Latipenem (Powder) Instructions for Use

ATC Code

J01DH51 (Imipenem and cilastatin)

Active Substances

Imipenem (Rec.INN registered by WHO)

Cilastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Systemic antibacterial agents; other beta-lactam antibacterial agents; carbapenems

Pharmacological Action

Broad-spectrum beta-lactam antibiotic. Suppresses bacterial cell wall synthesis and exerts a bactericidal effect against a wide range of gram-positive and gram-negative microorganisms, aerobic and anaerobic.

Imipenem is a thienamycin derivative belonging to the carbapenem group.

Cilastatin sodium inhibits dehydropeptidase, an enzyme that metabolizes imipenem in the kidneys, which significantly increases the concentration of unchanged imipenem in the urinary tract. Cilastatin has no intrinsic antibacterial activity and does not inhibit bacterial beta-lactamase.

Active against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis, and Bacteroides fragilis.

Resistant to destruction by bacterial beta-lactamase, making it effective against many microorganisms such as Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp., which are resistant to most beta-lactam antibiotics.

The antibacterial spectrum includes almost all clinically significant pathogenic microorganisms.

Active against gram-negative aerobic bacteria: Achromobacter spp., Acinetobacter spp. (formerly Mima – Herellea), Aeromonas hydrophila, Alcaligenes spp., Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis, Campylobacter spp., Capnocytophaga spp., Citrobacter spp. (including Citrobacter diversus, Citrobacter freundii), Eikenella corrodens, Enterobacter spp. (including Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including beta-lactamase-producing strains), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (including Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae), Moraxella spp., Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, Yersinia spp. (formerly Pasteurella), including Yersinia multocida, Yersinia enterocolitica, Yersinia pseudotuberculosis; Plesiomonas shigelloides, Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Providencia spp. (including Providencia alcalifaciens, Providencia rettgeri (formerly Proteus rettgeri), Providencia stuartii), Pseudomonas spp. (including Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas pseudomallei, Pseudomonas putida, Pseudomonas stutzeri), Salmonella spp. (including Salmonella typhi), Serratia spp. (including Serratia marcescens, Serratia proteamaculans), Shigella spp.; gram-positive aerobic bacteria: Bacillus spp., Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp., Pediococcus spp., Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus group C, Streptococcus group G, viridans streptococci including alpha- and gamma-hemolytic strains); gram-negative anaerobic bacteria: Bacteroides spp. (including Bacteroides distasonis, Bacteroides fragilis, Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus), Bilophila wadsworthia, Fusobacterium spp., including (Fusobacterium necrophorum, Fusobacterium nucleatum), Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus), Prevotella bivia (formerly Bacteroides bivius), Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Veillonella spp.; gram-positive anaerobic bacteria: Actinomyces spp., Bifidobacterium spp., Clostridium spp. (including Clostridium perfringens), Eubacterium spp., Lactobacillus spp., Microaerophilic streptococcus, Mobiluncus spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. (including Propionibacterium acne); other microorganisms: Mycobacterium fortuitum, Mycobacterium smegmatis. Some Staphylococcus spp. (methicillin-resistant), Streptococcus spp. (group D), Stenotrophomonas maltophilia, Enterococcus faecium, and some strains of Pseudomonas cepacia are not susceptible to imipenem.

Effective against many infections caused by bacteria resistant to cephalosporins, aminoglycosides, penicillins. In vitro acts synergistically with aminoglycosides against some strains of Pseudomonas aeruginosa.

Pharmacokinetics

With IM administration, the bioavailability of imipenem is 95%, cilastatin is 75%.

Plasma protein binding of imipenem is 20%, cilastatin is 40%. C_max of imipenem after IV administration of a dose of 250, 500, or 1000 mg over 20 minutes is 14-24, 21-58, and 41-83 mcg/ml, respectively; with IM administration of 500 or 750 mg – 10 and 12 mcg/ml, respectively. C_max of cilastatin after IV administration of a dose of 250, 500, or 1000 mg over 20 minutes is 15-25, 31-49, and 56-80 mcg/ml; with IM administration of 500 or 750 mg – 24 and 33 mcg/ml, respectively.

Rapidly and well distributed in most body tissues and fluids. The highest concentrations are achieved in pleural effusion, peritoneal and interstitial fluids, and reproductive organs. Low concentrations are found in CSF. V_d in adults is 0.23-0.31 l/kg, in children 2-12 years old – 0.7 l/kg, in newborns – 0.4-0.5 l/kg.

Blockade of tubular secretion of imipenem by cilastatin leads to inhibition of its renal metabolism and accumulation in urine unchanged. Cilastatin is metabolized to an N-acetyl compound.

With IM administration, T_1/2 of imipenem is 2-3 hours. With IV administration, T_1/2 of imipenem and cilastatin in adults is 1 hour, in children 2-12 years old – 1-1.2 hours, in newborns T_1/2 of imipenem is 1.7-2.4 hours, cilastatin – 3.8-8.4 hours; in renal impairment T_1/2 of imipenem is 2.9-4 hours, cilastatin – 13.3-17.1 hours.

Excreted mainly by the kidneys (70-76% within 10 hours) by glomerular filtration (2/3) and active tubular secretion (1/3); 1-2% is excreted through bile in feces and 20-25% by non-renal routes (mechanism unknown).

Rapidly and effectively (73-90%) removed by hemodialysis (75% of the administered dose is removed as a result of a 3-hour session of intermittent hemofiltration).

