in Adult Patients with Renal Impairment Patients with creatinine clearance less than 90 mL/min require dosage reduction of PRIMAXIN 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) × (140-age in years) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (value calculated for males) Table 3: Dosage of PRIMAXIN for Adult Patients in Various Renal Function Groups Based on Estimated Creatinine Clearance (CLcr) 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 than or equal to 15 Dosage of PRIMAXIN 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. If the infection is suspected or proven to be due to a susceptible bacterial species: 500 mg every 6 hours 400 mg every 6 hours 300 mg every 6 hours 200 mg every 6 hours OR 1000 mg every 8 hours 500 mg every 6 hours 500 mg every 8 hours 500 mg every 12 hours Dosage of PRIMAXIN , If the infection is suspected or proven to be due to bacterial species with intermediate susceptibility [see Microbiology (12.4) ]: 1000 mg every 6 hours 750 mg every 8 hours 500 mg every 6 hours 500 mg every 12 hours In patients with creatinine clearances of less than 30 to greater than or equal to 15 mL/min, there may be an increased risk of seizures [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ] . Patients with creatinine clearance less than 15 mL/min should not receive PRIMAXIN unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of PRIMAXIN for patients undergoing peritoneal dialysis. 2.4 Dosage in Hemodialysis Patients When treating patients with creatinine clearances of less than 15 mL/min who are undergoing hemodialysis , use the dosage recommendations for patients with creatinine clearances of less than 30 to greater than or equal to 15 mL/min in Table 3 above [see Dosage and Administration (2.3) ]. Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive PRIMAXIN after hemodialysis and at intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, PRIMAXIN is recommended only when the benefit outweighs the potential risk of seizures [see Warnings and Precautions (5.2) ]. 2.5 Reconstitution and Preparation of PRIMAXIN Solution for Intravenous Administration PRIMAXIN Vials Do not use diluents containing benzyl alcohol to reconstitute PRIMAXIN for administration to neonates because it has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Contents of the vials must be reconstituted by adding approximately 10 mL of the appropriate diluent to the vial. List of appropriate diluents are as follows : 0.9% Sodium Chloride Injection 5% Dextrose Injection 5% Dextrose and 0.9% Sodium Chloride Injection 5% Dextrose Injection with 0.225% or 0.45% saline solution Reconstituted Solutions of PRIMAXIN range from colorless to yellow. Variations of color within this range do not affect the potency of the product. The reconstituted suspension must not be administered by direct Intravenous Infusion After reconstitution, shake vial well and transfer the resulting suspension to 100 mL of an appropriate infusion solution before administering by intravenous infusion. Repeat transfer of the resulting suspension with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution. Agitate the resulting mixture until clear. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion of the infusion solution where applicable. 2.6 Storage of Reconstituted Solutions Vials (After Reconstitution) PRIMAXIN, as supplied in single dose vials and reconstituted with the appropriate diluents [see Dosage and Administration (2.5) ] , maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C). Do not freeze solutions of PRIMAXIN. 2.7 Incompatibility and Compatibility of PRIMAXIN with other Antibacterial Drugs Do not mix PRIMAXIN with, or physically add to, other antibacterial drugs. PRIMAXIN may be administered concomitantly with other antibacterial drugs, such as aminoglycosides.

PRIMAXIN is contraindicated in patients who have shown hypersensitivity to any component of this product. Known hypersensitivity to any component of PRIMAXIN ( 4 )

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 Merck Sharp & Dohme LLC at 1-877-888-4231 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 PRIMAXIN. Table 4 shows the incidence of adverse reactions reported during the clinical investigations of adult patients treated with PRIMAXIN. Table 4: Incidence (%) Adverse reactions with an incidence ≥0.2% of PRIMAXIN-treated adult patients. of Adverse Reactions Reported During Clinical Investigations of Adult Patients Treated with PRIMAXIN 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 2.0% 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 (%) Adverse reactions that occurred in >1% of PRIMAXIN-treated pediatric patients (greater than or equal to 3 months of age) of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Greater Than or Equal to 3 Months of Age Treated with PRIMAXIN 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 (%) Adverse reactions that occurred in >1% of PRIMAXIN-treated pediatric patients (neonates to 3 months of age) of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Neonates to 3 Months of Age Treated with PRIMAXIN 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 PRIMAXIN. 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 PRIMAXIN 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.

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 PRIMAXIN 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 PRIMAXIN 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 PRIMAXIN. These drugs should not be used concomitantly with PRIMAXIN unless the potential benefits outweigh the risks. 7.2 Probenecid Concomitant administration of PRIMAXIN 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 PRIMAXIN. 7.3 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including PRIMAXIN, 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 PRIMAXIN 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.

16.2 Storage and Handling Before Reconstitution: PRIMAXIN dry powder should be stored at a temperature below 25°C (77°F).