Sianem

Imipenem monohydrate, cilastatin sodium.

Each vial contains Imipenem monohydrate equivalent to Imipenem anhydrous 500 mg; Cilastatin sodium equivalent to Cilastatin 500 mg.
Imipenem and Cilastatin sodium are present in SIANEM IV INJECTION in a 1:1 ratio.
SIANEM IV INJECTION is buffered with sodium bicarbonate to provide solution in the pH range of 6.5 to 8.5.
SIANEM IV INJECTION contains 37.5 mg (1.6 millimole) of sodium per vial.

Pharmacology: SIANEM IV INJECTION is a fixed combination of Imipenem monohydrate, a semisynthetic carbapenem antibiotics of the thienamycin class, and Cilastatin sodium, the dehydropeptidase I (DHP I) competitive inhibitor present on the proximal renal tubular cells. Imipenem is hydrolyzed in vivo to an inactive metabolite by DHP I. Concurrent administration of Cilastatin prevents this renal metabolism of Imipenem, resulting in increased serum concentrations of active Imipenem better than administered alone. This will impact Imipenem's broad spectrum antibacterial activity.
Pharmacodynamics: Imipenem is a carbapenem antibiotics. It has a very broad spectrum of antibacterial activity. The antibacterial activity of Imipenem results from the inhibition of cell wall synthesis with a high affinity to penicillin binding proteins (PBPs) of susceptible microorganisms. The inhibition of mucopeptide synthesis leading to the formation of defective bacterial cell wall and cell death. Imipenem has bactericidal activity against Gram-positive and Gram-negative aerobic bacteria, anaerobic bacteria, β-lactamase-producing bacteria. Imipenem is also active against Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.
Cilastatin sodium has no direct antibacterial activity. When administered concomitantly it increases Imipenem activity by inhibiting DHP I on the brush border of proximal renal tubular cells. The resulting urinary and serum concentrations of active imipenem are higher than Imipenem administration alone. Cilastatin has no antimicrobial effect and does not affect the action of imipenem. Imipenem is active in vitro against the following microorganisms: Gram-positive Aerobic Bacteria: Cocci: penicillinase-and nonpenicillinase-producing strains of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyrogenes (group A β-hemolytic streptococci), Streptococcus agalactiae (group B β-hemolytic streptococci), Streptococcus viridians, Enterococcus faecalis (Streptococcus faecalis), Enterococcus durans (Streptococcus durans), Group C, G, and H Streptococci. But most strains of Enterococcus faecium (Streptococcus faecium) are considered resistant to the drug.
Bacilli: Nocardia asteroides, Listeria monocytogenes.
Gram-negative Aerobic Bacteria: Neisseria spp.: Neisseria meningitidis, penicillinase- and nonpenicillinase-producing strains of Neisseria gonorrhoeae.
Haemophilus spp.: Penicillinase- and nonpenicillinase-producing strains of Haemophilus influenzae, strains of Haemophilus influenza resistant to ampicillin, penicillinase- and nonpenicillinase-producing strains of Haemophilus parainfluenzae, Haemophilus ducreyi.
Enterobacteriaceae spp.: Citrobacter diversus, Citrobacter freundii, Enterobacter agglomerans, Enterobacter cloacae, Enterobacter aerogenes, Escherichia coli, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii (Proteus morganii), Proteus mirabilis, Proteus vulgaris, Providencia rettgeri (Proteus rettgeri), Providencia stuartii, Serratia liquefaciens, Serratia marcescens, Salmonella spp., Shigella spp., Yersinia enterocolitica, Yersinia pseudotuberculosis.
Pseudomonas spp.: Pseudomonas aeruginosa.
Other Gram-negative aerobic bacteria: Acinetobacter spp., Moraxella catarrhalis (Branhamella catarrhalis), Gardnerella vaginalis (Haemophilus vaginalis).
Gram-positive Anaerobic Bacteria: Actinomyces spp., Bifidobacterium spp., Clostridium perfringens, some strains of Clostridium difficile, Eubacterium spp., Lactobacillus spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp.
Gram-negative Anaerobic Bacteria: Bacteriodes fragilis, Bacteroides distasonis, Bacteroides thetaiotaomicron, Bacteroides vulgates, Fusobacterium spp.
Other organism: Mycobacterium species (in vitro), but no clinical studies.
Pharmacokinetics: Neither Imipenem nor Cilastatin sodium is appreciably absorbed from GI tract and, therefore, they must be given parenterally. Imipenem is widely distributed into the following tissues and fluids; sputum, saliva, aqueous humor, bone, bile, fallopian tube, myometrium, endometrium, pleural, peritoneal, interstitial and skin. Only low concentrations of Imipenem diffuse into CSF following IV administration (1-10%). However if meningitis occurs, the diffusion will be higher. Imipenem crosses the placenta and is distributed into milk. After IV administration for 20 minutes, peak plasma level, highest at 20% of Imipenem and 40% of Cilastatin, are bound to plasma proteins. In adults with normal renal function, the elimination half-life of IV Imipenem is 0.85-1.3 hours. The serum half-life of both Imipenem and Cilastatin are prolonged in patients with impaired renal function. If Imipenem is administered alone, the drug is partially hydrolyzed in the kidneys by dehydropeptidase I (DHP I) to a microbiologically inactive nephrotoxic metabolites, with only 5 to 43% of a dose excreted in the urine as unchanged active drug. However, when Cilastatin sodium is administered for inhibit dehydropeptidase I (DHP I) enzyme concurrently with Imipenem in 1:1 ratio as a solution, approximately 70% of Imipenem dose and 75% of Cilastatin dose are excreted as unchanged in urine within 10 hours. A 1:1 ratio of Imipenem to Cilastatin ensures that dehydropeptidase I (DHP I) is inhibited up to 8-10 hours. Imipenem is also metabolized to some extent by a nonrenal mechanism which is unrelated to dehydropeptidase I (DHP I). Approximately 20-30% of Imipenem dose is inactivated by nonspecific hydrolysis of the β-lactam ring. Cilastatin is partially metabolized in the kidney to N-acetylcilastatin, which is also an effective inhibitor of dehydropeptidase I (DHP I). Approximately 70-80% of IV dose of Cilastatin is excreted in urine as unchanged and 12% is excreted as N-acetylcilastatin. Both Imipenem and Cilastatin are removed by hemodialysis and peritoneal dialysis.