Indications

Intra-abdominal infections; lower respiratory tract infections; genitourinary system infections; bone and joint infections; skin and soft tissue infections; pelvic infections; sepsis; bacterial endocarditis; prevention of postoperative infections; mixed infections; nosocomial infections.

ICD codes

Dosage Regimen

Administer via intravenous infusion or intramuscular injection.

Determine the dosage individually based on the indication, severity of infection, renal function, and patient age.

For adults with normal renal function (CrCl >70 mL/min), the typical IV dosage is 250 mg to 500 mg every 6 hours or 500 mg to 750 mg every 8 hours.

For severe or life-threatening infections, increase the IV dose to 1 gram every 6 to 8 hours; do not exceed a total daily dose of 4 grams or 50 mg/kg/day, whichever is lower.

For intramuscular use, administer 500 mg or 750 mg every 12 hours; do not exceed 1.5 grams per day via the IM route.

For pediatric patients (3 months and older), administer IV 15-25 mg/kg every 6 hours; do not exceed 2-4 grams per day.

In patients with renal impairment, adjust the dosage based on creatinine clearance (CrCl).

For CrCl 41-70 mL/min, administer 250-500 mg every 8 hours.

For CrCl 21-40 mL/min, administer 250 mg every 8-12 hours.

For CrCl 6-20 mL/min, administer 250-500 mg every 12 hours.

For patients on hemodialysis, administer a supplemental dose after each dialysis session, as the drug is significantly removed.

Reconstitute the powder for IV infusion with 100 mL of a compatible diluent such as 0.9% Sodium Chloride or 5% Dextrose.

Infuse IV doses of 250 mg or 500 mg over 20-30 minutes; infuse 1-gram doses over 40-60 minutes.

For IM injection, reconstitute with 1% Lidocaine Hydrochloride solution (without epinephrine) to reduce pain at the injection site; administer deeply into a large muscle mass.

Do not use the IM reconstitution solution for intravenous administration.

Complete the full course of therapy as prescribed, even if symptoms improve.

Adverse Reactions

From the CNS and peripheral nervous system myoclonus, mental disorders, hallucinations, confusion, epileptic seizures, paresthesia.

From the urinary system oliguria, anuria, polyuria, acute renal failure (rarely).

From the digestive system nausea, vomiting, diarrhea, pseudomembranous enterocolitis, hepatitis (rarely).

From the hematopoietic organs and hemostasis system eosinophilia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, thrombocytosis, monocytosis, lymphocytosis, basophilia, decreased hemoglobin, prolonged prothrombin time, positive Coombs test.

From laboratory parameters increased activity of hepatic transaminases and ALP, hyperbilirubinemia, hypercreatininemia, increased blood urea nitrogen concentration; direct positive Coombs test.

Allergic reactions skin rash, itching, urticaria, multiforme exudative erythema (including Stevens-Johnson syndrome), angioneurotic edema, toxic epidermal necrolysis (rarely), exfoliative dermatitis (rarely), fever, anaphylactic reactions.

Local reactions skin hyperemia, painful infiltrate at the injection site, thrombophlebitis.

Other candidiasis, taste disturbance.

Contraindications

Hypersensitivity (including to carbapenems and other beta-lactam antibiotics); pregnancy (only for “vital” indications); early childhood (up to 3 months); in children – severe renal failure (serum creatinine concentration more than 2 mg/dl).

For suspension for IM injection prepared using lidocaine hydrochloride as a solvent: hypersensitivity to local anesthetics of the amide structure (shock, impaired intracardiac conduction).

With caution

CNS diseases, history of seizures, high seizure activity, anticonvulsant therapy with valproic acid (reduced therapy efficacy), chronic renal failure (CrCl less than 70 ml/min), patients on hemodialysis, elderly age, patients with a history of gastrointestinal diseases (including pseudomembranous colitis).

Use in Pregnancy and Lactation

Used during pregnancy only if the intended benefit to the mother outweighs the potential risk to the fetus.

The drug passes into breast milk in small amounts, so the issue of discontinuing breastfeeding during treatment should be considered.

Use in Renal Impairment

With caution: chronic renal failure (CrCl less than 70 ml/min), patients on hemodialysis.

Pediatric Use

Contraindication — early childhood (up to 3 months). Contraindication: severe renal failure in children (serum creatinine concentration more than 2 mg/dl).

Geriatric Use

It should be borne in mind that elderly patients are likely to have age-related renal impairment, which may require a dose reduction.

Special Precautions

Not recommended for the treatment of meningitis.

Stains urine reddish.

The dosage form for IM administration should not be used for IV and vice versa.

Before starting therapy, a thorough history should be taken regarding previous allergic reactions to beta-lactam antibiotics.

Persons with a history of gastrointestinal diseases (especially colitis) have an increased risk of developing pseudomembranous enterocolitis.

Antiepileptic drug therapy in patients with head trauma or a history of seizures should be continued throughout the treatment period (to avoid CNS side effects).

It should be borne in mind that elderly patients are likely to have age-related renal impairment, which may require a dose reduction.

Effect on ability to drive vehicles and mechanisms

Given the likelihood of CNS side effects, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Pharmaceutically incompatible with lactic acid salt, other antibacterial drugs.

When used concomitantly with penicillins and cephalosporins, cross-allergy is possible; exhibits antagonism towards other beta-lactam antibiotics (penicillins, cephalosporins, and monobactams).

Ganciclovir increases the risk of generalized seizures.

Drugs that block tubular secretion slightly increase the plasma concentration and T_1/2 of imipenem (if high concentrations of imipenem are required, concomitant use of these drugs is not recommended).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.