Imipenem And Cilastatin
FDA Drug Information • Also known as: Imipenem And Cilastatin
- Brand Names
- Imipenem And Cilastatin
- Dosage Form
- POWDER
- Product Type
- DRUG FOR FURTHER PROCESSING
Description
11 DESCRIPTION Imipenem and Cilastatin for Injection, USP is a sterile formulation of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor with sodium bicarbonate added as a buffer. Imipenem and Cilastatin for Injection, USP 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 Imipenem and Cilastatin for Injection, USP 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). Imipenem and Cilastatin for Injection, USP 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) ]. Imipenem and Cilastatin for Injection, USP 500 mg/500 mg vial contains 37.5 mg of sodium (1.6 mEq). Solutions of Imipenem and Cilastatin for Injection, USP range from colorless to yellow. Variations of color within this range...
What Is Imipenem And Cilastatin Used For?
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 is not indicated in patients with meningitis because safety and efficacy have not been established ( 1.9 ). Imipenem and Cilastatin for Injection, USP is not recommended in pediatric patients with CNS infections because of the risk of seizures ( 1.9 ). Imipenem and Cilastatin for Injection, USP 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 and other antibacterial drugs, Imipenem and Cilastatin for Injection, USP 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 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 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 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 is indicated for the...Dosage and Administration
2 DOSAGE AND ADMINISTRATION
The dosage of Imipenem and Cilastatin for Injection 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 Imipenem and Cilastatin for Injection unless hemodialysis is instituted within 48 hours ( 2.4 ). Reconstitute Imipenem and Cilastatin for Injection 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 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 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 Imipenem and Cilastatin for Injection 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 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 Imipenem and Cilastatin for Injection 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 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...Side Effects (Adverse Reactions)
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 WG Critical Care, LLC at 1-866-562-4708 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. Table 4 shows the incidence of adverse reactions reported during the clinical investigations of adult patients treated with imipenem and cilastatin for injection. Table 4: Incidence (%) Adverse reactions with an incidence ≥ 0.2% of imipenem and cilastatin for injection-treated adult patients. of Adverse Reactions Reported During Clinical Investigations of Adult Patients Treated with Imipenem and Cilastatin for Injection 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,...Drug Interactions
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 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 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. These drugs should not be used concomitantly with imipenem and cilastatin for injection unless the potential benefits outweigh the risks. 7.2 Probenecid Concomitant administration of imipenem and cilastatin for injection 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. 7.3 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including imipenem and cilastatin for injection, 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 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.Contraindications
4 CONTRAINDICATIONS Imipenem and cilastatin for injection is contraindicated in patients who have shown hypersensitivity to any component of this product.
Known hypersensitivity to any component of imipenem and cilastatin for injection (4)Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Available data from a small number of postmarketing cases with imipenem and cilastatin for injection use in pregnancy are not sufficient to identify any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Developmental toxicity studies with imipenem and cilastatin sodium (alone or in combination) administered to mice, rats, rabbits, and monkeys at doses 0.4 to 2.9 times the recommended human dose (RHD), (based on body surface area), showed no drug-induced fetal malformations. Embryofetal development studies with imipenem/cilastatin administered to cynomolgus monkeys at doses similar to the RHD (based on body surface area) showed an increase in embryonic loss (see Data) . The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Data Animal Data Reproductive toxicity studies with imipenem and cilastatin (alone or in combination) administered to mice, rats, and rabbits showed no evidence of effects on embryofetal (mice, rats and rabbits) or pre/postnatal (rats) development. Imipenem was administered intravenously to rats (gestation days (GD) 7 to 17) and rabbits (GD 6 to 18) at doses up to 900 and 60 mg/kg/day, respectively, approximately 2.9 and 0.4 times the RHD (based on body surface area). Cilastatin was administered subcutaneously to rats (GD 6 to 17) and intravenously to rabbits (GD 6 to 18) at doses up to 1000 and 300 mg/kg/day, respectively, approximately 3.2 and 1.9 times the RHD (based on body surface area). Imipenem/cilastatin was administered intravenously to mice at doses up to 320 mg/kg/day (GD 6 to 15). In two separate studies, imipenem/cilastatin was administered to rats (GD 6 to 17 and GD 15 to day 21...
Overdosage
10 OVERDOSAGE In the case of overdosage, discontinue imipenem and cilastatin for injection, treat symptomatically, and institute supportive measures as required. Imipenem and cilastatin for injection is hemodialyzable.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Imipenem and Cilastatin for Injection, USP is supplied as a sterile powder mixture in single-dose vials containing imipenem (anhydrous equivalent) and cilastatin (free acid equivalent) as follows: 500 mg imipenem equivalent and 500 mg cilastatin equivalent, and 20 mg sodium bicarbonate as a buffer: NDC 44567-705-01 single-dose vial NDC 44567-705-10 carton of 10 16.2 Storage and Handling Before Reconstitution: Imipenem and Cilastatin for Injection, USP dry powder should be stored at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.