Imipenem and Cilastatin sodium solution is used in treatment of serious infections caused by susceptible microorganisms in the conditions listed as follows: Lower respiratory tract infections; Urinary tract infections (complicated and uncomplicated); Intra-abdominal infections; Gynecologic infections; Bone and joint infections; Skin and skin structure infections; Bacterial septicemia; Endocarditis caused by Staphylococcus aureus (penicillinase-producing); Polymicrobic infections.
SIANEM IV INJECTION is not indicated for CNS infection.

Dosage of Imipenem and Cilastatin sodium is generally expressed in terms of the Imipenem content of fixed combination.
Prior to initiation Therapy with SIANEM IV INJECTION, appropriate specimens should be obtained for identification of causative organism and in vitro susceptibility tests.
The dosage of Imipenem should be given in equally divided doses based on type and severity of infection, susceptibility of the causative organism(s), and the patient's age, body weight and renal function.
SIANEM IV INJECTION is administered by Intravenous infusion (IV infusion).
Preparation of SIANEM IV INJECTION solution for Intravenous infusion (IV infusion): Aseptic technique must be used to prepare the IV solution.
1. Reconstitute SIANEM IV INJECTION powder in the vial with 10 mL of compatible IV solution (Compatible IV solutions are as the following: 0.9% sodium chloride injection, 5% dextrose injection, 10% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection, 5% dextrose and 0.225% sodium chloride injection, 5% dextrose and 0.15% potassium chloride injection, 5% mannitol, 10% mannitol etc.) to make an initial suspension. The resulting of initial turbid white suspension should be shaken well and then transferred to the 100-mL container of IV solution. The admixture should be agitated until it is clear to yield 5 mg/mL of Imipenem.
Note: The initial reconstituted suspension is not for direct infusion.
2. Aseptic technique must be used to reduce the risk of contamination during reconstitution. Discard the unused portion of the IV infusion solution.
3. Color of solution of SIANEM IV INJECTION ranges from clear and colorless to pale yellow. Variations of color within this range do not affect potency.
4. SIANEM IV INJECTION should be inspected visually for particulate matter or discoloration prior to administration.
Note: SIANEM IV INJECTION should not be prepared with IV infusion solution containing lactate.
Do not mix with other antimicrobial.
Solution of SIANEM IV INJECTION must be clear before administration.
Do not use when the Solution of SIANEM IV INJECTION is in turbid white suspension.
Agitation of admixture may result in the visible air bubbles while reconstituted solution which do not affect the potency.
Should not be heated to dissolution.
Stability: After reconstituted SIANEM IV INJECTION is stable for 4 hours at room temperature (25°C). Thus it is recommended to use the solution within the first hour after reconstituted. The reconstituted solution is stable for 24 hours if refrigerated at 2-8°C (do not freeze).
Discard the remaining after the mixture.
Dosage: Adult dosage: The dosage depends on the type and severity of the infections (see Table 1).
The maximum recommended IV dosage of Imipenem for adult is 50 mg/kg daily or 4 g daily, whichever is lower. The rate of IV infusion of Imipenem should generally be infused over 20-30 minutes.
However, patients who have received more than 500 mg dose of Imipenem should be infused over 40-60 minutes. If nausea and/or vomiting occur during administration of Imipenem, the rate of IV infusion should be decreased. (See Table 1.)

Click on icon to see table/diagram/image

Note: For surgical infection prophylaxis in adults, Imipenem 1 g may be given intravenously on induction of anesthesia, followed by a further 1 g three hours later, with additional 500 mg twice with 8 hours interval after induction if necessary.
For patients older than 12 years of age with cystic fibrosis and normal renal function, Imipenem may be given daily dosage up to 90 mg/kg (maximum daily dosage: 4 g), in divided doses.
Children dosage: Non CNS-infections dosage 15 to 25 mg/kg/dose IV every 6 hours but the maximum recommended IV dosage of Imipenem for children is 2 g daily in those with infections caused by fully susceptible bacteria or 4 g daily in those with infections caused by moderately susceptible bacteria (e.g. some strains of Pseudomonas aeruginosa).
When IV Imipenem and Cilastatin sodium is used in children, dose of 500 mg or less should be given by IV infusion over 15-30 minutes and doses greater than 500 mg should be given by IV infusion over 40-60 minutes.
Children dosage of Imipenem should be given in equally divided doses based on the patient's age and body weight.
3 months of age or older: 15-25 mg/kg every 6 hours.
4 weeks to 3 months of age and weight at least 1.5 kg: 25 mg/kg every 6 hours.
1 to 4 weeks of age and weight at least 1.5 kg: 25 mg/kg every 8 hours.
Up to 1 week of age and weight at least 1.5 kg: 25 mg/kg every 12 hours.
Note: 1. SIANEM IV INJECTION should not be used in children with CNS infections, due to risk of seizure.
2. SIANEM IV INJECTION should not be use in children with impaired renal function who have weight less than 30 kg because of insufficient safety data.
Dosage in renal function impairment: Adult dosage: Adult IV dosage of Imipenem should be reduced in patients with renal impairment based on the patient's creatinine clearance and body weight. (See Table 2.)

Click on icon to see table/diagram/image

Hemodialysis: Imipenem and Cilastatin sodium is cleared by hemodialysis. Doses should be given after hemodialysis and at 12-hour intervals time from the end of that dialysis session.
For patients on hemodialysis, Imipenem and Cilastatin sodium is recommended only when the benefits outweigh the potential risk of seizures and other CNS symptom. Carefully monitor dialysis patients.

Ataxia, clonic seizures, and death were reported in mice. Who received an overdose may have central nervous system symptoms such as confusion or seizure.
Treatment: In acute overdosage, the drug should be discontinued immediately and the patient should be treated symptomatically (including supportive measures). Although Imipenem and Cilastatin sodium is hemodialyzable, but the usefulness of this procedure in enhancing the elimination of Imipenem and Cilastatin sodium is questionable.

1. SIANEM IV INJECTION is contraindicated in patients who are hypersensitive to any ingredient in the formulation and/or to Carbapenem antibiotics.
2. SIANEM IV INJECTION should not be used in patients with meningitis because they may cause seizures.
3. Do not give SIANEM IV INJECTION in children with central nervous system infections because they may cause seizures.

Prior to initiation of therapy with Imipenem and Cilastatin sodium, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics, including penicillins and cephalosporins, or other β-lactam antibiotics. Because there is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics.
Nausea and/or vomiting or diarrhea generally occur during administration of Imipenem, ameliorated by decreasing the IV infusion rate.
Seizure has been reported in neonates and children 3 months of age or younger receiving the drug. In addition, there was a study shown that high incidence of seizures was observed in children 3 months to 12 years of age who received Imipenem and Cilastatin sodium for empiric treatment of bacterial meningitis.
Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with Imipenem and Cilastatin sodium.
Should not be used in children who weigh less than 30 kg with renal impairment because no safety data.
Use with caution in patients with CNS disorders (e.g. a history of seizures, recent head trauma) or patients with renal impairment. This may cause central nervous system disorders such as confusion or seizures. Those with a history of epilepsy may be necessary co-administration between anticonvulsants, Imipenem and Cilastatin sodium and doctors should monitor closely.
Prolonged use of Imipenem and Cilastatin sodium may result in overgrowth of nonsusceptible organisms, especially Candida spp., Enterococci, and Pseudomonas spp. If superinfection occurs, appropriate therapy should be instituted.
Because Clostridium difficile-associated diarrhea and colitis has been reported with Imipenem and Cilastatin sodium, it should be considered in the differential diagnosis of patients who develop diarrhea during or following therapy with the drug. Mild cases respond to the discontinuation of the drug alone. In the moderate to severe cases, treatment with an antibacterial drug effective against C. difficile colitis may be considered.
If hypersensitivity reactions occur during Imipenem and Cilastatin sodium therapy, the drug should be discontinued. Severe hypersensitivity or anaphylactic reactions should be treated with appropriate therapy (e.g. epinephrine, oxygen, IV corticosteroids, airway management including intubation) as indicated.
For patients with restricted sodium, Imipenem and Cilastatin sodium should be used with caution.
Use in Children: Should not be used in children who weigh less than 30 kg with renal impairment because no safety data.

Pregnancy: Category C. Both Imipenem and Cilastatin sodium cross the placenta and are distributed into cord blood and amniotic fluid in human. There are no adequate and controlled studies to date using Imipenem and Cilastatin sodium in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Lactation: Imipenem is distributed into milk. The drug should be used with caution in nursing women. If the drug is considered to use in nursing women, this patient should interrupt breastfeeding during therapy.

Gastrointestinal: Nausea, vomiting, diarrhea, pseudomembranous colitis, hemorrhagic colitis, staining of the teeth and/or tongue, gastroenteritis, abdominal pain, glossitis, papillar hypertrophy of the tongue, heartburn, pharyngeal pain, increased salivation, and taste perversion.
Central nervous system: Fever, seizure, dizziness, somnolence, tremor, confusion, myoclonus, paresthesia, vertigo, headache, myoclonus, encephalopathy, Psychic disturbances including hallucinations.
Dermatologic: Rash, pruritus, urticaria, allergic dermatitis, erythema multiforme, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis, flushing, cyanosis, candidiasis, hyperhidrosis, pruritus vulvae, pain and erythema at injection site, phlebitis.
Hematologic: Eosinophilia, leucopenia, neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, bone marrow depression, hemolytic anemia.
Renal: Increases in BUN and/or serum creatinine concentration, oliguria/anuria, polyuria, discoloration of urine, proteinuria, acute renal failure.
Hepatic: Increases in serum concentrations of AST, ALT, alkaline phosphatase, LDH, and bilirubin, jaundice, hepatitis.
Respiratory system: Chest discomfort, dyspnea, hyperventilation, thoracic spine pain.
Cardiovascular: Hypotension, palpitation, tachycardia.
Others: Hearing loss, tinnitus, polyarthralgia.

In patients treated with Aminoglycosides, the antibacterial activity of Imipenem and Aminoglycosides is additive or synergistic in vitro against some gram positive bacteria, but concomitant administration is generally neither synergistic nor antagonistic in vitro against most strains of Pseudomonas aeruginosa and Enterobacteriaceae. If Aminoglycosides is administered concomitantly with Imipenem and Cilastatin sodium, the drugs may be precipitated so should be administrated in separate containers through the same IV tubing.
In patients treated with Cyclosporine, the CNS side effect of both agents may be increased possibly because of additive or synergistic toxicity.
In patients treated with Gancyclovir, generalized seizures have occurred with co-administration. Do not use concomitantly.
In patients treated with Probenecid, coadministration produces higher and prolonged serum concentrations of Cilastatin but results is only minimal increased in serum concentrations and half-life of Imipenem. Therefore, there is no therapeutic benefit from concomitant use of the drugs. So, concomitant use of Probenecid and the combination is not recommended.

SIANEM IV INJECTION sterile powder should be stored below 30°C.
SIANEM IV INJECTION is stable for 4 hours at room temperature (25°C) or 24 hours when refrigerated at 2-8°C after reconstitution.
SIANEM IV INJECTION should not be freezed.

Other Beta-Lactams

J01DH51 - imipenem and cilastatin ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

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